Structural feature relevance of the chiral alkyl residue in the addition alkanesulfenic acids/enynes. Synthesis and diels-alder reactivity of enantiopure (E)-3-[(1S-exo)-2-bornylsulfinyl]-1methoxybuta-1,3-dienes

Full text of DOI:10.1021/jo981262a

2114
J . Org. Chem. 1999, 64, 2114-2118
Str u ctu r a l F ea tu r e Releva n ce of th e Ch ir a l
Alk yl Resid u e in th e Ad d ition
Alk a n esu lfen ic Acid s/En yn es. Syn th esis
a n d Diels-Ald er Rea ctivity of En a n tiop u r e
(E)-3-[(1S-exo)-2-Bor n ylsu lfin yl]-1-
m eth oxybu ta -1,3-d ien es
Maria C. Aversa,* Anna Barattucci,
Paola Bonaccorsi, and Placido Giannetto
Dipartimento di Chimica organica e biologica, Universita`
degli Studi di Messina, Salita Sperone 31 (vill. S. Agata),
98166 Messina, Italy
Francesco Nicolo`
Dipartimento di Chimica inorganica, chimica analitica e
chimica fisica, Universita` degli Studi di Messina, Salita
Sperone 31 (vill. S. Agata), 98166 Messina, Italy
Received J une 29, 1998
In tr od u ction
our interest in evaluating the role of the hydroxy function
of the alkyl residue in dienes 1a , and consequently the
influence of intramolecular hydrogen bonding in their
synthesis and reactivity. Our final purpose was the
assessment of structural characteristics required by
chiral precursors to be effective in the synthesis of our
enantiopure 2-sulfinyldienes to comprise a larger number
of terpene derivatives in the pool of suitable starting
products.
DA reactions of dienes 10 with N-phenylmaleimide
(NPM) or methyl acrylate, followed by removal of the
sulfinyl auxiliary, afforded highly functionalized and
enantiomerically pure cyclohexanones, useful intermedi-
ates in the synthesis of pseudosugars and related com-
pounds.2
The high degree of stereochemical control observed in
Diels-Alder (DA) reactions of enantiopure diene sulfox-
ides holds a large synthetic interest toward this novel
class of chiral dienes.1 Investigations of their reactivity
with common dienophiles have shown that cycloadditions
generally occur under mild conditions in good yields and
very high endo/exo and facial diastereoselectivities.
We have recently described the synthesis of 3-hydroxy-
alkylsulfinyl-1-methoxybuta-1,3-dienes 1 and their highly
stereocontrolled DA reactions with methyl acrylate in the
presence of LiClO4.1e The synthetic strategy for these
2-sulfinyldienes was based on the sulfenic acid/enyne
addition and counted four steps starting from enan-
tiopure hydroxyalkanethiols. The choice of hydroxythiols
R*SH (R* ) a -c) was mainly grounded on intramolecu-
lar hydrogen bonding between OH and SO functional-
ities, which sterically characterizes the corresponding
sulfenic acids, so enhancing the diastereoselectivity of
their reaction with enynes and facilitating the chromato-
graphic separation of the obtained diene epimers. A
comparative evaluation of synthetic potential of dienes
1 has confirmed the relevant utility of the camphor
skeleton included in the chiral auxiliaries based on
sulfoxides.
Resu lts a n d Discu ssion
The synthesis of (E)-3-[1S-exo)-2-bornylsulfinyl]-1-
methoxybuta-1,3-dienes 10 was performed starting from
thiol 5 and following the previously described procedure
(Scheme 1).1e Compound 5 was obtained, in two steps,
from the commercially available [(1S)-endo]-(-)-borneol
(3) using the Mitsunobu-Rollin reaction,3 followed by
LiAlH4 reduction.4 Thermolysis of cyanosulfoxides 7 in
the presence of (E)-1-methoxybut-1-en-3-yne (9)5 was
performed in mixed xylenes (140 °C).
Addition of sulfenic acids such as 2 or 8 to enynes opens
the way to the synthesis of 2-sulfinyl dienes that are not
easily accessible by different routes.1c,6 However, the most
common reaction of sulfenic acids is their self-condensa-
tion to thiosulfinates, and this behavior can represent a
We now report the synthesis of (E)-3-[1S-exo)-2-bornyl-
sulfinyl]-1-methoxybuta-1,3-dienes 10 (Scheme 1) in
which some of the crucial structural features, already
present in dienes 1a , were maintained, such as the highly
sterically demanding camphor skeleton and the methoxy
group. The directing effect of this last substituent guar-
antees complete regioselectivity in DA cycloadditions. We
designed the new sulfinyldienes 10, lacking in the
hydroxy substituent which is present in 1a , because of
(2) Acen˜a, J . L.; Arjona, O.; Ferna´ndez de la Pradilla, R.; Plumet,
J .; Viso, A. J . Org. Chem. 1994, 59, 6419-6424 and references therein.
