Asymmetric Induction of the Iodolactonization Reaction of α-Sulfurated γ-Unsaturated Amides

Article abstract of DOI:10.1021/jo035488b

The 1,3-asymmetric iodolactonization reaction of enantiopure α-sulfurated γ-unsaturated amides has been investigated. With sulfinyl and sulfonyl groups, a poorly stereoselective reaction was observed, whereas with a sulfanyl moiety, the diastereoselectivi

Full text of DOI:10.1021/jo035488b

Asym m etr ic In d u ction of th e Iod ola cton iza tion Rea ction of
r-Su lfu r a ted γ-Un sa tu r a ted Am id es
Virginie Blot, Vincent Reboul,* and Patrick Metzner*
Laboratoire de Chimie Mole´culaire et Thioorganique (UMR CNRS 6507), ENSICAEN-Universite´ de Caen,
6, Boulevard du Mare´chal J uin, 14050 Caen, France
reboul@ismra.fr
Received October 9, 2003
The 1,3-asymmetric iodolactonization reaction of enantiopure R-sulfurated γ-unsaturated amides
has been investigated. With sulfinyl and sulfonyl groups, a poorly stereoselective reaction was
observed, whereas with a sulfanyl moiety, the diastereoselectivity can be high as 96:4. The role of
the oxygen atom on the sulfur moiety is discussed.
In tr od u ction
Resu lts a n d Discu ssion
The iodolactonization is a useful reaction1 to prepare
cyclic compounds from γ-unsaturated carboxylic acids,2
esters,3 or amides.4 When these compounds are substi-
tuted in the R position, a high 1,3-asymmetric induction
is usually observed: trans selectivity with amides in
contrast with cis selectivity with acids. Various substi-
tuents have been studied: alkyl,5 oxygenated,3 and
halogenated6 functions, amino groups,7 and phospho-
nate.8 Surprisingly, the cyclization of sulfurated amides
(with an unsubstituted double bond) has not been stud-
ied.9 The stereocontrolled iodocyclization has been suc-
cessfully investigated using an amide bearing a chiral
auxiliary on the nitrogen atom10 or a chiral primary
amine as a ligand.11
Recently, we have disclosed an efficient asymmetric
synthesis of R-sulfinyl γ-unsaturated amide 4b (or its
enantiomer) from cyclohexyl thiol and a very cheap chiral
auxiliary: diacetone-D-glucose (Scheme 1).12 This syn-
thesis was carried out in five steps and 40% overall yield.
The thioamide 3 was obtained by an asymmetric thio-
Claisen rearrangement of the (Z)-ketene aminothioacetal
2 directed by the cyclohexylsulfinyl group with both
absolute and relative stereocontrol (Scheme 1). The
substrate for the rearrangement was easily obtained by
deprotonation of (R)-1 with t-BuLi and subsequent allyl-
ation of the resulting enethiolate at the sulfur atom by
allyl bromide. The rearrangement of this compound13 into
(SS,2S)-3 was improved using CeCl3 as a catalyst at room
temperature: an excellent diastereomeric ratio of 97:3
(99:1 after recrystallization), an enantiomeric excess of
96%, and a yield of 83% were obtained.14 Then, this
thioamide 3 was selectively converted to the correspond-
ing amide 4b with an oxidizing agent, dimethyldiox-
irane,15 formed in situ from oxone, acetone, and NaHCO3.
The oxidation of the sulfoxide and the double bond can
be avoided by slow addition of oxone and by monitoring
Here, we report a novel example of the 1,3-asymmetric
iodolactonization of R-sulfurated γ-unsaturated amides:
enantiopure sulfinyl 4b, sulfanyl 4a , and sulfonyl 4c.
* Corresponding author.
(1) Robin, S.; Rousseau, G. Tetrahedron 1998, 54, 13681-13736.
(2) For a recent example: Wang, M.-X.; Zhao, S.-M. Tetrahedron:
Asymmetry 2002, 13, 1695-1702.
(3) For a recent example: Macritchie, J . A.; Peakman, T. M.; Silcock,
A.; Willis, C. L. Tetrahedron Lett. 1998, 39, 7415-7418.
(4) For a recent example: Rozner, E.; Liu, Y. Org. Lett. 2003, 5,
181-184.
(5) Ha, H.-J .; Lee, S.-Y.; Park, Y.-S. Synth. Commun. 2000, 30,
3645-3650.
(6) (a) Ogu, K.-I.; Akazome, M.; Ogura, K. Tetrahedron Lett. 1998,
39, 305-308. (b) Nubbemeyer, U. J . Org. Chem. 1996, 61, 3677-3686.
(7) (a) Anderson, J . C.; Flaherty, A. J . Chem. Soc., Perkin Trans. 1
2001, 267-269. (b) Mues, H.; Kazmaier, U. Synlett 2000, 7, 1004-
1006.
1
the conversion of 3 by H NMR.
The iodolactonization16 was tested first on the enan-
tiopure sulfoxide 4b (Scheme 2 and Table 1).
Using standard conditions, THF-H2O-iodine (entry
1, Table 1), a mixture of two products was isolated: 3-(R)-
cyclohexane-sulfinyl-5-iodomethylfuran-2(5H)-one 6b and
iodohydrin 7b in 60 and 38% yields, respectively.
(8) (a) Lee, C. W.; Gil, J . M.; Oh, D. Y. Heterocycles 1997, 45, 943-
948. (b) Zhao, Y.; Pei, C.; Wong, Z.; Xi, S. Phosphorus, Sulfur Silicon
Relat. Elem. 1992, 66, 115-125.
