Iodolactonization: Synthesis, stereocontrol, and compatibility studies

Article abstract of DOI:10.1002/ejoc.201101343

Generalized iodolactonization conditions have been developed for the formation of both cis- and trans-γ-lactones from 3-pentenoic acid derivatives containing various protected alcohol moieties. Kinetic control of the reaction using iodine and base at 0 °C for 6 h provided the cis-lactone with good selectivity (75:25), and thermodynamic control at room temperature for 24 h provided the trans-lactone with excellent selectivity (98:2).

Full text of DOI:10.1002/ejoc.201101343

FULL PAPER
DOI: 10.1002/ejoc.201101343
Iodolactonization: Synthesis, Stereocontrol, and Compatibility Studies
Martins S. Oderinde,[a] Howard N. Hunter,[a] Stacy W. Bremner,[a] and Michael G. Organ*[a]
Keywords: Synthetic methods / Diastereoselectivity / Lactones / Natural products / Iodolactonization
Generalized iodolactonization conditions have been devel-
oped for the formation of both cis- and trans-γ-lactones from
3-pentenoic acid derivatives containing various protected
alcohol moieties. Kinetic control of the reaction using iodine
and base at 0 °C for 6 h provided the cis-lactone with good
selectivity (75:25), and thermodynamic control at room tem-
perature for 24 h provided the trans-lactone with excellent
selectivity (98:2).
lactone with moderate selectivity.[1] Iodolactonization con-
ditions cannot be generalized, because the diastereoselectiv-
ity and reactivity are sensitive to functional groups, steric
hindrance, and electronic effects.[7,8] For instance, the dia-
stereochemical outcome of the iodolactonization of γ-ole-
finic carboxylic acids 5a and 5b, having either a β-phenyl
or β-methyl group, respectively, varies slightly under
thermodynamic control but significantly under kinetic con-
trol [Scheme 1 (A)].[7]
Introduction
Iodolactonization of olefin-containing carboxylic acids
and amides with high stereochemical fidelity continues to
attract interest in organic synthesis, particularly in the total
synthesis of bioactive compounds.[1] More specifically, γ-
olefinic carboxylic acids and their derivatives can be trans-
formed readily into primary iodo-γ-lactones.[2] γ-Lactone
moieties exist in the structure of natural products, in both
the trans and cis forms; thus, their diastereoselective synthe-
ses are of general interest (see Figure 1 for examples).[3–6]
Scheme 1. Thermodynamically and kinetically controlled iodo-
lactonization of β-substituted γ-olefinic carboxylic acids and
amides. Reagents and conditions:[7,8] (a) I2, aqueous NaHCO3,
CHCl3, 0 °C, 6 h; (b) I2, MeCN, 0 °C to room temp., 24 h; (c) I2,
MeCN/H2O, reflux, 24 h.
Figure 1. Representatives of natural products possessing cis and
trans-γ-lactone cores.
As the iodolactonization of β-substituted γ-olefinic carb-
oxylic acids can be thermodynamically or kinetically con-
trolled to provide either the trans- or cis-iodo-γ-lactone
with moderate to good selectivity, the iodolactonization of
γ-olefinic esters and amides gives mainly the trans-iodo-γ-
Similarly, the stereocontrol in the iodolactonization of
γ-olefinic amides 8a and 8b is strongly affected by steric
hindrance and electronic effects [Scheme 1 (B)].[8] The reac-
tion proceeded with dimethylamide 8a, whereas it failed to
proceed with diisopropylamide 8b. The diastereochemical
outcome of the iodolactonization of 8a was also solvent-
dependent, rationalized as a consequence of the dipolar
character of the transition states in the conformational
equilibrium.[8] As iodolactonization conditions are either
[a] Department of Chemistry, York University,
4700 Keele Street, Toronto, ON, M3J 1P3, Canada
Fax: +1-416-736-5936
E-mail: organ@yorku.ca
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101343.
Eur. J. Org. Chem. 2012, 175–182
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
175

M. S. Oderinde, H. N. Hunter, S. W. Bremner, M. G. Organ
FULL PAPER
acidic or basic, the compatibility of any sensitive functional
groups in the substrates must also be considered before
choosing a method.
