Toward a total synthesis of okilactomycin. 2. A metathesis-based approach to the heavily functionalized cyclohexane ring

Article abstract of DOI:10.1055/s-2002-28511

An attempt to access in an enantioselective fashion, a highly substituted cyclohexane as required for the northeastern sector of okilactomycin is described. The application of Oppolzer's sultam chemistry, involving in particular an optically and chemicall

Full text of DOI:10.1055/s-2002-28511

PAPER
895
Toward a Total Synthesis of Okilactomycin. 2. A Metathesis-Based Approach
to the Heavily Functionalized Cyclohexane Ring
Toward a
T
ota
e
l
S
ynthesis
r
of Okila
g
c
tomycin e L. Boulet, Leo A. Paquette*
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210, USA
Fax +1(614)2921685; E-mail: paquette.1@osu.edu
Received 19 November 2001; revised 14 March 2002
Abstract: An attempt to access in an enantioselective fashion, a
highly substituted cyclohexane as required for the northeastern sec-
tor of okilactomycin is described. The application of Oppolzer’s
sultam chemistry, involving in particular an optically and chemical-
CO2Me
O
N
RO
O
O
ly efficient asymmetric conjugate addition of a functionalized ally-
lic Grignard reagent in tandem with ring closing metathesis forms
the basis of a direct, highly stereocontrolled route to the cyclohex-
enylmethanol 10. Ensuing Sharpless epoxidation very efficiently
leads to construction of epoxide 11. This intermediate and its benzyl
ether were found to undergo regiocontrolled oxirane ring cleavage
with cyanide and chloride ions. However, this precedence was not
matched when alternative carbon nucleophiles (particularly allyl)
were brought into play. Under no circumstances was a desired prod-
uct detected. The all-equatorial array of substituents on the cyclo-
hexane is likely responsible for the lack of reactivity toward
organometallic reagents.
SO2
BnO
O
1
2
Scheme 1
The pathway to 2 began by capitalizing on the ability of
enoyl sultam 3 to enter into conjugate addition reactions
with high diastereoselectivity.2,3 However, the envisioned
pathway to 2 required that a functionalized allylic reagent
participate in 1,4-conjugate addition to the sultam, a reac-
tion that has not been demonstrated with much success.
The functionalized Grignard reagent 4 planned as the re-
action partner proved expectedly to be an ill-behaved spe-
cies. Notwithstanding, adaptation of those conditions
recently uncovered by Lipshutz4 caused the conversion to
5 to be exceptionally workable (Scheme 2). Only when
CuBr SMe2, lithium chloride, and chlorotrimethylsilane
are present in combination with 1.2 equivalents of 4 was
5 produced efficiently (98% yield, >95% de). For several
reasons, confirmation of the stereochemical course of the
Key words: metathesis, sultams, cyanation, carbocupration, ep-
oxide, asymmetric conjugate addition
In the preceding article,1 a retrosynthetic analysis of
okilactomycin was outlined in which the coupling of an
aldehyde to a highly functionalized cyclohexane related to
1 was defined. Herein, we report an approach to 2
(Scheme 1), which employs an asymmetric conjugate ad-
dition plus a ring-closure metathesis reaction and demon-
strate the limited reactivity profile of its oxirane ring.
CuBr•SMe2,
LiCl, Me3SiCl
O
ClMg
OPMB
THF, -78 °C
98%
(>95% de)
N
SO2
3
4
O
O
KHMDS;
RO
N
PMBO
I
N
SO2
SO2
HMPA, THF
-78 ºC
64%
6, R = PMB
7, R = H
(>95% de)
DDQ
97%
5
Scheme 2
Synthesis 2002, No. 7, 21 05 2002. Article Identifier:
1437-210X,E;2002,0,07,0895,0900,ftx,en;M05701SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

896
S. L. Boulet, L. A. Paquette
PAPER
conjugate addition reaction was considered advisable. For drogenation of 8, the chiral auxiliary was replaced by
example, the 1,4-addition of simple alkyl Grignard re- means of methoxymagnesium bromide,6 and the resulting
agents to chiral enoylsultams in the presence3 or absence2 methyl ester was reduced with DIBAL-H at 0 °C. The
of a catalytic amount of copper salt has been shown to af- [ ]D22 of alcohol 9 was determined to be 1.67 in CHCl3,7
ford opposite diastereomers. Also, related reactions in- and must therefore be the S enantiomer8 as required for
volving phosphine-stabilized organocopper species occur okilactomycin.