(3) Rollin, P. Tetrahedron Lett. 1986, 27, 4169-4170.
(4) A previously reported procedure (Blanco, J . M.; Caaman˜o, O.;
Eirin, A.; Ferna´ndez, F.; Medina, L. Synthesis 1990, 584-586) for the
synthesis of thiol 5, from commercial borneol 3, was performed in three
steps and 59% total yield.
(5) Brandsma, L. Preparative Acetylenic Chemistry; Elsevier: Am-
sterdam, 1971.
(6) Ferna´ndez de la Pradilla, R.; Mart´ınez, M. V.; Montero, C.; Viso,
A. Tetrahedron Lett. 1997, 38, 7773-7776.
(1) (a) Arce, E.; Carren˜o, M. C.; Cid, M. B.; Garc´ıa Ruano, J . L. J .
Org. Chem. 1994, 59, 3421-3426. (b) Gosselin, P.; Bonfand, E.; Hayes,
P.; Retoux, R.; Maignan, C. Tetrahedron: Asymmetry 1994, 5, 781-
784. (c) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P.
Tetrahedron: Asymmetry 1997, 8, 1339-1367. (d) Carren˜o, M. C.; Cid,
M. B.; Garc´ıa Ruano, J . L.; Santos, M. Tetrahedron: Asymmetry 1997,
8, 2093-2097. (e) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.;
Giannetto, P.; J ones, D. N. J . Org. Chem. 1997, 62, 4376-4384.
10.1021/jo981262a CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/25/1999

Notes
J . Org. Chem., Vol. 64, No. 6, 1999 2115
Sch em e 1
F igu r e 1. Transition states (A) for the formation of diene 10R
and (B, lower energy) for 10S.
thiosulfinate formation, supports our interpretation. The
moderate diastereoselectivity observed in the addition of
sulfenic acid 8 to enyne 9 is interpretable on the basis of
relative stabilities of transition states originated from the
approach of enyne to the less hindered side of the sulfenic
moiety in 8. An evaluation of rotamers of (1S-exo)-2-
bornanesulfenic acid (8) around the C-S bond suggests
that the conformations of 8 depicted in Figure 1 are
almost equally populated. The predominance of diene 10S
among the reaction products can be ascribed to the
presence of the angular methyl group in 8, near the
reactive site, which causes unfavorable steric interactions
in the transition state A with respect to B, precursor of
major diene 10S (Figure 1). The two epimeric dienes were
readily separated by chromatography on silica gel, the
minor isomer 10R being much more mobile than the
major isomer 10S (TLC ∆Rf ) 0.25, EtOAc/petroleum
ether 70:30).
a
Reagents: (i) Zn[SC(S)NMe2]2, DEAD, Ph3P; (ii) LiAlH4; (iii)
CH2)CHCN, THF, Triton B, -78 up to 0 °C; (iv) m-CPBA, CH2Cl2,
0 °C; (v) mixed xylenes at reflux.
serious drawback in their synthetic use. Sulfenic acids
that form intramolecular hydrogen bonds are in general
less reactive in the thiosulfinate formation.7 Thus, the
less prone sulfenic acid is to thiosulfinate formation the
higher the yield in diene sulfoxides, when a trapping
enyne is added during the sulfenic acid generation by
thermolysis. We had these considerations in mind when
we chose to synthesize sulfenic acid 2 as the precursor
of dienes 1a , and the results confirmed the expectations.1e
However, the presence of an intramolecular hydrogen
bonding involves the presence of a hydroxy group in a
suitable position. This can be a limitation both for the
choice of starting products from the chiral pool and for
the chemical behavior of the synthesized diene systems,
i.e. some unexpected and undesired reactions of the
hydroxy function.8 Thiol 5 represented a suitable precur-
sor for the generation of sulfenic acid 8 with some
remarkable structural characteristics, such as the cam-
phor skeleton directly linked to the sulfur function, but
having no possibilities of forming intramolecular hydro-
gen bonds.