Results and Discussion
The study began by evaluating the γ-olefinic amides di-
The lack of general methods for and functional-group methylamide 16 and pyrrolidine amide 19, both with a p-
sensitivity in iodolactonization reactions were of concern as methoxybenzyl (PMB) ether moiety, to see how the choice
we developed our synthetic strategy to approach the en- of amide would affect the selectivity in the iodolacton-
antio- and diastereoselective total synthesis of cis,cis-germ- ization reaction (Scheme 2). The synthesis of 16 began with
acranolide (1). This bioactive natural product, recently iso- vinyllactone 14, which was obtained from 13 according to
lated from Mikania thapsoides DC.,[3] has yet to be synthe- a literature procedure.[13] Compound 14 was converted to
sized chemically. Our retrosynthetic approach, illustrated in hydroxy dimethylamide 15 by treatment with Me2NH·HCl
Figure 2, begins with an enantioselective conjugate addition and AlMe3. The alcohol was then protected as PMB ether
to lactone 13,[9] thus setting the absolute stereochemistry of 16 in good yield by using standard conditions.[14] Similarly,
the final target molecule. Diastereoselective iodolacton- treatment of 14 with pyrrolidine gave hydroxy pyrrolidine
ization[7,8] of addition product 12 will set the lactone amide 18 quantitatively, and protection of the alcohol pro-
stereocenters. Negishi cross-coupling[10] and Nozaki- vided PMB ether 19.
Hiyama-Kishi (NHK) allylation[11] will provide the carbon
Iodolactonization of 16 and 19 under basic conditions
atoms necessary to form the medium-sized ring by relay [I2 (4 equiv.), aqueous NaHCO3, THF, –10 °C, 24 h] gave
ring-closing metathesis (RRCM).[12] Since the total synthe- trans-iodo-γ-lactone 17a in 40 and 45% yield, respectively.
sis of this complex natural product requires protection of The product mixture also contained compounds without
the reactive functional groups, the “R” group in 12 must be the PMB group, and some of the desired iodolactone
compatible with the iodolactonization reaction conditions. underwent a reaction with the released amine. The dr values
Herein, we describe a practical protocol for the preparation of crude 17a resulting from 16 and 19 differed. PMB ether
of γ-olefinic carboxylic acids, amides, and esters containing 16 gave 17a with a dr of 64:36, and 19 gave 17a with a dr
β-alcohol derivatives and the development of a general pro- of 75:25 (Table 1, Entries 1 and 2). Next, we replaced the
tocol for their use in diastereoselective iodolactonization re- PMB group with the bulkier protecting groups tert-butyldi-
actions under thermodynamic and kinetic control to pro- phenylsilyl (TBDPS) and pivalate (Piv) to study their effect
vide either trans- or cis-iodolactone derivatives, respectively. on the iodolactonization of the γ-olefinic pyrrolidine amide.
Figure 2. Retrosynthetic approach to cis,cis-germacranolide (1).
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Iodolactonization: Synthesis, Stereocontrol, and Compatibility Studies
Although the separation of iodolactone diastereomers is
generally difficult,[1–8] the ability to separate them by col-
umn chromatography on silica gel depended on the type
of protecting group on the alcohol. More specifically, the
iodolactone diastereomers with a TBDPS ether moiety were
easily separated, whereas those with the other protecting
groups were not.
With the results of the iodolactonization of γ-olefinic
amides in hand, we turned our attention to the iodolacton-
ization of γ-olefinic carboxylic acids and esters. The hydrol-
ysis of amide 20 to its corresponding carboxylic acid under
various conditions resulted in the deprotection and loss of
the silyl group. The reduction of 20 with both DIBALH
and LAH gave a mixture of products; however, treatment of
20 with Schwartz’s reagent [Cp2Zr(H)Cl] gave the aldehyde
cleanly, but in only 30% yield.[15] As a result, the γ-olefinic
carboxylic acids were synthesized instead from 14
(Scheme 3). Although the hydrolysis of 14 with NaOH fol-
lowed by acidification resulted in rapid relactonization, the
alcohol of sodium carboxylate 24 was readily protected as
the TBDPS ether to give γ-olefinic carboxylic acid 25 in
good recovery from 14.
Scheme 2. Reagents and conditions: (a) Me2NH·HCl, AlMe3, tolu-
ene, 60 °C, 16 h, 59%; (b) PMBCl, NaH, TBAI (tetra-n-butylam-
monium iodide), THF, room temp., 16 h, 85%; (c) I2, THF, aque-
ous NaHCO3, 24 h; (d) pyrrolidine, benzene, 60 °C, 16 h, 99%;
(e) for 19: PMBCl, NaH, TBAI, THF, room temp., 16 h, 85%; for
20: TBDPSCl, imidazole, CH2Cl2, room temp., 16 h, 90%; for 21:
PivCl, DMAP, pyridine, THF, room temp., 16 h, 92%.