with opposite face stereodifferentiation when mediated by
Acylated camphorsultams have also been shown to be
BF3 OEt2 or EtAlCl2.5 In the present instance, stere-
useful chiral auxiliaries for stereoselective -alkylation,
ochemical proof was gained by adding allylmagnesium
bromide to 3 under totally analogous conditions. As be-
fore, the yield of 8 was nearly quantitative and the de was
excellent (>95%) (Scheme 3). Following the catalytic hy-
although competitive C C bond formation involving the
activated methylene group adjacent to the sulfonamide
functionality has been noted.9 After considerable experi-
mentation, it was found that the enolization of 5 with 1.05
equivalents of KHMDS in THF at 78 °C followed by ad-
dition of a solution of allyl iodide in THF/HMPA at this
temperature gave rise to 6 in an optimized 64% yield. The
high diastereomeric purity of 6 (>95% ee) is likely due to
the cooperative contributions arising from the two chiral
components resident in 5.
MgBr
CuBr•SMe2
O
3
LiCl, Me3SiCl
THF, -78 °C
96%
N
SO2
With 6 in hand, attention was focused on building of the
six-membered cycle via ring closing metathesis.10 For rea-
sons of economy of catalyst, the feasibility of removing
the PMB group first was investigated, notwithstanding
our awareness of the problems that allylic hydroxyls can
sometimes bring on in the presence of a ruthenium cata-
lyst.11 Fortunately in this instance, only the activating ef-
fect of the OH group10b,11,12 manifested itself. Indeed, as
shown in Scheme 4, stirring 7 with only 0.75 mol percent
of the Grubbs catalyst in CH2Cl2 at 20 °C led very conve-
(>95% de)
8
1. H2, Pd/C
2. MeOMgBr,
OH
MeOH, THF
3. DIBAL-H,
CH2Cl2, 0 °C
9
[α]2D2 -1.67
Scheme 3
PCy3
Cl
Ru
Ti(Oi-Pr)4
(-)-DET
Cl
O
Ph
PCy3
7
TBHP, CH2Cl2
4Å MS, -20 °C
84%
CH2Cl2, rt
97%
N
SO2
HO
(>95% de)
10
O
N
O
NaH, THF
Bu4NI, BnBr
N
or
PvCl, CH2Cl2
0 °C
20-44%
SO2
SO2
HO
RO
O
O
H
H
12, R = Bn
13, R = Piv
11
TiCl4 or
Ti(Oi-Pr)2Cl2,
Ti(Oi-Pr)4
KCN, Bu4NI
DMSO, rt
83%
SiMe3
28%
O
O
N
N
SO2
SO2
HO
BnO
HO
CN
HO
Cl
14
15
Scheme 4
Synthesis 2002, No. 7, 895–900 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Toward a Total Synthesis of Okilactomycin
897
niently to 10 in 97% isolated yield. Cyclohexenyl alcohols
similar to 10 have been successfully epoxidized under
Sharpless conditions with acceptable selectivities.13 In
line with this precedent, the use of ( )-diethyl tartrate af-
forded the desired epoxide 11. The diastereomeric bias
was very high (>95% de), with only one epoxy alcohol in
O
O
Aux
N
TiCl4
O
SO2
O
O
Si
Cl
17
O
1
H
evidence upon high-field H NMR analysis. The feature
Si
Cl3Ti
that all of the ring substituents in 11 are equatorial likely
contributes to the exceptionally high stereoselectivity ob-
served in this step.
16
The aldehyde obtained from 11 by tetrabutylammonium
perruthenate oxidation proved to be a very unstable sub-
stance, decomposing readily under mild conditions in-
cluding the Noyori protocol for acetalization with 1,2-
bis(trimethylsiloxy)ethane at 78 °C.14 As a consequence,
our focus was redirected to deferral of this oxidative step
to a later stage.
O
N
SO2
HO
HO
18
The opening of cyclohexane epoxides is generally recog-
nized to be a difficult process due to unfavorable stere-
oalignment issues, although many successful examples
have been reported. Notwithstanding, 11 and its protected
derivatives 12 and 13 proved to be totally resistant to the
action of such reagents as allylCu(CN)Li2, allylMgBr/Cu-
Br SMe2/BF3 OEt2, allylSnBu3/Ti(i-PrO)4, allylSiMe3/
Ti(i-PrO)4, allylMn(Me)2Li, allylTi(i-PrO)3 and the like.