Although the concerted addition sulfenic acid 8/enyne
9 was less diastereoselective, if compared with previous
results concerning sulfenic acid 2,1e the epimeric mixture
of sulfinyldienes 10S and 10R was obtained in high yield
(75%). The high steric requirements of camphor residue
in 8 played a role similar to the one of intramolecular
hydrogen bonding in enhancing the sulfenic acid stability
and preventing thiosulfinate formation pro sulfenic acid/
enyne addition. The isolation of 9-triptycenesulfenic acid,9
which can be stabilized only by steric inhibition of
Cycloadditions of epimeric dienes 10S and 10R with
electron-deficient dienophiles were investigated (Scheme
2). Conditions and catalyst were selected on the basis of
preceding experience.1e
As concerns the diastereomeric
composition of the adduct mixtures, endo/exo and facial
ratios were established by NMR spectrometry from the
relative intensities of well-separated vinyl and methoxy-
carbonyl proton signals. The obtained results are col-
lected in Table 1.
The choice of dienophiles relapsed into methyl acrylate,
for comparing the efficiency of diene systems 10 with the
previously investigated 1a ,1e and NPM, for its intrinsic
ability to produce crystalline cycloadducts with very high
endo/exo and facial diastereoselectivities.10 As a matter
of fact, cycloadduct 11S was obtained as a unique and
crystalline product in the cycloaddition of diene 10S with
NPM (entry 1 in Table 1). It was recrystallized from ethyl
acetate, and its absolute configuration was established
as (1S,1′S,2S,2′S,4′S,6S,SS) by X-ray crystallographic
analysis (Flack parameter ) 0.06(9);11 Figure 2). This
result is in line with the configurational control on the
newly-formed stereogenic centers exerted by sulfur con-
figuration during the cycloaddition. Moreover, it confirms
the absolute configurations tentatively assigned to dienes
10 on the basis of the stereochemical outcome of the
sulfenic acid/enyne addition under study.
(9) Nakamura, N. J . Am. Chem. Soc. 1983, 105, 7172-7173.
(10) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P.;
Panzalorto, M.; Rizzo, S. Tetrahedron: Asymmetry 1998, 9, 1577-1587.
(11) Rogers, D. Acta Crystallogr. 1981, A37, 734-741. Flack, H. D.
Acta Cryst. 1983, A39, 876-881.
(7) Davis, F. A.; J enkins, L. A.; Billmers, R. L. J . Org. Chem. 1986,
51, 1033-1040.
(8) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Bruno, G.; Gian-
netto, P.; Nicolo`, F. J . Chem. Soc., Perkin Trans. 2 1997, 273-277.

2116 J . Org. Chem., Vol. 64, No. 6, 1999
Notes
Sch em e 2
Ta ble 1. Cycloa d d ition s of Su lfin yld ien es 10 w ith Meth yl Acr yla te a n d NP M in CH2Cl2 a t Room Tem p er a tu r e
adducts
entry
diene
dienophile
NPM
methyl acrylate
methyl acrylate
methyl acrylate
catalyst
time
endo
11S
12S:13S:
12S:13S:
13R:12R:
exo
(ratio)
100
38:26:25:11
93:7:0:0
1
2
3
4
10S
10S
10S
10R
none
none
LiClO4
none
2.5 h
20 d
5 h
14S:15S
14S:15S
15R:14R
20 d
44:34:13:9
Sch em e 3
F igu r e 2. Perspective view (with labeling scheme) of the
asymmetric unit represented by one molecule of 11S. Dotted
lines denote H interactions with another adjacent molecule
(dashed fragment) in the equivalent positions (i) ) 1 - x, -1/2
+ y, 1 - z. Thermal ellipsoids are drawn at 20% of probability
while hydrogen size is arbitrary.
acrylate in the presence of LiClO4 afforded only the two
endo cycloadducts 12S and 13S in a 93:7 ratio. This
stereochemical outcome can be interpreted as previously
described.1e 1H NMR data of 12-15 are in line with their
assigned absolute configurations. It is worthy of note that
our 3-methoxy-4-methoxycarbonyl cycloadducts, bearing
the sulfur functionality at C-1, always show conforma-
tional preferences such as the measured J 2,3 appear
indicatively affected by the steric relationship between
3-OMe and 4-CO2Me (J 2,3eq 4.0-4.6 for cis and J 2,3ax 1.9
for trans 3,4-disubstitution).
Cycloadduct 12S was converted into the polyfunctiona-
lyzed enantiopure cyclohexanone 18 by a sequence of
highly stereoselective reactions (Scheme 3). This pro-
cess2,13 was exploited after having unsuccessfully tried
common desulfurization reactions, such as Raney nickel
cleavage of the C-S bond. The cyclic vinyl sulfone 16 was
Reaction of major diene epimer 10S with methyl
acrylate gave rise to moderate facial and endo/exo dias-
tereoselectivities (entry 2 in Table 1), while the same
cycloaddition performed with the minor epimer 10R
showed an increased endo/exo diastereoselectivity (entry
4). Energy-minimized models of 10R and 10S were
compared by overlay of methoxydiene moieties to sulfur
atoms:12 the (1S-exo)-2-bornane group appears more
impending over the reactive diene faces in 10S than in
10R, and this increased sterical hindrance by the chiral
alkyl group in 10S should disfavor the formation of the
endo transition states. Cycloaddition of 10S with methyl
(12) Molecular Modeling Program: CS Chem3D Pro, version 3.5.