(9) An example with a phenylsulfonyl group has been described, but
the stereochemistry of the lactone was not mentioned: Lee, J . W.; Oh,
D. Y. Heterocycles 1990, 31, 1417-1421. Lee, J . W.; J ung, J . H.; Oh,
D. Y. Bull. Korean Chem. Soc. 1994, 15, 842-845.
(10) Moon, H.-S.; Eisenberg, S. W. E.; Wilson, M. E.; Schore, N. E.;
Kurth, M. J . J . Org. Chem. 1994, 59, 6504-6505.
(11) Haas, J .; Piguel, S.; Wirth, T. Org. Lett. 2002, 4, 297-300.
(12) Nowaczyk, S.; Alayrac, C.; Reboul, V.; Metzner, P.; Averbuch-
Pouchot, M.-T. J . Org. Chem. 2001, 66, 7841-7848.
(13) It is also possible to carry out this reaction without isolation of
2.
(14) On a large scale and in the absence of CeCl3: 80% yield and
90:10 dr.
(15) Mukaiyama, T.; Uchiro, H.; Shiina, I.; Kobayashi, S. Chem. Lett.
1990, 1019-1022.
(16) Dr was measured before purification, as epimerization on the
asymmetric center in position 3 easily takes place on silica gel.
10.1021/jo035488b CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/22/2004
1196
J . Org. Chem. 2004, 69, 1196-1201

R-Sulfurated γ-Unsaturated Amides
TABLE 1. Resu lts of th e Iod ola cton iza tion Rea ction of Am id es 4a , 4b a n d 4c
lactone 6
% yielde
iodohydrin 7
% yielde
(drf)
entry
amide
solvents/additive
temp, time
(trans:cisf)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4b
THF:H2Oa/none
rt, 1 h
rt, 4 h
rt, 1 h
rt, 24 h
rt, 1 h
rt, 1 h
rt, 1 h
-23 °C, 20 h
rt, 1 h
rt, 1 h
rt, 0.75 h
rt, 24 h
rt, 0.75 h
-23 °C, 2 h
rt, 0.75 h
-23 °C, 17 h
rt, 0.75 h
6b
60 (72:28)
7b
38 (79:21)
CH3CN:H2Oa/none
DME:H2Oa/none
60 (81:19)
62 (76:24)
39 (79:21)
66 (82:18)
53 (75:25)
66 (84:16)
69 (85:15)
60 (77:23)
65 (72:28)
96 (94:06)
78 (95:05)
89 (94:06)
98 (95:05)
82 (94:06)
93 (94:06)
80 (62:38)
36 (81:19)
36 (76:24)
61 (60:40)
31 (72:28)
34 (78:22)
19 (68:32)
25 (76:24)
37 (77:23)
21 (73:27)
THF:H2Oa/NaHCO3
THF:H2Oa/HCl
THF:H2O:MeOHb/none
THF:H2O:MeOHb/HClc
THF:H2O:MeOHb/HClc
d
THF:H2Oa/CuCl2
d
THF:H2Oa/CuCl2
4a
4c
THF:H2Oa/none
6a
6c
CH3CN:H2Oa/none
DME:H2Oa/none
THF:H2Oa/none
THF:H2Oa/NaHCO3
THF:H2O:MeOHb/HClc
THF:H2Oa/none
a
b
d
1
Solvent/water ) 8:1. THF/water/MeOH ) 8:1:1. c HCl: 2.5 equiv. CuCl2: 0.5 or 1 equiv. e Isolated yield. f Determined by H NMR
on the crude product.
SCHEME 1. Th io-Cla isen Tr a n sp osition
iodoimidate at pH < 7 is known to facilitate the lactone
formation. Thus, in the presence of 2.5 equiv of HCl
(entry 5), the yield of lactone 6b (66%) and the diaster-
eoselectivity (82:18) were improved but the iodohydrin
was still present.18 To facilitate the hydrolysis of imidate19
5b, the reaction was performed in the presence of MeOH
(entry 6). Again, a similar result was obtained. However,
the combination of MeOH and HCl (entries 7 and 8)
afforded the best result in terms of yield and diastereo-
selectivity: 69% and 85:15 dr at low temperature (-23
°C).18
It is interesting to note that the sulfinyl group en-
hances the reaction rate: only 1 h instead of more than
24 h is required in most cases.
SCHEME 2. Iod ola cton iza tion
To confirm the absolute configuration of the new
stereogenic center of 6b, the mixture of trans- and cis-
lactone was desulfinylated by mild reduction20 in the
presence of SmI2-THF-HMPA. The resulting lactone
was analyzed by enantioselective HPLC (Daicel AD
column). By comparison with an enantiopure sample of
the (R)-lactone,21 we were able to assign the (R) config-
uration to the major trans isomer of 6b.
According to the literature, whatever the substituent
in R position of the amide is, the 1,3-chirality transfer
has been always very efficient due to a favored transition
state, avoiding A1,3 interactions between the 2-substitu-
ent and the imidate function (Scheme 3).22 Thus, the
Moreover, these two compounds were formed in a
mixture of trans and cis isomers in the respective ratios
of 72:28 and 79:21. These results were similar in DME-
H2O and CH3CN-H2O (entries 2 and 3). As these ratios
were similar, these two compounds should have the same
precursor, the imidate 5b, which can be hydrolyzed
according to two different pathways (Scheme 2: pathway
a or b).
We have been surprised by the low diastereoselectivity
and the formation of the iodohydrin 7b. This compound
was usually obtained during the hydrolysis of the sup-
posed iodoimidate salt 5b under basic conditions.17
However, the reaction performed with NaHCO3 (entry
4) was not selective and a mixture of 6b and 7b was still
obtained.18 On the other hand, the hydrolysis of the
(17) (a) Maligres, P. E.; Weissman, S. A.; Upadhyay, V.; Cianciosi,
S. J .; Reamar, R. A.; Purick, R. M.; Sager, J .; Rossen, K.; Eng, K. K.;
Askin, D.; Volante, R. P.; Reider, P. J . Tetrahedron 1996, 52, 3327-
3338. (b) LeBlond, C. R.; Rossen, K.; Gortsema, F. P.; Zavialov, I. A.;
Cianciosi, S. J .; Andrews, A. T.; Sun, Y. Tetrahedron Lett. 2001, 42,
8603-8606.