When recourse was made to allylSiMe3 in the presence of
TiCl4 or Ti(i-PrO)2Cl2, 12 was transformed in modest
yield into the chlorohydrin 15, the chloride ion from the
Lewis acid serving as the nucleophile. A still more suc-
cessful transformation involved the conversion of 11 into
14 (83%) upon exposure of the epoxy alcohol to Ti(i-
PrO)4, KCN, and BuN+I– in DMSO at room temperature.15
Scheme 5
at r.t. for 30 min, heated at reflux for 1 h, cooled to r.t., and poured
into a pressure-equalizing dropping funnel. The reaction flask was
rinsed with anhyd THF (50 mL). This mixture was added dropwise
over 90 min to a stirred soln of 3-chloro-2-(chloromethyl)-1-pro-
pene (65.01 g, 520 mmol) in anhyd THF (400 mL). The dropping
funnel was rinsed with anhyd THF (50 mL). The reaction mixture
was stirred at r.t. overnight and then poured into a separatory funnel
containing Et2O (250 mL), hexanes (250 mL), brine (500 mL), and
H2O (500 mL). The separated aq layer was extracted with Et2O
hexanes, 1:1. The combined organic extracts were washed with
H2O, dried, and concentrated under reduced pressure, and purified
by flash chromatography (EtOAc hexanes, 7:93) to afford 54.33 g
(75%) of the monoether as a pale yellow oil.
1H NMR (500 MHz, CDCl3): = 3.81 (s, 3 H), 4.09 (br s, 2 H), 4.13
(br s, 2 H), 4.46 (br s, 2 H), 5.26 (br s, 1 H), 5.32 (br s, 1 H), 6.89
(d, J = 8.6 Hz, 2 H), 7.28 (d, J = 8.6 Hz, 2 H).
13C NMR (125 MHz, CDCl3): = 45.2, 55.2, 70.0, 72.0, 113.8 (2
C), 116.7, 129.3 (2 C), 130.1, 142.1, 159.3.
Our hope to introduce the required allyl substituent ulti-
mately rested on the allyldimethylsilyl ether 16, whose
role was to enter into intramolecular allyl transfer in the
presence of TiCl416 (see 17, Scheme 5). However, this ex-
tension of Reetz’s work proved unsuccessful as well.
These insights revealed that the usual explanations ad- HRMS (EI): m/z calcd for C12H15ClO2 (M+), 226.0761; found,
226.0768.
vanced for the unreactive topology of cyclohexene oxides
are valid for the systems specifically substituted as in 11
Acylsultam 5
13. In the final analysis, the susceptibility of 11 and 12 to
To a mechanically stirred suspension of freshly ground magnesium
nucleophilic oxirane ring opening by chloride and cyanide
turnings (58.22 g, 2.39 mol) in anhyd, degassed THF (900 mL) was
ion cannot be exploited for alkenyl C C bond formation.
Alternative routes to 1 obviously require development.
Their development is currently in progress.
added 1,2-dibromoethane (5.2 mL, 0.060 mol) via syringe. (The an-
hyd THF was degassed by repeated cycles of exposing the anhyd
solvent to house vacuum during sonication and subsequent purging
with argon). After a slight induction period (1 3 min), evolution of
gas was observed and the reaction was slightly exothermic. The re-
action mixture was stirred at r.t. for 30 min and a soln of the allylic
chloride (54.3 g, 0.240 mol) in anhyd, degassed THF (225 mL) was
introduced dropwise during 5.5 h. After an additional 1.5 h, the stir-
rer was removed, the flask was stoppered and stored in the freezer
(~ 5 °C) overnight to give a gray-colored soln of 4 in a total vol-
ume of 1105 mL of THF. Titration established the concentration to
be 0.12 M (55%).17
Melting points are uncorrected. The column chromatographic sepa-
rations were performed with Woelm silica gel (230 400 mesh).
Solvents were reagent grade and in most cases dried prior to use.
The purity of all compounds was shown to be approximately >95%
by TLC and high field 1H and 13C NMR spectroscopy. The high-res-
olution mass spectra were obtained at the Ohio State University
Campus Chemical Instrumentation Center. Elemental analyses
were performed at Atlantic Microlab, Inc., Norcorss, GA.