To this end, 18 was converted into silyl ether 20 and pivalate
21 in excellent yields (Scheme 2).[14] The iodolactonizations
of 20 and 21 resulted in improved diastereoselectivity of the
trans-iodo-γ-lactones 22a and 23a (dr for both was 80:20),
but gave products in only moderate yields (Table 1, En-
tries 3 and 4). Unlike the benzyl moiety, both the TBDPS
and Piv groups were stable under the reaction conditions.
When the iodolactonization of 20 was carried out at 0 °C,
the starting material was completely consumed within 5 h,
but the yield and dr of 22a decreased to 30% and 60:40,
respectively (Table 1, Entry 5). No reaction occurred when
the iodolactonization of 21 was carried out in THF/H2O or
MeCN/H2O[8] at room temperature or heated at reflux, and
the starting amide was recovered quantitatively (Table 1,
Entry 6), which suggests that the reaction proceeds only un-
der basic conditions.
Scheme 3. Reagents and conditions: (a) NaOH, MeOH, 80 °C, 5 h;
(b) TBDPSCl, imidazole, CH2Cl2, room temp., 16 h, 70%; (c) I2,
–
MeCN, 0 °C to room temp., 24 h; (d) (CH3)3O+BF4 , iPr2NEt,
CH2Cl2, room temp., 24 h, 94%; (e) I2, CHCl3, H2O, NaHCO3, 6 h,
72%.
Attempts at the iodolactonization of 25 under thermo-
dynamic conditions led to the regeneration of 14 as the only
product. For a complete study, we converted 25 into γ-ole-
finic ester 26 by an esterification with Meerwein’s reagent
–
[(CH3)3O+BF4 ] and then subjected 26 to the same thermo-
Table 1. Iodolactonization of γ-olefinic amides 16, 19, 20, and 21.
dynamic iodolactonization conditions.[16] Here, trans-iodo-
γ-lactone 22a, vinyllactone 14, and the desilylated trans-
iodo-γ-lactone were obtained, and hence desilylation was
competitive with the iodolactonization. Similiar results
were obtained when a TBS (tert-butyldimethylsilyl) protect-
ing group was used in place of the TBDPS group.
Entry Substrate γ-Lactone Temp. [°C]
dr[c]
Yield [%][d]
1[a]
2[a]
3[a]
4[a]
5[a]
6[b]
16
19
20
21
20
21
17a
17a
22a
23a
22a
23a
–10
–10
–10
–10
0
64:36
75:25
80:20
80:20
60:40
–
40
45
56
52
30
–
23
We attributed the desilylation to the presence of I–/HI in
the solution and then rationalized that the presence of a
base should prevent the desilylation by neutralizing the HI
generated in situ. Hence, the iodolactonization of 25 was
carried out with I2 and anhydrous K2CO3 in MeCN at
[a] Reactions in Entries 1–5 were performed under condition (c) in
Scheme 2. [b] Reactions were performed with I2, THF/H2O, –10 °C
to room temp., 24 h. [c] Obtained by 1H NMR spectroscopy.
[d] Yield of isolated diastereomeric mixture after silica gel purifica-
tion.
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M. S. Oderinde, H. N. Hunter, S. W. Bremner, M. G. Organ
FULL PAPER
room temperature for 24 h to give the cis-iodo-γ-lactone went PDC (pyridinium dichromate) oxidation to give the
22b with a dr of 56:44 (Table 2, Entry 2). The same result desired γ-olefinic carboxylic acid 27 in good yield.[18] Iodo-
was obtained when the reaction was carried out with KI/I2 lactonization of 27 under thermodynamic control gave
and NaHCO3 in THF/H2O at room temperature for trans-iodo-γ-lactone 23a in 98% yield with a dr of 98:2
24 h.[17] To improve the dr of 22b, we carried out the iodo- (Table 3, Entry 1). Similarly, esterification of γ-olefinic
lactonization of 25 under kinetic control. The expected cis- carboxylic acid 27 to γ-olefinic ester 31 using Meerwein’s
iodo-γ-lactone 22b was obtained quantitatively with a max- reagent followed by iodolactonization under thermo-
imiun dr of 75:25 (Table 2, Entry 3). The major cis isomer dynamic control gave 23a in 89% yield with a dr of 98:2
was quantitatively separated from the minor trans isomer, (Table 3, Entry 2). γ-Olefinic acid 32 containing an acetyl
and both were fully characterized by NMR spectroscopy. group was prepared as illustrated in Scheme 6 with iodolac-
This three-step diastereoselective synthesis of cis-iodo-γ- tonization under thermodynamic control to give trans-iodo-
lactone 22b from commercially available lactone 13 will γ-lactone 33a in good yield with a dr of 97:3 (Table 3, En-
serve as a powerful approach for the total synthesis of bio- try 3).
active natural products such as 2 and 3 (Figure 1).