Force field: MM2.

Notes
J . Org. Chem., Vol. 64, No. 6, 1999 2117
obtained in high yield from cycloadduct 12S by m-CPBA
oxidation. The reaction of sulfone 16 with lithium tert-
butylperoxide afforded epoxide 17 as a unique compound,
showing a complete diastereoselectivity. Epoxide 17 was
used without further purification in the next and final
step of the process. Epoxide ring opening and concomitant
loss of the alkylsulfonyl group were achieved by means
of MgBr2‚Et2O, and diastereoselection was complete. The
stereochemistry depicted in the Scheme 3 for 17 and 18
opens the way to the use of such enantiopure cyclic
derivatives in target-oriented syntheses.
Exp er im en ta l Section
The general experimental information is similar to that
recently described.1e
(1S-exo)-2-Bor n yl N,N-Dim eth yldith iocar bam ate (4). Com-
pound 4 was obtained as a crystalline compound (71% yield) from
(1S-endo)-borneol (3), DEAD, Ph3P, and zinc dimethyldithiocar-
bamate (ZIRAM) following the previously reported procedure:1e
1
has been tentatively established on the basis of their H
mp 138 °C; [R]25 -10 (c 0.01, CHCl3); 1H NMR δ 4.38 (dd, 1H),
D
NMR resonances and taking into account previous re-
lated results.10 The proton resonance spectrum of bromo
derivative 18 shows H-4 resonating as a double doublet
of doublets, characterized by an axial-axial (11.5 Hz) and
an axial-equatorial coupling constant (5.5 Hz) with H2-
5. The axial preference of H-4, together with the absolute
configuration (3S,4S) of the cyclohexene 12S, used as
starting material, allows for the assignment of the
2S,3S,4S configuration to the resulting bromocyclohex-
anone 18 (Scheme 3), if we assume the clear preference
of Br substituent for the equatorial position.2,13d The
stereochemistry assigned to oxirane 17 is anchored to the
one of 18 owing to the bromine delivery from the face
opposite to the epoxide ring in its cleavage and removal
of sulfone moiety. Actually, the vicinal spin-spin cou-
pling constant J 2,3eq (4.4 Hz) in 16 is reduced to 1.8 Hz
in oxirane 17.
In conclusion, the structural features of the alkyl
residue directly linked to the sulfur function in enan-
tiopure 2-alkylsulfinyldienes play a relevant role in their
synthesis on the basis of sulfenic acid/enyne addition. A
comparison between previous work1e and results de-
scribed in this paper clearly points out that the presence
in the diene precursor of a functionality in the alkyl
residue, suitable to form intramolecular hydrogen bond
with the sulfoxide oxygen, constitutes an important but
not necessary requirement. It certainly enhances the
diastereoselectivity observed in the addition of sulfenic
acid to enyne causing a sharp preferential formation of
one sulfinyldiene epimer. However, the sterical require-
ments of the alkyl skeleton can be sufficient alone to
prevent self-condensation of sulfenic acid to thiosulfinate,
so increasing the total yield in dienes. Therefore, a large
number of monoterpene systems, some of which already
belonging to the chiral pool, can be used as starting
products in the synthesis of 2-sulfinyldienes based on
sulfenic acid/enyne addition.
3.56 (s, 3H), 3.37 (s, 3H), 2.08 (dd, 1H), 1.85 (m, 1H), 1.8-1.2
(m, 5H), 0.95 (s, 3H), 0.91 (s, 3H), 0.85 (s, 3H); 13C NMR δ 198.8,
58.7, 49.7, 47.6, 45.8, 45.6, 41.4, 39.1, 37.9, 27.2, 20.3, 19.8, 13.4;
MS/FAB m/z 258 (M + 1, 28), 137 (100), 122 (38), 88 (40), 81
(38). Anal. Calcd for C13H23NS2: C 60.65; H, 9.00. Found: C,
60.64; H, 9.00.
(1S-exo)-2-Bor n a n eth iol (5). Reduction of dimethyldithio-
carbamate 4 with LiAlH4 was performed as previously reported,1e
giving thiol 5 as a low-melting solid not needing purification
(92% yield): [R]25 +47.5 (c 5.06, CHCl3) [lit.4 mp 24-26 °C;
D
[R]25D +48.3 (c 11.8, MeOH)]; IR (CHCl3) 2990, 2954, 2878, 1455,
1389 cm-1; MS/FAB m/z 137 (M + 1 - H2S, 100), 138 (25), 136
(85), 107 (14), 81 (62), 77 (15).