(18) In these conditions, some variation of dr between the lactone
and the iodohydrin was observed (Table 1; entries 4, 5, 7, and 8)
without any rational explanation.
(19) Kantlehner, W.; Gutbrod, H.-D. Liebigs Ann. Chem. 1980,
1677-1688.
(20) Handa, Y.; Inanaga, J .; Yamaguchi-ku, M. J . Chem. Soc., Chem.
Commun. 1989, 298-299.
(21) Prepared from (R)-dihydro-5-(hydroxymethyl)-2(3H)-furanone
by iodation: Artis, D. R.; Cho, I.-S.; J aime-Figueroa, S.; Muchowski,
J . M. J . Org. Chem. 1994, 59, 2456-2466.
(22) Tamaru, Y.; Mizutani, M.; Furukawa, Y.; Kawamura, S.;
Yoshida, Z.; Yanagi, K.; Minobe, M. J . Am. Chem. Soc. 1984, 106,
1079-1085.
J . Org. Chem, Vol. 69, No. 4, 2004 1197

Blot et al.
SCHEME 3. Or igin of Dia ster eoselectivity
F IGURE 1. Amides 8b and 9b.
SCHEME 5. Syn th esis of Am id es 4a a n d 4c
SCHEME 4. In ter a ction s w ith Su lfin yl Am id e
Der iva tive
lectivity were not improved. Surprisingly, neither lactone
6b nor the corresponding iodohydrin was observed with
the amide 9b, which was not recovered in the crude.
To remove the presumed interactions (models B and
C), we modified the sulfur moiety. We performed the
iodolactonization reaction with the R-sulfanyl γ-unsatur-
ated amide 4a and the R-sulfonyl γ-unsaturated amide
4c.
The amide 4a was selectively obtained by reduction of
4b in the presence29 of P4S10 in 90% yield, and the
oxidation of 4b by m-CPBA gave access to amide 4c
(Scheme 5).
model A, where the substituent is located at the pseudo-
axial position, is sterically favored in comparison to the
model B, where the substituent is oriented at the
pseudoequatorial position. Consequently, the trans-lac-
tone is often the only isolated product.
To explain the moderate selectivity that we have
observed in the sulfinyl series, we suggest a strong
electrostatic attraction between the polarized S-O bond
and the amide dipole (N+dC-O-) stabilizing the transi-
tion state B (Scheme 4). A similar observation has
already been made with a R-phosphorylated amide.23
A stabilization between the oxygen atom of the sulfinyl
group and the iodonium could also be proposed,24 as
suggested in a similar case with an R-amino25 or an
R-hydroxylated26 starting material. Thus, the model C,
a conformer of model A, could also explain the formation
of the cis-lactone.
To decrease this interaction, we tried to use copper
salts, which are known to complex the oxygen atom of
the sulfinyl group.27 Unfortunately, with CuCl2 or other
salts28 (entries 9 and 10), comparable results were
obtained.
We have also investigated steric effects of the amide
function. The N,N-diethyl and N,N-diisopropyl deriva-
tives (8b and 9b) have been synthesized using the same
strategy as in Scheme 1 (Figure 1). However, with 8b as
starting material, the diastereoselectivity and the chemose-
Whatever the solvent used (THF, CH3CN, or DME),
without additive, the iodolactonization of 4a at room
temperature afforded the desired lactone 6a (entries 11-
13) in almost quantitative yield and, as expected, with
an excellent diastereomeric ratio of 94:6.30 This ratio was
not dependent upon the temperature reaction (entry 14).
Addition of NaHCO3 or HCl to the reaction (entries 15-
16) did not either affect this ratio. The two diastereiso-
mers were easily separated by chromatography on silica
gel. Moreover, as this reaction was highly selective, we
decided to characterize the intermediate, the cyclic imi-
date salt 5a , by 1H and 13C NMR analysis. For this
purpose, the reaction was performed in an aprotic
solvent, CDCl3, in the NMR tube.31
When the amide 4c was used (entry 17) and under
standard conditions, a mixture of trans and cis isomers
of 3-cyclohexanesulfonyl-5-iodomethylfuran-2(5H)-one 6c
was obtained in a modest ratio of 62:38 and in 80% yield.
As expected, the interaction described above (between the
oxygen atom of the sulfone and the iodonium or the
imidate functions) could also explain this modest selec-
tivity.
On the other hand, surprisingly, the iodohydrins 7a
and 7c were not detected in the crude product. Although
we have not been able to obtain clear evidence for the
high selectivity so far, we suggest a competition of the
two reactions when the sulfinyl amide 4b was used: the
classical iodolactonization reaction between the amide
(23) In this case, the imidate salt was not hydrolyzed by water. See
ref 8b.
(24) This model was suggested by one of the three reviewers.
(25) Ohfune, Y.; Kurokawa, N. Tetrahedron Lett. 1985, 26, 5307-
5308. See also ref 7a.
(26) Chamberlin, A. R.; Dezube, M.; Dussault, P., McMills, M. C. J .
Am. Chem. Soc. 1983, 105, 5819-5825. Chamberlin, A. R.; Mulholland,
R. L.; Kahn, S. D.; Hehre, W. J . J . Am. Chem. Soc. 1987, 109, 672-
677.