Table 2. Iodolactonization of γ-olefinic carboxylic acid 25.
Entry Substrate γ-Lactone Temp. [°C]
dr[d]
Yield [%][e]
1[a]
2[b]
3[c]
25
25
25
22a
22b
22b
23
23
0
–
–
53
72
56:44
75:25
[a] Reaction was performed under condition (c) in Scheme 3.
[b] Reaction was performed with I2, MeCN, anhydrous K2CO3,
room temp., 24 h. [c] Reaction was performed under condition (e)
in Scheme 3. [d] Obtained by 1H NMR spectroscopy. [e] Yield of
isolated, pure cis isomer after silica gel purification.
We reasoned that by replacing the silyl group in 25 with
a pivalate group, which is more stable under mildly acidic
and basic conditions, we would enable the smooth iodo-
lactonization of the γ-olefinic acid under thermodynamic
control. Attempts to protect the alcohol of sodium carb-
oxylate 24 as a pivalate under various conditions gave an
inseparable mixture (50:50) of the desired γ-olefinic carb-
Scheme 5. Reagents and conditions: (a) LAH, Et2O, THF, room
temp., 12 h, 85%; (b) PivCl, DMAP, pyridine, room temp., 16 h,
65%; (c) PDC, DMF, 25 °C, 24 h, 84%; (d) I2, MeCN, 0 °C to
–
room temp., 24 h, 98–100%; (e) (CH3)3O+BF4 , iPr2NEt, CH2Cl2,
room temp., 24 h, 93%; (f) I2, CHCl3, H2O, NaHCO3, 0 °C, 6 h,
oxylic acid 27 and 14 (Scheme 4). Lactonization of mixed 93–100%.
anhydride 28, generated in situ, would give rise to 14.
Table 3. Thermodynamically and kinetically controlled iodolacton-
ization of γ-olefinic carboxylic acids 27 and 32 and ester 31.
Entry Substrate γ-Lactone Temp. [°C]
dr[e]
Yield [%][f]
1[a]
2[a]
3[b]
4[c]
5[d]
27
31
32
27
32
23a
23a
33a
23b
33b
23
23
23
0
98:2
98:2
97:3
50:50
45:55
98
89
90
97
95
0
[a] Reactions were performed under condition (d) in Scheme 5.
[b] Reaction was performed under condition (b) in Scheme 6.
[c] Reaction was performed under condition (f) in Scheme 5. [d] Re-
action was performed under condition (c) in Scheme 6. [e] Ob-
tained by 1H NMR spectroscopy. [f] Yield of isolated dia-
stereomeric mixture after silica gel purification.
Scheme 4. Reagents and conditions: (a) PivCl, DMAP, pyridine,
THF, room temp., 16 h, 50:50 mixture of 27/14.
On the other hand, the kinetically controlled iodolacton-
ization of γ-olefinic carboxylic acids 27 and 32 gave cis-
iodo-γ-lactones 23b and 33b with disappointing diastereo-
However, reduction of 14 with LAH gave diol 29 in good selectivities (dr of 50:50 and 45:55, respectively; Table 3, En-
yield (Scheme 5). Treatment of 29 with PivCl gave the mono- tries 4 and 5). Unlike 22, the diastereomers of 23 and 33
protected alcohol 30 in moderate yield, which then under- were inseparable by column chromatography on silica gel.
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Iodolactonization: Synthesis, Stereocontrol, and Compatibility Studies
between the adjacent methine protons Hb and Hc in the lact-
one ring. This interaction supports the trans stereochemical
assignment. In Figure 4, this relationship is reversed indicat-
ing that methine protons Hb and Hc have a cis stereochemis-
try.[19] In addition to the through-space evidence, other
trends are observed with the chemical shifts and coupling
constants between the methine protons. The shift for meth-
ine proton Hc is approximately 0.5 ppm larger in the cis than
the trans lactone. Likewise, the methine proton Hb in the cis
isomer is deshielded by approximately 0.3 ppm.[19] In ad-
dition to the shift values, the vicinal 3J coupling between the
methine protons is notably larger in the cis in comparison
to the trans lactone rings. The chemical shift and J coupling
trends are consistent with other lactone rings that we have
synthesized and are listed in Table 4.