(1S-exo)-2-Bor n yl 2-Cya n oeth yl Su lfid e (6). Bornanethiol
5 was reacted with acrylonitrile in the presence of benzyltrim-
ethylammonium hydroxide (Triton B) following the previously
reported procedure.1e The sulfide 6 was obtained as an oil, not
needing purification (96% yield): [R]25 +59.9 (c 5.09, CHCl3);
D
1H NMR δ 2.80 (split ABd, 1H), 2.72 (split ABd, 1H), 2.64 (dd,
1H), 2.59 (split t, 2H), 1.91 (dd, 1H), 1.84 (ddd, 1H), 1.7-1.1 (m,
5H), 0.97 (s, 3H), 0.92 (s, 3H), 0.81 (s, 3H); 13C NMR: δ 118.2,
54.8, 49.2, 47.0, 45.5, 40.7, 38.1, 29.8, 27.0, 20.1, 19.9, 18.8, 13.7;
IR (neat oil) 2951, 2876, 2249 (CN), 1455, 1389 cm-1; MS/FAB
m/z 224 (M + 1, 9), 223 (16), 138 (22), 137 (100), 95 (22), 81
(35).
m -CP BA Oxid a tion of Su lfid e 6. This reaction, performed
as previously described,1e gave (2-cyanoethyl)sulfoxides 7 (91%
yield, 1:1 mixture of sulfur epimers) usable for synthesizing
sulfinyldienes 10 without purification. The epimeric mixture can
be separated by column chromatography, eluting with petrol/
EtOAc (75:25). (1S-exo)-2-Bor n yl 2-cya n oeth yl (SS)-su lfoxid e
(7S): first eluted solid, mp 79-80 °C; [R]25 +41.5 (c 1.77,
D
1
CHCl3); H NMR δ 3.0-2.8 (m, 4H), 2.64 (dd, 1H), 2.37 (dddd,
1H), 1.90 (t, 1H), 1.9-1.2 (m, 4H), 1.49 (dd, 1H), 1.04 (s, 3H),
0.97 (s, 3H), 0.89 (s, 3H); 13C NMR δ 117.5, 69.4, 50.0, 48.2, 47.5,
45.1, 39.0, 28.2, 27.3, 20.0, 19.7, 13.4, 11.7; MS/FAB m/z 240 (M
+ 1, 8), 137 (100), 95 (19), 81 (45), 69 (19), 55 (21). (1S-exo)-2-
bor n yl 2-cya n oeth yl (RS)-su lfoxid e (7R): oil; [R]25 +89.4 (c
D
2.69, CHCl3); 1H NMR δ 3.1-2.6 (m, 5H), 1.8-1.2 (m, 7H), 1.21
(s, 3H), 0.96 (s, 3H), 0.90 (s, 3H); 13C NMR δ 117.7, 70.7, 50.0,
47.7, 44.8, 39.1, 31.3, 26.9, 20.0, 19.6, 13.7, 10.5; MS/FAB m/z
240 (M + 1, 14), 138 (22), 137 (100), 81 (23).14
Th er m olysis of Su lfoxid es 7 in th e P r esen ce of (E)-1-
Meth oxybu t-1-en -3-yn e (9). Sulfoxides 7 (1 g, 4.2 mmol) in
mixed xylenes (12 mL) containing enyne 9 (1.1 g, 13.5 mmol)
were maintained at reflux temperature. When the reaction
appeared complete by TLC (20 min), the solution was concen-
trated under reduced pressure and the obtained reaction mixture
was separated by column chromatography. First (RS,E)-3-[(1S-
exo)-2-bor n ylsu lfin yl]-1-m eth oxybu ta -1,3-d ien e (10R) was
eluted with petroleum ether/EtOAc (95:5) as a light yellow oil
The obtainment of epimeric dienes 10 in good yields,
and their easy separation by chromatography, represent
favorable elements from a synthetic point of view. Start-
ing from [(1S)-endo]-(-)-borneol, which is the only com-
mercially available enantiomer, we have obtained two
epimeric sulfinyldienes, with opposite sulfur configura-
tions, which were reacted separately in a DA manner
giving access to enantiopure cycloadducts of opposite
stereochemistry after removal of the alkylsulfinyl sub-
stituent.