(27) Kagan, H. B.; Ronan, B. Rev. Heteroatom Chem. 1992, 7, 92-
116.
(29) Still, I. W. J .; Hasan, S. K.; Turnbull, K. Synthesis 1977, 468-
469.
(30) Trans:cis assignments were determined by comparison of 1H
NMR spectra of lactone 6a , obtained by lactonization of 4a , and 6a
obtained by reduction (P4S10) of 6b.
(28) Other copper salts have been studied without noticeable
improvement: CuSO4, Cu(OAc)2, or Cu(NO3)2.
(31) Kitagawa, O.; Hanano, T.; Hirata, T.; Inoue, T.; Taguchi, T.
Tetrahedron Lett. 1992, 33, 1299-1302.
1198 J . Org. Chem., Vol. 69, No. 4, 2004

R-Sulfurated γ-Unsaturated Amides
(m, 2H), 5.71-5.82 (m, 1H); 13C NMR (CDCl3, 100.6 MHz) δ
22.4, 25.3, 25.4, 26.0, 28.5, 36.6, 42.1, 44.0, 54.4, 68, 119.4,
132.7, 196.6; IR (KBr) ν 3072, 2930-2854, 1518, 1450-1434,
1394, 1266, 1140, 1036, 916 cm-1; MS (70 eV, EI) m/z (%) 274
(MH+, 1), 247 (2), 190 (1), 108 (21), 83 (56), 55 (100), 45 (42);
Anal. Calcd for C13H23NOS2: C, 57.12; H, 8.49; N, 5.13; O, 5.86;
S, 23.41. Found: C, 56.99; H, 8.55; N, 5.18; O, 6.03; S, 23.35.
SCHEME 6. Iod oh yd r in F or m a tion w ith In ver sion
of Con figu r a tion on Su lfu r
(S)-2-Cycloh exylsu lfa n yl-N,N-d im eth ylp en t-4-en ea m -
id e (4a ). P4S10 (2.65 g, 5.06 mmol) was added slowly to a
stirred solution of (SS,2S)-4b (dr 99:1, 3.04 g, 11.80 mmol) in
dichloromethane (95 mL) at room temperature. The reaction
was monitored by TLC. After 45 min, the dichloromethane
layer was filtered through a pad of Celite; the crude was
washed with dichloromethane, and then the filtrate was placed
in a separatory funnel. The organic layer was washed with
water 2x and then dried over MgSO4. The solvent was removed
under reduced pressure, and the crude product was purified
by column chromatography on silica gel (CH2Cl2; Rf ) 0.37)
to afford 4a (2.52 g, 10.46 mmol) as a yellow oil in 90% yield:
1H NMR (CDCl3, 400 MHz) δ 1.10-2.20 (m, 10H), 2.41-2.54
(m, 1H), 2.89-2.78 (m, 2H), 2.99 (s, 3H), 3.13 (s, 3H), 3.57 (dd,
J ) 6.1 Hz, J ) 8.8 Hz, 1H), 5.03-5.15 (m, 2H), 5.78-5.89
(m, 1H); 13C NMR (CDCl3, 62.9 MHz) δ 25.6, 26.0, 34.5, 34.7,
36.1, 37.4, 42.2, 42.8, 117.0, 135.6, 170.9; IR (NaCl) ν 2928,
2852, 1646, 1490, 1448, 1396, 1338, 1264, 1206, 1140, 1104,
1056, 914, 818 cm-1; MS m/z (%) 242 (MH+, 22), 127 (100),
112 (26), 98 (26), 87 (18), 72 (61), 55 (26). C13H23NOS. Exact
mass: calcd 242.1578; found 242.1570.
function and the double bond, but also the intramolecular
nucleophilic attack by the sulfinyl group of iodonium ion
followed by hydrolysis through attack of water on sulfur
atom (Scheme 6).32 Moreover, the postulated intermediate
could be also stabilized by the above-mentioned interac-
tion between the oxygen atom of the sulfinyl and the
iodonium.
Con clu sion
In conclusion, the influence of a sulfur substituent on
the selectivity of the iodolactonization is demonstrated.
Whereas the sulfinyl and sulfonyl groups were not
efficient, an excellent 1,3-induction has been obtained
with an R-sulfanylamide function (dr up to 96:4). We now
envisage applying this methodology to the total synthesis
of natural lactones bis-lactones such as iso-avenaciolide
or ethisolide33 from lactone 6b.
(SS,2S)-2-Cycloh exylsu lfin yl-N,N-d im eth ylp en t-4-en -
a m id e (4b). To a solution of (SS,2S)-3 (dr 99:1, 2.00 g, 7.3
mmol) in acetone (100 mL) were added sodium bicarbonate
(2.33 g, 27.7 mmol) and water (10 mL). This suspension was
cooled at 0 °C. Then, 0.25 equiv of oxone (1.12 g) was first
added. After 10 min of stirring, 0.25 equiv of oxone was added
every 10 min (5 × 1.12 g). The reaction was monitored by TLC
(EtOAc) and 1H NMR. Water (200 mL) was then added. The
aqueous layer was extracted with ethyl acetate (4 x 200 mL).
The combined organic phases were dried over MgSO4 and then
evaporated to dryness. Chromatography on silica gel (EtOAc;
Rf ) 0.23) afforded 4b (1.55 g, 6.0 mmol) in 83% yield. White
Exp er im en ta l Section
(S)-2-Cycloh exylsu lfin yl-1-(N,N-dim eth ylam in o)-1-(pr op-
2-en ylsu lfa n yl)-(Z)-eth en e (2). To a solution of thioamide
(R)-1 (11 g, 47 mmol) in THF (140 mL) was slowly added a
1.6 M solution of t-BuLi in pentane (32.5 mL, 52 mmol) at -40
°C. The reaction mixture was stirred at -40 °C for 1 h, and
then allyl bromide (5.3 mL, 61.1 mmol) was added dropwise.