Scheme 6. Reagents and conditions: (a) (i) AcCl, DMAP, pyridine,
room temp., 16 h, 60%; (ii) PDC, DMF, 25 °C, 24 h, 84%; (b) I2,
MeCN, 0 °C to room temp., 24 h, 90–98%; (c) I2, CHCl3, H2O,
NaHCO3, 0 °C, 6 h, 97%.
Table 4. Chemical shift and 3J coupling values for the methine pro-
tons of the lactone ring.
3
Entry γ-Lactone cis/trans Hc [ppm] Hb [ppm] Jβ-γ [Hz]
The stereochemistry of the γ-lactone ring was determined
by using 2D NOESY NMR spectroscopic data for com-
pounds 22a and 22b as shown in Figures 3 and 4, respec-
tively. In Figure 3, the dipolar interaction between methine
proton Hc in the lactone ring and the acyclic meth-
ylene protons Ha is much more intense than the interaction
1
2
3
4
5
6
17a
22a
23a
22b
23b
23a
trans
trans
trans
cis
cis
trans
4.16
4.12
4.12
4.69
4.68
4.14
2.47
2.55
2.44
2.87
2.71
2.44
4.2
3.3
3.2
6.0
5.6
3.7
Figure 3. 400 MHz 2D NOESY spectrum of 22a. Arrow A indicates the region void of dipolar interactions between methine protons Hb
and Hc in the lactone ring. Arrow B indicates the dipolar interaction between γ-methine proton Hc and acyclic methylene protons Ha.
Eur. J. Org. Chem. 2012, 175–182
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179

M. S. Oderinde, H. N. Hunter, S. W. Bremner, M. G. Organ
FULL PAPER
Figure 4. 400 MHz 2D NOESY spectrum of 22b. Arrow A indicates the dipolar interaction between methine protons Hb and Hc in the
lactone ring. Arrow B indicates the region void of dipolar interactions between γ-methine proton Hc and acyclic methylene protons Ha.
oxylic acids containing acetate and pivalate groups gave ex-
Conclusions
cellent yields and diastereoselectivities under thermo-
We have described a practical approach for the diastereo-
dynamic control, whereas excellent yields and poor dia-
selective iodolactonization reaction under thermodynamic
and kinetic control of γ-olefinic carboxylic acids, amides,
and esters containing sensitive functional groups. Although
the PMB ether was not particularly stable, using the
TBDPS and pivalate groups instead provided stability, but
gave low to moderate yields during the iodolactonization of
γ-olefinic amides. The bulkiness of the tert-butyldiphenyl-
silyl ether and pivalate groups slightly improved the dia-
stereoselectivities were obtained under kinetic control.
We believe the results of this iodolactonization study of-
fer a practical synthetic advantage in the synthesis of lact-
one-containing natural products. The use of cis-iodo-γ-lact-
one 22b and trans-iodo-γ-lactone 23a for the total synthesis
of (+)-sundiversifolide (3) and cis,cis-germacranolide 1 are
currently underway in our laboratories.
stereoselectivity of the trans-iodo-γ-lactone product. In all
cases, the iodolactonization of the γ-olefinic amides we
studied resulted in low yields and moderate diastereoselec-
Experimental Section
General Methods: NMR spectra were recorded at room tempera-
ture with either a Bruker AV 400 with a 5 mm BBFO-Z-ATM
probe or a Bruker DRX 600 with a 5 mm TXI (1H, 13C, 15N) z-
gradient probe. The chemical shifts for the 1H NMR spectroscopic
data are given in parts per million (ppm) and referenced to the
residual CHCl3 signal at δ = 7.26 ppm in deuterated chloroform.
All NMR experiments were performed by using the standard
Bruker pulse program library without further modification. For
tivity.