A suspension of CuBr Me2S (30.52 g, 148.5 mmol) and anhyd LiCl
(6.78 g, 160 mmol) in anhyd THF (250 mL) was stirred at r.t. for
15 20 min and added via cannula to a cold ( 78 °C) stirred soln of
418 (1100 mL, 0.12 M in THF, 132 mmol) from above. The reaction
flask was rinsed with anhyd THF (10 mL). To the reaction mixture
2-(Chloromethyl)-3-p-(methoxybenzyloxy)propene
A stirred suspension of anhyd, oil-free NaH (10.0 g, 417 mmol) in
anhyd THF (300 mL) was treated dropwise with a soln of 4-meth-
oxybenzyl alcohol (44.24 g, 320 mmol) in anhyd THF (70 mL). An-
hyd DMF (80 mL) was added and the reaction mixture was stirred
Synthesis 2002, No. 7, 895–900 ISSN 0039-7881 © Thieme Stuttgart · New York

898
S. L. Boulet, L. A. Paquette
PAPER
was added TMSCl (19 mL, 150 mmol) followed by a soln of 3
(32.36 g, 114 mmol) in anhyd THF (260 mL) via an addition funnel.
The funnel was rinsed with anhyd THF (30 mL). The reaction mix-
ture was stirred at 78 °C for 90 min, diluted with aq NH4Cl-
NH4OH (pH 8 9, 200 mL), warmed to r.t., and stirred until the aq
layer was a deep blue color. Et2O and H2O were added, the separat-
ed aq layer was extracted with Et2O, the combined organic extracts
were washed successively with H2O and brine, dried, and concen-
trated. The residue consisted of only one diastereomer as indicated
by high field 1H NMR (> 95% de). To the crude oil thus obtained
was added MeOH (50 mL) hexanes (100 mL), and the soln was
stored in the freezer (~ –5 °C) overnight to afford colorless crystals.
The crystals were filtered and the mother liquor was concentrated in
advance of flash chromatography (EtOAc hexanes, 2:8). There
was isolated a total of 53.48 g (98%) of 5 as colorless crystals; mp
53.5–55 °C.
113.3, 113.7 (2 C), 117.2, 129.2 (2 C), 130.6, 135.0, 144.2, 159.1,
174.3.
HRMS (EI): m/z calcd for C29H41NO5S (M+), 515.2705; found,
515.2675.
Anal. Calcd for C29H41NO5S (515.71): C, 67.54; H, 8.01. Found: C,
67.36; H, 8.01.
Deprotection of 6
To a vigorously stirred soln of 6 (20.00 g, 38.64 mmol) in CH2Cl2
(390 mL) and H2O (39 mL) was added DDQ (13.18 g, 58.1 mmol).
The reaction mixture turned green immediately and faded to orange
over time with the formation of a precipitate. After 45 min, sat.
NaHCO3 soln (200 mL) and H2O were added to the reaction mix-
ture, the separated aq layer was extracted with CH2Cl2, and the com-
bined organic extracts were washed with H2O, dried, and
concentrated. The residue was recrystallized from MeOH hexanes
with cooling in the freezer. The acquired colorless crystals were fil-
tered and the mother liquor was concentrated and purified by flash
chromatography (EtOAc hexanes, 2:3) to give a total of 14.76 g
(97%) of 7 as a colorless solid; mp 108 108.5 °C.
[ ]D22 +68.6 (c 3.4, CHCl3).
1
IR (neat): 1694, 1612, 1513, 1455, 1329 cm .
1H NMR (500 MHz, CDCl3): = 0.952 (d, J = 6.5 Hz, 3 H), 0.954
(s, 3 H), 1.13 (s, 3 H), 1.22–1.42 (m, 3 H), 1.81–1.92 (m, 2 H), 1.98–
2.12 (m, 4 H), 2.28–2.38 (m, 1 H), 2.49 (dd, J = 16.1, 7.6 Hz, 1 H),
2.75 (dd, J = 16.1, 5.8 Hz, 1 H), 3.44 (ABq, JAB = 13.8 Hz,
AB = 27.4 Hz, 2 H), 3.80 (s, 3 H), 3.86 (dd, J = 6.6, 6.6 Hz, 1 H),
3.92 (ABq, JAB = 12.8 Hz, AB = 14.8 Hz, 2 H), 4.42 (ABq,
JAB = 11.5 Hz, AB = 8.6 Hz, 2 H), 4.94 (br s, 1 H), 5.09 (br s, 1 H),
6.87 (d, J = 8.6 Hz, 2 H), 7.27 (d, J = 8.6 Hz, 2 H).