The reaction mixture was allowed to warm to room temper-
ature over 1.5 h. Then, the reaction mixture was cooled before
the hydrolysis (50 mL). The aqueous layer was acidified with
diluted sulfuric acid (5%) and extracted with dichloromethane
(3 x 150 mL); the combined organic layers were washed with
saturated aqueous NaCl (150 mL), dried over MgSO4, and then
concentrated to obtain keteneaminothioacetal 2 as a colorless
oil, Rf ) 0.03 (EtOAc). 1H NMR characteristic signals (CDCl3,
250 MHz) δ 2.99 (s, 6H), 5.17 (s, 1H). This compound was
immediadely used for the next step without any purification.
(SS,2S)-2-Cycloh exylsu lfin yl-N,N-dim eth ylpen t-4-en eth -
ioa m id e (3). CeCl3 (1.17 g, 4.7 mmol) was added to a stirred
solution of (Z)-2 (12.83 g, 47 mmol) in THF (350 mL) at room
temperature. The reaction was monitored by TLC. After 17 h,
1
solid: mp 73 °C; H NMR (CDCl3, 400 MHz) δ 0.98-1.81 (m,
10H), 2.45 (tt, J ) 3.8 Hz, J ) 11.9 Hz, 1H), 2.62-2.68 (m,
2H), 2.81 (s, 3H), 2.92 (s, 3H), 3.69-3.75 (m, 1H), 4.91-5.08
(m, 2H), 5.57-5.71 (m, 1H); 13C NMR (CDCl3, 62.9 MHz) δ
22.6, 24.9, 25.0, 25.4, 27.7, 32.3, 35.3, 37.5, 55.5, 60.6, 118.5,
132.6, 167.7; IR (KBr) ν 3072, 2930, 2854, 1518, 1450-1434,
1394, 1266, 1140, 1036, 916 cm-1; MS (70 eV, EI) m/z (%) 257
(M+, 0.71), 175 (73), 149 (13), 134 (60), 128 (46), 98 (15), 83
(98), 55 (59), 53 (100), 44 (69). Anal. Calcd for C13H23NO2S:
C, 60.7; H, 9.0; N, 5.4; S, 12.5. Found: C, 60.6; H, 9.0; N, 5.8;
S, 12.6.
(S)-2-Cycloh exylsu lfon yl-N,N-d im et h ylp en t -4-en a m -
id e (4c). To a cooled (0 °C) solution of (SS,2S)-4b (dr 99:1,
100 mg, 0.39 mmol) in dichloromethane (6 mL) was added
m-CPBA (130 mg). The reaction was monitored by TLC. The
dichloromethane layer was washed with a solution of saturated
NaHCO3 (3 x 15 mL) and then treated with saturated aqueous
NaCl (15 mL). The organic layer was dried over MgSO4 and
evaporated to dryness. The residue was chromatographed on
silica gel (petroleum ether-EtOAc, 1:1; Rf ) 0.38) to afford
4c (100 mg, 0.37 mmol) in 94% yield. White solid: mp 52 °C.
1H NMR (CDCl3, 250 MHz) δ 1.10-2.28 (m, 10H), 2.72-2.85
(m, 1H), 2.94-3.09 (m, 1H), 3.04 (s, 3H), 3.17 (s, 3H), 3.38 (tt,
J ) 3.6 Hz et J ) 11.9 Hz, 1H), 4.22 (dd, J ) 3.3 Hz, J ) 11.2
Hz, 1H), 5.05-5.22 (m, 2H), 5.59-5.77 (m, 1H); 13C NMR
(CDCl3, 62.9 MHz) δ 25.1, 25.2, 25.2, 25.3, 26.5, 32,9, 36.6,
38.4, 60.2, 65.3, 118.8, 132.7, 165.0; IR (KBr) ν 3074, 2932,
2860, 1656, 1490, 1454, 1432, 1398, 1268, 1204, 1186, 1122,
1054, 996, 936 cm-1; GC/MS m/z (%) 274 (MH+, 7), 127 (100),
112 (21), 98 (24), 83 (16), 72 (69), 55 (41), 44 (14). C13H23NO3S.
Exact mass: calcd 273.1398; found 273.1397.
the reaction mixture was hydrolyzed with
a solution of
saturated NaHCO3 (200 mL) and extracted with dichlo-
romethane (3 x 150 mL). Then, the organic layers were washed
with a solution of saturated NaHCO3 (2 x 200 mL) and
saturated aqueous NaCl (200 mL), dried over MgSO4, and
concentrated to dryness to afford the crude thioamide. The
diastereomeric ratio was determined by 1H NMR analysis:
(SS,2S):(SS,2R) ) 97:3. Chromatography on silica gel (EtOAc;
Rf ) 0.29) afforded 3 (10.7 g, 39 mmol) in 83% yield. After
crystallization from EtOAc-petroleum ether 9:1, (SS,2S)-3 (8.5
g, 31 mmol) in 66% yield was isolated. Yellow solid: mp 76
°C. 1H NMR (CDCl3, 400 MHz) δ 1.15-1.99 (m, 10H), 2.83 (tt,
J ) 3.9 Hz, J ) 12.1 Hz, 1H), 3.06-3.12 (m, 2H), 3.37 (s, 3H),
3.49 (s, 3H), 4.13 (dd, J ) 5.7 Hz, J ) 9.1 Hz, 1H), 5.08-5.27
(32) Raghavan, S.; Rasheed, A.; J oseph, S. C.; Rajender, A. Chem.
Commun. 1999, 1845-1846.