In the case of γ-olefinic carboxylic acids, cleavage of the
TBDPS ether dominated under thermodynamically con-
trolled iodolactonization; however, with a γ-olefinic ester,
iodolactonaization was competitive with desilylation. Un-
der kinetic control, desilylation was completely avoided,
and decent selectivity for the cis-iodolactone resulted. Ad-
ditionally, diastereomers of the iodolactones with a TBDPS
ether moiety were easily separated by column chromatog-
1
chemical shift and coupling determination, the 1D H NMR spec-
tra were acquired at 600 MHz with 8 scans with a spectral width
raphy on silica gel. Iodolactonization of γ-olefinic carb- of 8865 Hz and 32k data points. A 1D selective COSY experiment
180 Eur. J. Org. Chem. 2012, 175–182
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Iodolactonization: Synthesis, Stereocontrol, and Compatibility Studies
with a 270° selective pulse of 75 ms was used to determine specific
J coupling values shown in Table 4.[20] The 1H spectra were pro-
cessed by using a Gaussian broadening value of 0.5 and an ex-
ponential broadening value of –0.5 Hz. Compounds 22a and 22b
were fully assigned by using 2D COSY, NOESY, HSQC (hetero-
nuclear single quantum coherence), HMBC, and 1D 13C experi-
ments. The 2D NOESY experiments were acquired with 2048ϫ256
data points by using 64 scans per increment and a mixing time of
600 ms. One zero fill was performed in both domains by using a
shifted (sinebell)2 window function.
= 175.2, 135.4, 133.1, 133.1, 129.8, 127.7, 82.9, 61.3, 38.3, 35.9,
34.8, 26.8, 19.0, 6.9 ppm. HRMS (ESI): calcd. for C23H29IO3Si [M
+ H]+ 509.1009; found 509.1009.
Preparation of trans-2-[2-(Iodomethyl)-5-oxotetrahydrofuran-3-yl]-
ethyl Pivalate (23a)
From Ester 31: To a stirred solution of ester 31 (6.18 g, 25.48 mmol)
in MeCN (100 mL) at 0 °C in a flask that was wrapped with alu-
minium foil was added I2 (19.50 g, 76.45 mmol). The reaction mix-
ture was warmed to room temp. and stirred for 24 h. The reaction
mixture was then quenched with an excess amount of a 1:1 mixture
of saturated aqueous Na2S2O3 and saturated aqueous NaHCO3
and the mixture stirred until it was colorless. The mixture was then
extracted with Et2O (4ϫ100 mL), and the combined organic layers
were dried with anhydrous MgSO4, filtered, and concentrated in
vacuo. Purification by silica gel column chromatography (50%
Et2O in pentane; Rf = 0.30) afforded 23a (8.05 g, 89%, dr 98:2) as
a yellow oil.
Preparation of trans-5-(Iodomethyl)-4-{2-[(4-methoxybenzyl)oxy]-
ethyl}dihydrofuran-2(3H)-one (17a)
From Dimethyl Amide 16: To a solution of dimethylamide 16
(58.10 mg, 0.19 mmol) in THF (1 mL) and saturated aqueous
NaHCO3 (0.50 mL) at –10 °C in a flask that was wrapped with
aluminum foil was added I2 (0.20 g, 0.79 mmol). The mixture was
stirred in the dark at –10 °C for 24 h. Saturated aqueous Na2S2O3
(1.60 mL) and Et2O (2 mL) were added to quench the reaction. The
aqueous layer was extracted with Et2O (3ϫ2 mL). The combined
organic layers were dried with anhydrous MgSO4, filtered, and con-
centrated in vacuo. The residue was purified by silica gel column
chromatography (50% Et2O in pentane and then 100% Et2O; Rf =
0.13 in 100% Et2O) to afford 17a (30 mg, 40%, dr 80:20) as a yel-
low oil.
From Acid 27: To a stirred solution of acid 27 (10.00 g, 43.81 mmol)
in MeCN (500 mL) at 0 °C in a flask that was wrapped with alu-
minium foil was added I2 (33.36 g, 131.42 mmol). The reaction
mixture was warmed to room temp. and stirred for 24 h. The reac-
tion mixture was quenched with an excess amount of a 1:1 mixture
of saturated aqueous Na2S2O3 and saturated aqueous NaHCO3
and stirred until it was colorless. The mixture was then extracted
with Et2O (4ϫ120 mL), and the combined organic layers were
dried with anhydrous MgSO4, filtered, and concentrated in vacuo.