(271 mg, 1.01 mmol, 24% yield): [R]25 +48.5 (c 1.25, CHCl3);
D
1H NMR δ 6.90 (d, 1H), 5.56 (s, 1H), 5.48 (s, 1H), 5.46 (d, 1H),
3.66 (s, 3H), 2.67 (dd, 1H), 2.24 (dddd, 1H), 1.8-1.2 (m, 6H),
1.11 (s, 3H), 0.98 (s, 3H), 0.86 (s, 3H); 13C NMR δ 151.3, 112.9,
98.3, 68.8, 56.7, 50.2, 47.1, 45.2, 39.4, 27.4, 26.3, 20.3, 19.6, 13.5;
Removal of the chiral auxiliary from our cycloadducts
represent an important achievement in this research and
(14) The sulfur configurations in 7R and 7S are tentatively assigned
taking into account the cogent analogies (chromatographic retention
times and NMR data) to epimeric dienes 10 whose absolute configura-
tions were allocated for a certainty on the basis of X-ray crystal-
lographic analysis of the adduct of diene 10S with NPM (Figure 1).
Note that the sulfur configuration in 7R is identical to that in 10S (and
7S to 10R), although they have different designations according to the
CIP system.
(13) (a) Durst, T.; Tin, K. C.; De Reinach-Hirtzbach, F.; Decesare,
J . M.; Ryan, M. D. Can. J . Chem. 1979, 57, 258-266. (b) Clark, C.;
Hermans, P.; Meth-Cohn, O.; Moore, C.; Taljaard, H. C.; van Vuuren,
G. J . Chem. Soc., Chem. Commun. 1986, 1378-1380. (c) J ackson, R.
F. W.; Standen, S. P.; Clegg, W.; McCamley, A. Tetrahedron Lett. 1992,
33, 6197-6200. (d) Bueno, A. B.; Carren˜o, M. C.; Garc´ıa Ruano, J . L.
Tetrahedron Lett. 1993, 34, 5007-5010.

2118 J . Org. Chem., Vol. 64, No. 6, 1999
Notes
MS/FAB m/z 269 (M + 1, 16), 138 (19), 137 (100), 81 (36), 57
(17), 39 (19). The less mobile (SS,E)-3-[(1S-exo)-2-bor n ylsu lfi-
n yl]-1-m eth oxybu ta -1,3-d ien e (10S) was eluted with petro-
leum ether/EtOAc (85:15) as a light yellow oil (542 mg, 2.02
CHCl3); 1H NMR δ 6.95 (dt, 1H), 4.19 (t, 1H), 3.74 (s, 3H), 3.43
(s, 3H), 3.05 (t, 1H), 2.69 (dt, 1H), 2.53 (ABdddd, 1H), 2.40
(ABdddd, 1H), 2.2-1.2 (m, 9H), 1.26 (s, 3H), 1.11 (s, 3H), 0.88
(s, 3H); 13C NMR δ 172.0, 142.7, 134.3, 72.7, 67.7, 57.8, 52.1,
51.8, 47.8, 44.8, 43.3, 40.5, 33.2, 26.7, 23.8, 20.7, 20.3, 19.7, 13.2;
MS/FAB m/z 371 (M + 1, 4), 217 (25), 137 (100), 95 (32), 93 (23),
81 (87).
mmol, 48% yield): [R]25 +10.1 (c 1.50, CHCl3); 1H NMR δ 7.08
D
(d, 1H), 5.64 (d, 1H), 5.55 (s, 1H), 5.41 (s, 1H), 3.68 (s, 3H), 2.68
(dd, 1H), 1.8-1.2 (m, 7H), 1.24 (s, 3H), 0.92 (s, 3H), 0.89 (s, 3H);
13C NMR δ 151.9, 115.7, 96.5, 96.1, 71.5, 56.7, 49.3, 47.9, 45.0,
39.0, 32.4, 27.1, 20.1, 19.7, 13.6; MS/FAB m/z 269 (M + 1, 14),
138 (11), 137 (100), 95 (11), 83 (14), 81 (39).
DA Cycloa d d ition s of Dien es 10 w ith Meth yl Acr yla te
a n d NP M. Some experimental conditions are reported in Table
1. All the cycloadditions were performed in CH2Cl2 (3 mL for
0.6 mmol of diene and 3.6 mmol of dienophile). In the catalyzed
cycloaddition, solid LiClO4 was added to the solution of diene
and dienophile in a diene/catalyst ratio of 1:0.8. The reaction
mixture was stirred until the diene was totally disappeared, as
verified by TLC monitoring, and the isolation of adducts was
performed by column chromatography. Total yields in cycload-
duct mixtures were always higher than 95%.