(33) Martin, V. S.; Rodriguez, C. M.; Martin, T. Org. Prep. Proced.
Int. 1998, 30, 291-324.
J . Org. Chem, Vol. 69, No. 4, 2004 1199

Blot et al.
Im id a te (5a ). To a solution of (2S)-4a (10 mg, 0.04 mmol)
in CDCl3 (0.5 mL) was added iodine (31 mg, 0.12 mmol) at
room temperature. After 5 min, the mixture was analyzed by
1H NMR and 13C NMR. Signals of the (3S,5R)-major isomer:
1H NMR (CDCl3, 400 MHz) δ 1.24-2.26 (m, 10H), 2.88 (dd, J
) 5.2 Hz, J ) 13.7 Hz, 1H), 3.05 (ddd, J ) 7.2 Hz, J ) 10.5
Hz, J ) 13.8 Hz, 1H), 3.12 (m, 1H), 3.51 (s, 3H), 3.67 (s, 3H),
3.64-3.70 (m, 1H), 3.75 (dd, J ) 6.1 Hz, J ) 10.6 Hz, 1H), 4.6
(d, J ) 7.0 Hz, 1H), 5.48-5.55 (m, 1H); 13C NMR (CDCl3, 100.6
MHz) δ 2.1, 25.4, 26.1, 26.2, 33.7, 33.8, 40.6, 42.1, 43.4, 44.9,
47.1, 91.4, 178.5.
J ) 14.3 Hz, 1H), 3.4 (dd, J ) 6.5 Hz, J ) 10.7 Hz, 1H), 3.46
(dd, J ) 3.9 Hz, J ) 10.7 Hz, 1H), 3.52 (tt, J ) 3.9 Hz, J )
11.2 Hz, 1H), 3.70 (dd, J ) 2.6 Hz, J ) 10.2 Hz, 1H), 4.69-
4.74 (m, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 8.1, 24.8, 25.1,
25.3, 26.2, 33.2, 54.9, 57.2, 77.7, 169.5; IR (KBr) ν 2920, 2852,
1760, 1446, 1336, 1178, 1040 cm-1; MS (70 eV, EI) m/z (%)
357 (MH+, 37), 274 (26), 147 (14), 97 (22), 83 (63), 55 (100).
Anal. Calcd for C11H17IO3S: C, 37.08; H, 4.81. Found: C, 37.26;
H, 4.79. 7b is colorless oil: Rf ) 0.1 (EtOAc). Signals of the
major isomer: 1H NMR (CDCl3, 250 MHz) δ 1.20-2.05 (m,
10H), 2.31 (dt, J ) 3.7 Hz, J ) 14.3 Hz, 1H), 2.39-2.47 (m,
1H), 2.92 (tt, J ) 4.0 Hz, J ) 11.3 Hz, 1H), 3.01 (s, 3H), 3.22
(s, 3H), 3.27-3.30 (m, 1H), 3.36 (dd, J ) 4.9 Hz, J ) 10.3 Hz,
1H), 3.62-3.75 (m, 1H), 4.32 (dd, J ) 3.9 Hz, J ) 8.7 Hz, 1H);
13C NMR (CDCl3, 100.6 MHz) δ 13.6, 23.5, 24.0, 25.1, 25.4,
27.8, 31.6, 36.5, 38.1, 54.9, 56.5, 69.3, 167.6. Signals of the
minor isomer: 1H NMR (CDCl3, 250 MHz) δ 1.20-2.05 (m,
11H), 2.39-2.47 (m, 1H), 2.85 (tt, J ) 3.7 Hz, J ) 11.7 Hz,
1H), 3.03 (s, 3H), 3.21 (s, 3H), 3.27-3.30 (m, 1H), 3.34-3.40
(m, 1H), 3.41-3.63 (m, 1H), 4.54 (dd, J ) 3.7 Hz, J ) 9.7 Hz,
1H); 13C NMR (CDCl3, 100.6 MHz) δ 14.6, 23.0, 25.0, 25.1, 25.5,
27.8, 32.2, 36.5, 38.1, 55.0, 56.0, 67.4, 167.2; IR (NaCl) ν 3344,
2932, 2856, 1764, 1700, 1684, 1636, 1560, 1540, 1496, 1400,
1344, 1258, 1180, 1138, 1024 cm-1; MS (eV, EI) m/z (%) 402
Gen er a l P r oced u r e for th e Syn th esis of La cton es (6)
a n d Iod oh yd r in (7) by Iod ola cton iza tion . Amide 4 was
diluted in solvent (THF, DME, or CH3CN)-H2O (8:1 v/v, 0.06
M) or THF-H2O-MeOH (8:1:1 v/v, 0.05 M). Iodine (3 equiv)
was added at the temperature indicated in Table 1. The
reaction was monitored by TLC. After the time indicated in
the Table 1, the mixture was diluted with dichloromethane
and treated twice with Na2S2O3 aqueous solution. The organic
layers were washed with a saturated solution of NaHCO3 and
with saturated aqueous NaCl. After drying over MgSO4, the
organic phase was evaporated to dryness. The crude mixture
1
was analyzed by H NMR to determine the diastereoisomeric
ratio. The crude was chromatographed on silica gel.
(MH+, 0.13), 319 (1), 274 (5), 97 (22), 83 (43), 55 (100). C18H24
INO3S. Exact mass: calcd 402.0599; found 402.0623.