Purification by silica gel column chromatography (50% Et2O in
pentane; Rf = 0.30) afforded 23a (15.52 g, 98%, dr 98:2) as a yellow
From Pyrrolidinyl Amide 19: To a solution of pyrrolidine amide
19 (60.31 mg, 0.19 mmol) in THF (1 mL) and saturated aqueous
NaHCO3 (0.50 mL) at –10 °C in a flask that was wrapped with
aluminum foil was added I2 (0.20 g, 0.79 mmol). The mixture was
stirred in the dark at –10 °C for 24 h. Saturated aqueous Na2S2O3
(1.60 mL) and Et2O (2 mL) were added to quench the reaction. The
aqueous layer was extracted with Et2O (3ϫ2 mL). The combined
organic layers were dried with anhydrous MgSO4, filtered, and con-
centrated in vacuo. The residue was purified by silica gel column
chromatography (50% Et2O in pentane and then 100% Et2O; Rf =
0.13 in 100% Et2O) to afford 17a (33 mg, 45%, dr 80:20) as a yel-
low oil. 1H NMR (400 MHz, CDCl3): δ = 7.30–7.14 (d, J = 7.2 Hz,
2 H), 6.89 (d, J = 7.2 Hz, 2 H), 4.43 (s, 2 H), 4.34–4.12 (m, 1 H),
3.82 (s, 3 H), 3.75–3.38 (m, 3 H), 3.38–3.26 (m, 1 H), 2.79 (dd, J
= 17.8, 9.1 Hz, 1 H), 2.63–2.35 (m, 1 H), 2.35–2.26 (m, 1 H), 1.90
(dd, J = 13.8, 6.5 Hz, 1 H), 1.72 (dd, J = 13.7, 6.7 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 175.4, 175.2, 159.2, 129.9, 129.8,
129.3, 129.2, 128.9, 113.8, 83.1, 72.7, 67.5, 67.3, 55.2, 38.8, 35.1,
33.2, 7.3 ppm. HRMS (ESI): calcd. for C15H19IO4 [M + H]+
391.0406; found 391.0408.
1
oil. H NMR (400 MHz, CHCl3): δ = 4.13 (dt, J = 10.5, 5.1 Hz, 3
H), 3.37 (ddd, J = 15.4, 11.0, 5.0 Hz, 2 H), 2.85 (dd, J = 17.6,
8.9 Hz, 1 H), 2.49–2.41 (m, 1 H), 2.40 (dd, J = 16.0, 7.2 Hz, 1 H),
1.99–1.93 (m, 1 H), 1.81–1.72 (m, 1 H), 1.20 (s, 9 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 178.2, 174.6, 82.5, 61.7, 38.6, 38.3,
34.7, 32.3, 27.1, 6.5 ppm. HRMS (ESI): calcd. for C12H19IO4 [M
+ H]+ 355.0406; found 355.0406. C12H19IO4 (354.18): calcd. C
40.69, H 5.41; found C 40.33, H 5.47.
cis-4-{2-[(tert-Butyldiphenylsilyl)oxy]ethyl}-5-(iodomethyl)dihydro-
furan-2(3H)-one (22b): A mixture of 25 (0.15 g, 0.39 mmol) and
NaHCO3 (99 mg, 1.18 mmol) in water (2.5 mL) was stirred at room
temp. for 10 min before adding chloroform (2.5 mL). The mixture
was cooled to 0 °C and stirred for 15 min before adding I2 (200 mg,
0.78 mmol) in the dark. The mixture was stirred at 0 °C for 6 h,
and then it was quenched with saturated aqueous NaS2O3 and the
mixture agitated until the solution turned colorless or pale yellow.