(1R,2R,3S,4S)-1-[(1S-exo)-2-Bor n ylsu lfon yl]-3-m eth oxy-
4-m eth oxyca r bon ylcycloh exen e Oxid e (17). BuLi 1.6 M in
hexanes (1.07 mL, 1.71 mmol) was added to a stirred solution
of t-BuOOH (0.52 mL of 3.3 M toluene solution,17 1.71 mmol) in
anhydrous THF (6 mL) at -78 °C, under nitrogen atmosphere.
After the mixture was stirred for 15 min, the sulfone 16 (210
mg, 0.57 mmol), dissolved in anhydrous THF (3 mL), was added
at -78 °C. The reaction mixture was allowed to reach room
temperature spontaneously, maintaining the stirring overnight,
and then quenched with saturated NaCl aqueous solution (5 mL)
and extracted with EtOAc (3 × 25 mL). The collected organic
layers were dried over Na2SO4, and the solvent was evaporated.
The epoxide 17 (200 mg, 0.52 mmol, 91% yield), obtained as a
low-melting solid, was used in the next step without further
purification: 1H NMR δ 4.13 (m, 1H), 3.97 (d, 1H), 3.73 (s, 3H),
3.47 (s, 3H), 3.21 (t, 1H), 2.8-1.2 (m, 12H), 1.22 (s, 3H), 1.06 (s,
3H), 0.88 (s, 3H); 13C NMR δ 172.3, 74.5, 72.5, 66.9, 59.1, 56.7,
53.0, 51.8, 47.5, 45.2, 40.7, 40.4, 32.9, 26.9, 22.1, 17.2, 20.5, 19.9,
13.7; MS/FAB m/z 387 (M + 1, 4), 185 (41), 137 (100), 95 (41),
91 (35), 81 (88).
(2S ,3S ,4S )-2-Br om o-3-m e t h oxy-4-m e t h oxyc a r b on yl-
cycloh exa n on e (18). An ethereal solution of MgBr2 was
prepared by reacting Mg (126 mg, 5.2 mmol) with a solution of
BrCH2CH2Br (0.45 mL, 5.2 mmol) in Et2O (15 mL). The mixture
was stirred at room temperature for 30 min, and a solution of
epoxide 17 (200 mg, 0.52 mmol) in THF (5 mL) was added. The
stirring was continued at room temperature, checking the
disappearance of the starting product by TLC (CH2Cl2/EtOAc
90:10) and 1H NMR. After completion of the reaction (ap-
proximately 72 h), a saturated aqueous solution of NaCl was
added. The reaction mixture was extracted with Et2O, and the
organic extracts were dried over Na2SO4 and concentrated under
reduced pressure. The crude product was purified by column
chromatography (petroleum ether/CH2Cl2 75:25) affording 111
(1S,2S,6S,SS)-4-[(1S-exo)-2-Bor n ylsu lfin yl]-2-m eth oxy-8-
p h en yl-8-a za bicyclo[4.3.0]n on -3-en e-7,9-d ion e (11S). Com-
pound 11S was the only product of the cycloaddition between
10S and NPM (entry 1 in Table 1). Its isolation was achieved by
column chromatography eluting with CH2Cl2/EtOAc 80:20: mp
1
210-211 °C; [R]25 -170.4 (c 0.18, CHCl3); H NMR δ 7.5-7.3
D
(m, 5H), 6.74 (dd, 1H), 4.52 (dd, 1H), 3.46 (ABdd, 1H), 3.36 (ddd,
1H), 3.13 (dd, 1H), 2.72 (t, 1H), 2.26 (ABddd, 1H), 1.6-1.2 (m,
7H), 1.25 (s, 3H), 0.95 (s, 3H), 0.90 (s, 3H); MS/FAB m/z 442 (M
+ 1, 4), 274 (33), 137 (100), 81 (77), 57 (31), 55 (32).
Cycloa d d u cts fr om d ien e 10S a n d m eth yl a cr yla te (en-
tries 2 and 3 in Table 1) are reported in order of increasing
retention times on chromatographic column (eluant petroleum
ether/EtOAc 75:25).
(3R,4R,SS)-1-[(1S-exo)-2-bor n ylsu lfin yl]-3-m eth oxy-4-m eth -
oxycar bon ylcycloh exen e (13S): mp 193-195 °C; [R]25D +187.4
(c 0.29, CHCl3); 1H NMR δ 6.55 (split d, 1H), 4.15 (dd, 1H), 3.75
(s, 3H), 3.40 (s, 3H), 2.92 (m, 1H), 2.66 (dd, 1H), 2.54 (dt, 1H),
2.1-1.1 (m, 10H), 1.23 (s, 3H), 0.92 (s, 3H), 0.89 (s, 3H); 13C
NMR δ 172.3, 146.1, 130.7, 72.3, 69.9, 57.5, 51.8, 49.2, 47.8, 45.4,
44.9, 38.8, 32.4, 27.1, 20.0, 19.8, 19.1, 18.8, 13.6; MS/FAB m/z
355 (M + 1, 14), 155 (21), 149 (70), 138 (28), 137 (100).