-
4,5-Dih yd r o-3-cycloh exylsu lfa n yl-5-iod om eth yl-2(3H)-
fu r a n on e (6a ). Obtained from (2S)-4a (2.50 g, 10.3 mmol)
according to entry 11. Chromatography on silica gel (CH2Cl2-
petroleum ether, 7:3) afforded 6a (3.33 g, 9.8 mmol) in 95%
yield. White solid: mp 58 °C. Rf ) 0.45 (minor) and 0.57
(major) (CH2Cl2-petroleum ether, 7:3). Signals of the (3S,5R)-
major isomer: 1H NMR (CDCl3, 400 MHz) δ 1.21-2.18 (m,
10H), 2.27-2.43 (m, 2H), 3.05-3.17 (m, 1H), 3.32 (dd, J ) 7.1
Hz, J ) 10.5 Hz, 1H), 3.43 (dd, J ) 4.4 Hz, J ) 10.5 Hz, 1H),
(4,5)-Dih ydr o-3-cycloh exylsu lfon yl-5-iodom eth yl-2(3H)-
fu r a n on e (6c). Obtained from (2S)-4c (54 mg, 0.2 mmol)
according to entry 17. Chromatography on silica gel (n-
pentane-EtOAc, 7:3; Rf ) 0.41) afforded 6c (59 mg, 0.16 mmol)
in 80% yield. White solid: mp 147 °C. Signals of the (3S,5R)-
major isomer: 1H NMR (CDCl3, 400 MHz) δ 1.18-2.30 (m,
10H), 2.41 (ddd, J ) 7.6 Hz, J ) 10.6 Hz, J ) 14.7 Hz, 1H),
3.13 (ddd, J ) 3.6 Hz, J ) 7.3 Hz, J ) 14.7 Hz, 1H), 3.37-
3.52 (m, 2H), 3.56 (tt, J ) 3.5 Hz, J ) 12.1 Hz, 1H), 4.27 (dd,
J ) 3.6 Hz, J ) 10.6 Hz, 1H), 4.23-4.82 (m, 1H); 13C NMR
(CDCl3, 100.6 MHz) δ 7.9, 22.6, 24.8, 25.0, 25.1, 26.8, 28.8,
59.0, 59.5, 77.8, 168.3. Signals of the (3S,5S)-minor isomer:
1H NMR (CDCl3, 400 MHz) δ 1.18-2.30 (m, 10H), 2.72 (ddd,
J ) 6.8 Hz, J ) 7.5 Hz, J ) 14.5 Hz, 1H), 2.89 (ddd, J ) 7.6
Hz, J ) 10.6 Hz, J ) 14.5 Hz, 1H), 3.37-3.52 (m, 2H), 3.68
(tt, J ) 3.5 Hz, J ) 12.1 Hz, 1H), 4.31 (dd, J ) 7.5 Hz, J )
10.6 Hz, 1H), 4.23-4.82 (m, 1H); 13C NMR (CDCl3, 100.6 MHz)
δ 4.8, 22.6, 24.8, 25.1, 26.8, 27.1, 58.2, 59.3, 78.3, 168.2; IR
(KBr) ν 2932, 2854, 1752, 1448, 1412, 1312, 1274, 1212, 994
cm-1; GC/MS m/z (%) 373 (M+, 3), 226 (100), 99 (49), 71 (16),
55 (34). Anal. Calcd for C15H27O2S: C, 63.12; H, 9.53; N, 4.91.
Found: C, 62.90; H, 10.11; N, 4.89.
3.73 (dd, J ) 2.9 Hz, J ) 8.0 Hz, 1H), 4.62-4.72 (m, 1H); 13
C
NMR (CDCl3, 62.9 MHz) δ 6.9, 25.6, 25.7, 25.9, 32.6, 33.4, 36.8,
39.0, 43.3, 77.0, 174.3. Signals of the (3S,5S)-minor isomer:
1H NMR (CDCl3, 400 MHz) δ 1.20-2.14 (m, 10H), 2.02 (ddd,
J ) 6.6 Hz, J ) 7.7 Hz, J ) 13.8 Hz, 1H), 2.89 (ddd, J ) 7.0
Hz, J ) 9.2 Hz, J ) 13.8 Hz, 1H), 3.09-3.18 (m, 1H), 3.37
(dd, J ) 8.5 Hz, J ) 10.1 Hz, 1H), 3.50 (dd, J ) 4.9 Hz, J )
10.1 Hz, 1H), 3.72 (dd, J ) 9.2 Hz, J ) 7.7 Hz, 1H), 4.53-4.63
(m, 1H); 13C NMR (62.9 MHz, CDCl3) δ 6.3, 25.8, 25.9, 26.0,
33.2, 33.6, 36.2, 39.4, 44.0, 77.4, 175.2; IR (KBr) ν 2926, 2848,
1754, 1446, 1366, 1336, 1306, 1264, 968, 920 cm-1; GC/MS m/z
(%): 340 (M+, 13), 226 (30), 213 (15), 115 (100), 99 (5), 81 (50),
55 (33). Anal. Calcd for C11H17IO2S: C, 38.83; H, 5.04; S, 9.43.
Found: C, 39.05; H, 5.07; S, 9.02.
4,5-Dih yd r o-3-cycloh exylsu lfin yl-5-iod om eth yl-2(3H)-
fu r a n on e (6b) a n d Iod oh yd r in (7b). Obtained from (2S,SS)-
4b (2.60 g, 10.12 mmol) according to entry 8. Chromatography
on silica gel (CH2Cl2-MeOH, 98:2) afforded 6b (2.40 g, 6.74
mmol) in 67% yield and 7b (1.00 g, 2.49 mmol) in 25% yield.