trans-4-{2-[(tert-Butyldiphenylsilyl)oxy]ethyl}-5-(iodomethyl)dihy-
drofuran-2(3H)-one (22a): To a solution of amide 20 (0.96 g, Et2O (20 mL) was added, and the layers were separated. The aque-
2.20 mmol) in THF (12.80 mL) and saturated aqueous NaHCO3
(6.80 mL) at –10 °C in a flask that was wrapped with aluminium
foil was added I2 (2.24 g, 8.80 mmol). The mixture was stirred in
the dark at –10 °C for 23 h. Saturated aqueous Na2S2O3 (25 mL)
and Et2O (25 mL) were added to quench the reaction. The colorless
aqueous layer was extracted with Et2O (2ϫ25 mL). The combined
organic layers were dried with anhydrous MgSO4, filtered, and con-
centrated in vacuo. The residue was purified by silica gel column
chromatography (40% Et2O in pentane; Rf = 0.48) to afford 22a
(0.63 g, 56 %, dr 80:20) as a yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 7.65 (d, J = 6.7 Hz, 4 H), 7.45–7.36 (m, 6 H), 4.12
(dd, J = 10.4, 5.2 Hz, 1 H), 3.93–3.56 (m, 2 H), 3.42 (dd, J = 11.0,
5.0 Hz, 1 H), 3.32 (dd, J = 11.0, 4.6 Hz, 1 H), 2.70 (dd, J = 17.7,
9.1 Hz, 1 H), 2.53 (dd, J = 16.1, 9.9 Hz, 1 H), 2.25 (dd, J = 17.7,
7.7 Hz, 1 H), 1.84 (dt, J = 12.8, 5.3 Hz, 1 H), 1.61 (dt, J = 13.8,
ous layer was extracted with Et2O (20 mL), and the combined or-
ganic layers were washed successively with water (10 mL) and then
brine (10 mL). The organic layer was dried with anhydrous MgSO4,
filtered, and concentrated in vacuo. The diastereomeric mixture
was separated by silica gel column chromatography (40% Et2O in
pentane; Rf = 0.53) to afford 22b (0.63 g, 72%, single diastereomer)
as a yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.62 (d, J =
7.0 Hz, 4 H), 7.47–7.35 (m, 6 H), 4.67 (q, J = 6.6 Hz, 1 H), 3.75
(dt, J = 10.3, 5.0 Hz, 1 H), 3.68–3.54 (m, 1 H), 3.28 (dd, J = 10.5,
6.6 Hz, 1 H), 3.19 (dd, J = 10.4, 7.1 Hz, 1 H), 2.90–2.79 (m, 1 H),
2.45 (qd, J = 17.5, 7.2 Hz, 2 H), 1.93–1.82 (m, 1 H), 1.50–1.27 (m,
1 H), 1.04 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.4,
135.4, 133.1, 129.8, 127.7, 81.4, 77.3, 76.9, 76.6, 61.4, 35.5, 34.2,
29.5, 26.8, 19.1, 1.1 ppm. HRMS (ESI): calcd. for C23H29IO3Si [M
+ H]+ 509.1009; found 509.1008. C23H29IO3Si (508.47): calcd. C
6.7 Hz, 1 H), 1.06 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ 54.33, H 5.75; found C 54.34, H 5.74.
Eur. J. Org. Chem. 2012, 175–182
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
181

M. S. Oderinde, H. N. Hunter, S. W. Bremner, M. G. Organ
FULL PAPER
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trans-2-[2-(Iodomethyl)-5-oxotetrahydrofuran-3-yl]ethyl
Acetate
(33a): To a stirred solution of acid 32 (1.50 g, 8.06 mmol) in MeCN
(100 mL) at 0 °C in the dark using a flask wrapped in aluminium
foil was added I2 (6.14 g, 24.19 mmol). The mixture was stirred at
room temp. for 16 h. The reaction was quenched with an excess
amount of saturated aqueous Na2S2O3 and the mixture stirred until
it turned colorless. This mixture was extracted with Et2O
(3ϫ20 mL), and the combined organic layers were dried with an-
hydrous MgSO4, filtered, and concentrated in vacuo. Purification
by silica gel column chromatography (80% Et2O in pentane; Rf =
1
0.37) afforded 33a (2.26 g, 90%, dr 97:3) as a yellow oil. H NMR
(400 MHz, CDCl3): δ = 4.31–4.08 (m, 3 H), 3.39 (ddd, J = 15.4,
11.0, 5.0 Hz, 2 H), 2.86 (dd, J = 17.7, 8.9 Hz, 1 H), 2.53–2.41 (m,
1 H), 2.35 (dd, J = 17.7, 7.4 Hz, 1 H), 2.08 (s, 3 H), 2.02–1.93 (m,
1 H), 1.83–1.74 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
174.7, 170.7, 82.7, 61.8, 38.3, 34.8, 32.20, 20.8, 6.5 ppm. HRMS
(ESI): calcd. for C9H13IO4 [M + H]+ 312.9937; found 312.9936.
C9H13IO4 (312.10): calcd. C 34.63, H 4.20; found C 35.00, H 4.42.
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Supporting Information (see footnote on the first page of this arti-
1
cle): Synthetic procedures and H and 13C NMR spectra.
Acknowledgments
This work was supported by the National Science and Engineering
Council of Canada (NSERC) and the Ontario Research and Devel-
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Received: September 14, 2011
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Published Online: ᭿
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