(3S,4S,SS)-1-[(1S-exo)-2-Bor n ylsu lfin yl]-3-m eth oxy-4-m eth -
oxycar bon ylcycloh exen e (12S): mp 105-107 °C; [R]25D -119.3
(c 1.04, CHCl3); 1H NMR δ 6.49 (dt, 1H), 4.15 (t, 1H), 3.73 (s,
3H), 3.40 (s, 3H), 2.81 (dt, 1H), 2.71 (t, 1H), 2.5-1.2 (m, 11H),
1.22 (s, 3H), 0.92 (s, 3H), 0.89 (s, 3H); 13C NMR δ 172.3, 145.2,
131.8, 73.4, 70.1, 57.6, 51.7, 49.3, 47.8, 45.0, 43.5, 38.9, 32.3,
27.0, 20.0, 19.9, 19.8, 19.2, 13.6; MS/FAB m/z 355 (M + 1, 10),
187 (14), 138 (12), 137 (100), 95 (12), 81 (43).15
mg (0.42 mmol) of 18 (80% yield) as a low-melting solid: [R]25
D
-67.0 (c 0.36, CHCl3); 1H NMR δ 4.24 (d, 1H), 4.24 (split dd,
1H), 3.76 (s, 3H), 3.43 (ddd, 1H), 3.41 (s, 3H), 3.04 (ddd, 1H),
2.4-2.2 (m, 3H); 13C NMR δ 202.7, 172.3, 83.0, 58.4, 52.2, 45.6,
40.6, 34.1, 22.0; MS/EI m/z 234 (15) and 232 (15) (M - MeOH),
207 (5) and 205 (6) (M - CO2Me), 149 (100).
Ack n ow led gm en t . Financial support from the
(3R ,4R ,R S )-1-[(1S -exo)-2-Bor n ylsu lfin yl]-3-m e t h oxy-
4-m eth oxyca r bon ylcycloh exen e (13R). It was the main prod-
uct of the cycloaddition between 10R and methyl acrylate (entry
4 in Table 1). Its isolation was achieved by column chromatog-
raphy eluting with petroleum ether/Et2O 70:30: mp 114-115
°C; [R]25D +196.2 (c 0.40, CHCl3); 1H NMR δ 6.60 (ddd, 1H), 4.16
(t, 1H), 3.74 (s, 3H), 3.40 (s, 3H), 2.67 (dt, 1H), 2.52 (dd, 1H),
2.3-1.1 (m, 11H), 1.11 (s, 3H), 0.99 (s, 3H), 0.87 (s, 3H); 13C
NMR δ 172.4, 146.9, 126.5, 72.6, 67.8, 57.5, 51.7, 50.1, 47.1, 45.2,
44.8, 39.5, 27.3, 26.9, 22.6, 20.3, 19.6, 19.5, 13.4.16
MURST of Italy is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal information, X-ray crystallographic data for 11S, NMR
assignments, spin-spin coupling constants, and copies of NMR
spectra for compounds 4-6, 7R, 7S, 10R, 10S-13S, 13R, and
16-18. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O981262A
(3S,4S)-1-[(1S-exo)-2-Bor n ylsu lfon yl]-3-m eth oxy-4-m eth -
oxyca r bon ylcycloh exen e (16). m-CPBA oxidation of the ad-
duct 12S, performed as previously described,1e gave the sulfo-
nylcyclohexene 16 (215 mg, 0.58 mmol, 98% yield), which did
(16) Major endo adduct 13R was the less mobile product. Minor endo-
12R [(3S,4S,RS), more mobile adduct] and exo adducts 14R (3S,4R,RS)
and 15R (3R,4S,RS), showing different retention times, intermediate
between the ones of 12R and 13R, were not isolated but easily
recognized in the chromatographic fractions having different composi-
tions. Typical 1H NMR resonances such as vinyl multiplets and 4-CO2-
Me singlets were monitored: 12R (6.62 and 3.39), 14R (6.45 and 3.42),
15R (6.45 and 3.43 ppm).
not need any purification: mp 95-97 °C; [R]25 -77.0 (c 1.08,
D
(15) Minor exo-adducts 15S (3R,4S,SS) and 14S (3S,4R,SS), showing
intermediate retention times between 13S and 12S, were not isolated
but only recognized in the crude adduct mixture by typical 1H NMR
resonances such as vinyl multiplets at δ 6.39 and 6.36, respectively.
(17) Pfenninger, A. Synthesis 1986, 89-115.