13C NMR (75 MHz, CDCl3): = 19.6, 20.8, 26.5, 28.0, 32.8, 38.5,
40.8, 42.8, 44.7, 47.7, 48.3, 53.0, 55.2, 65.2, 71.7, 72.4, 113.6,
113.7 (2 C), 129.2 (2 C), 130.6, 144.0, 159.1, 171.3 (one signal not
observed).
[ ]D22 +87.6 (c 5.3, CHCl3).
1
IR (neat): 3490, 1638, 1456, 1393 cm .
1H NMR (300 MHz, CDCl3): = 0.93 (d, J = 6.7 Hz, 3 H), 0.95 (s,
3 H), 1.15 (s, 3 H), 1.28–1.45 (m, 2 H), 1.64 (br s, 1 H), 1.75 (dd,
J = 13.9, 11.1 Hz, 1 H), 1.80–1.94 (m, 3 H), 1.97–2.12 (m, 3 H),
2.36–2.55 (m, 3 H), 3.02 (ddd, J = 8.0, 8.0, 5.0 Hz, 1 H), 3.46 (ABq,
JAB = 13.8 Hz, AB = 18.1 Hz, 2 H), 3.90 (dd, J = 6.4, 6.4 Hz, 1 H),
4.03 (br s, 2 H), 4.87 (br s, 1 H), 4.98 (dd, J = 10.1, 0.8 Hz, 1 H),
5.06 (dd, J = 17.1, 1.6 Hz, 1 H), 5.07 (br s, 1 H), 5.73–5.88 (m, 1 H).
13C NMR (75 MHz, CDCl3): = 17.4, 19.9, 20.8, 26.4, 32.0, 32.9,
35.0, 36.6, 38.5, 44.6, 47.7, 48.0, 50.0, 53.3, 65.5, 65.6, 111.1,
117.3, 134.9, 147.0, 174.4.
HRMS (EI): m/z calcd for C26H38NO5S (M + 1)+, 476.2471; found,
476.2367.
Anal. Calcd for C26H37NO5S (475.64): C, 65.66; H, 7.84. Found: C,
65.37; H, 7.86.
HRMS (EI): m/z calcd for C21H32NO4S (M+–1), 394.2052; found,
394.2033.
Anal. Calcd for C21H33NO4S (394.54): C, 63.93; H, 8.17. Found: C,
63.73; H, 8.29.
Allylation of 5
To a cold (–78 °C) stirred soln of 5 (47.37 g, 99.6 mmol) in anhyd
THF (500 mL) was added KHMDS (218 mL, 0.48 M in toluene,
104.6 mmol) dropwise over 20 min. The reaction mixture was
stirred at –78 °C for 1.5 h, a soln of allyl iodide (50.19 g, 299 mmol)
and anhyd HMPA (52.0 mL, 299 mmol) in anhyd THF (150 mL)
was added over 10 min, and the reaction mixture was stirred at –78
°C for 70 min before dilution with H2O (200 mL), brine (200 mL)
and warming to r.t. Et2O was added and the separated aq layer was
extracted with Et2O. The combined organic extracts were washed
with H2O, dried, and concentrated under reduced pressure. The res-
idue consisted of only one diastereomer as indicated by high field
1H NMR (> 95% de). Purification by flash chromatography
(EtOAc hexanes, 2:8) afforded 6 (33.18 g, 64%) as a colorless sol-
id; mp 92–93 °C.
Cyclization of 7 by Ring-Closing Metathesis
To a soln of 7 (11.85 g, 30.0 mmol) in anhyd CH2Cl2 (550 mL) was
added a soln of the Grubbs’ catalyst (183 mg, 0.22 mmol) in anhyd
CH2Cl2 (50 mL) via cannula. The soln was stirred at r.t. for 23 h pri-
or to solvent evaporation, and the residue was twice recrystallized
from MeOH. The mother liquor was purified by flash chromatogra-
phy (EtOAc hexanes, 2:3) to furnish a total of (10.73 g, 97%) of 10
as a colorless solid: m.p. 209–211 °C.
[ ]D22 +158 (c 3.5, CHCl3).
1
IR (neat): 3302, 1681, 1400, 1326 cm .