6b is a white solid: mp 81 °C. Rf ) 0.6 (EtOAc). Signals of
(3S,SS,5R)-6b: 1H NMR (CDCl3, 400 MHz) δ 1.25-2.12 (m,
10H), 2.29 (ddd, J ) 6.2 Hz, J ) 10.0 Hz, J ) 14.3 Hz, 1H),
2.77 (tt, J ) 3.6 Hz, J ) 11.6 Hz, 1H), 3.12 (ddd, J ) 5.0 Hz,
J ) 7.8 Hz, J ) 14.3 Hz, 1H), 3.38-3.43 (m, 2H), 3.91 (dd, J
) 5.0 Hz, J ) 10.0 Hz, 1H), 4.58-4.67 (m, 1H); 13C NMR
(CDCl3, 100.6 MHz) δ 8.9, 24.4, 24.9, 25.1, 26.2, 26.4, 25.9,
56.9, 58.8, 77.6, 172.1. Signals of (3S,SS,5S)-6b: 1H NMR
(CDCl3, 400 MHz) δ 1.25-2.12 (m, 10H), 2.60-2.71 (m, 3H),
3.29 (dd, J ) 8.4 Hz, J ) 10.0 Hz, 1H), 3.38-3.56 (m, 1H),
(SS,2S)-2-Cycloh exylsu lfin yl-N,N-et h ylp en t -4-en a m -
id e (8b). Amide 8b was synthesized using the procedure
described for amide 4b. White solid: mp 114 °C. Rf ) 0.4
(EtOAc); 1H NMR (CDCl3, 400 MHz) δ 0.93-1.89 (m, 10H),
1.01 (t, J ) 7.1 Hz, 3H), 1.08 (t, J ) 7.1 Hz, 3H), 2.58 (tt, J )
3.7 Hz, J ) 11.9 Hz, 1H, CH-Cy), 2.66-2.81 (m, 2H), 3.14-
3.36 (m, 4H), 3.69 (dd, J ) 4.9 Hz, J ) 9.0 Hz, 1H), 4.98-5.13
(m, 2H), 5.63-5.75 (m, 1H); 13C NMR (CDCl3, 100.6 MHz) δ
13.0, 14.6, 23.4, 23.5, 25.4, 25.8, 26.0, 33.2, 40.2, 42.6, 55.9,
61.6, 119.1, 133.1, 167.2; IR (KBr) ν 3078, 2974, 2856, 1616,
1456, 1358, 1264, 1216, 1138, 1042, 912 cm-1. Anal. Calcd for
C
11H17IO4S: C, 35.49; H, 4.60; S, 8.61. Found: C, 35.48; H,
4.62; S, 8.88.
(SS,2S)-2-Cycloh exylsu lfon yl-N,N-et h ylp en t -4-en a m -
id e (9b). Amide 9b was synthesized using the procedure
described for amide 4b. White solid: mp 125 °C; Rf ) 0.51
(EtOAc); 1H NMR (CDCl3, 400 MHz) δ 1.17-2.03 (m, 10H),
1.20 (d, J ) 6.6 Hz, 3H), 1.22 (d, J ) 6.6 Hz, 3H), 1.38 (d, J )
6.6 Hz, 3H), 1.40 (d, J ) 6.6 Hz, 3H), 2.70 (tt, J ) 3,6 Hz, J )
12,1 Hz, 1H), 2.78-2.92 (m, 2H), 3.40 (sept, J ) 6,6 Hz, 1H),
3.78 (dd, J ) 4.8 Hz, J ) 8.7 Hz, 1H), 4.04 (sept, J ) 6.6 Hz,
1H), 5.11-5.25 (m, 2H), 5.77-5.89 (m, 1H); 13C NMR (CDCl3,
100.6 MHz) δ 20.5, 20.6, 21.0, 21.3, 22.9, 25.5, 26.1, 28.5, 33.4,
46.7, 49.7, 55.5, 63.0, 118.9, 133.3, 167.2; IR (KBr) ν 2928,
3.90 (dd, J ) 8.5 Hz, J ) 13.0 Hz, 1H), 4.74-4.84 (m, 1H); 13
C
NMR (CDCl3, 100.6 MHz) δ 5.7, 24.6, 25.1, 25.2, 25.7, 24.8,
56.9, 58.6, 78.2, 172.1. Signals of the (3R,SS,5R)- 6b: 1H NMR
(CDCl3, 400 MHz) δ 1.25-2.12 (m, 10H), 2.60-2.71 (m, 1H),
3.04-3.09 (m, 1H), 3.38-3.56 (m, 2H), 3.61-3.69 (m, 1H), 3.76
(dd, J ) 5.9 Hz, J ) 11.1 Hz, 1H), 4.58-4.86 (m, 1H); 13C NMR
(CDCl3, 100.6 MHz) δ 5.9, 24.6, 24.7, 25.8, 26.4, 30.4, 53.8,
56.0, 77.9, 169.5. Signals of (3R,SS,5S)-6b: 1H NMR (CDCl3,
400 MHz) δ 1.25-2.12 (m, 10H), 2.63 (ddd, J ) 8.5 Hz, J )
10.2 Hz, J ) 14.3 Hz, 1H), 2.98 (ddd, J ) 2.6 Hz, J ) 6.8 Hz,
1200 J . Org. Chem., Vol. 69, No. 4, 2004

R-Sulfurated γ-Unsaturated Amides
2856, 1616, 1452, 1374, 1270, 1208, 1120, 1040, 912 cm-1
Anal. Calcd for C17H31O2S: C, 65.13; H, 9.97; N, 4.47. Found:
C, 64.98; H, 10.21; S, 4.37.
.
(FEDER funding). We also thank Ludovic Mortain and
Catherine Miniejew for their contribution to this work.
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support from the “Ministe`re de la Recherche et
des Nouvelles Technologies” (Virginie Blot), CNRS
(Centre National de la Recherche Scientifique), the
“Re´gion Basse-Normandie”, and the European Union
Su p p or tin g In for m a tion Ava ila ble: General procedure
and NMR spectra for various compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O035488B
J . Org. Chem, Vol. 69, No. 4, 2004 1201