1H NMR (300 MHz, CDCl3): = 0.96 (s, 3 H), 1.00 (d, J = 6.2 Hz,
3 H), 1.13 (s, 3 H), 1.28–1.46 (m, 2 H), 1.54 (br s, 1 H), 1.72–1.93
(m, 4 H), 2.01–2.22 (m, 5 H), 2.44 (br d, J = 16.7 Hz, 1 H), 2.89
(ddd, J = 10.7, 10.7, 5.2 Hz, 1 H), 3.47 (ABq, JAB = 13.8 Hz,
AB = 16.8 Hz, 2 H), 3.92 (dd, J = 6.2, 6.2 Hz, 1 H), 3.98 (br s, 2 H),
5.63 (br s, 1 H).
13C NMR (125 MHz, CDCl3): = 19.5, 19.8, 20.8, 26.4, 29.7, 30.6,
32.8, 33.4, 38.5, 44.6, 47.4, 47.7, 48.2, 53.2, 65.0, 66.7, 120.0,
137.4, 175.1.
[ ]D22 +54.3 (c 3.1, CHCl3).
1
IR (neat): 1680, 1649, 1613, 1586, 1513 cm .
1H NMR (300 MHz, CDCl3): = 0.93 (d, J = 6.6 Hz, 3 H), 0.96 (s,
3 H), 1.16 (s, 3 H), 1.24–1.48 (m, 2 H), 1.76 (dd, J = 13.8, 11.4 Hz,
1 H), 1.82–1.93 (m, 3 H), 2.01–2.16 (m, 3 H), 2.34–2.57 (m, 3 H),
3.01 (ddd, J = 8.3, 8.3, 4.6 Hz, 1 H), 3.45 (ABq, JAB = 16.9 Hz,
AB = 24.9 Hz, 2 H), 3.80 (s, 3 H), 3.82–3.96 (m, 1 H), 3.90 (ABq,
JAB = 11.5 Hz, AB = 8.6 Hz, 2 H), 4.42 (ABq, JAB = 11.9 Hz,
HRMS (EI): m/z calcd for C19H29NO4S (M+), 367.1817; found,
367.1801.
AB = 20.2 Hz, 2 H), 4.93 (br s, 1 H), 4.96 (dd, J = 10.2, 0.7 Hz, 1
H), 5.04 (dd, J = 17.0, 1.0 Hz, 1 H), 5.10 (br s, 1 H), 5.73 (m, 1 H),
6.87 (d, J = 8.6 Hz, 2 H), 7.27 (d, J = 8.6 Hz, 2 H).
13C NMR (75 MHz, CDCl3): = 17.4, 19.9, 20.8, 26.4, 31.9, 32.9,
35.3, 37.0, 38.5, 44.6, 47.7, 47.9, 50.3, 53.3, 55.2, 65.5, 71.7, 72.5,
Anal. Calcd for C19H29NO4S (367.50): C, 62.10; H, 7.95. Found: C,
61.84; H, 7.84.
Synthesis 2002, No. 7, 895–900 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Toward a Total Synthesis of Okilactomycin
899
Asymmetric Epoxidation of 10
HRMS (EI): m/z calcd for C26H35NO5S (M+), 473.2236; found,
To a cold (–20 °C) stirred soln of (–)-diethyl tartrate (680 mg, 3.30
mmol) in anhyd CH2Cl2 (170 mL) containing freshly activated,
dried, and crushed 4 Å molecular sieves (13.8 g) was added neat
Ti(i-PrO)4 (0.81 mL, 2.74 mmol) and stirring was maintained at –20
°C for 20 min. A soln of 10 (10.10 g, 27.5 mmol) in anhyd CH2Cl2
(150 mL) was introduced via cannula over 20 min and the mixture
was stirred at –20 °C for an additional 20 min. A soln of tert-butyl
hydroperoxide in CH2Cl2 (16.0 mL, 5.3 M in CH2Cl2 stored over
molecular sieves prior to the addition, 84.8 mmol) was added and
the mixture was stirred at –20 °C for 3 h prior to the addition of neat
dimethyl sulfide (7.5 mL), stirred at –20 °C for 1 h, warmed to r.t.,
and filtered to remove the sieves. To the filtrate was added a soln of
11% (w/v) of aq citric acid (160 mL) and the reaction mixture was
stirred at r.t. overnight. The separated aq phase was extracted with
CH2Cl2 and Et2O. The combined organic extracts were washed with
H2O, dried, and concentrated. The residue consisted of only one di-
473.2236.
Pivalate Ester 13
To a cold (0 °C) stirred soln of 11 (210 mg, 0.55 mmol) in anhyd
CH2Cl2 (5 mL) was added pivaloyl chloride (104 mol, 0.844
mmol) and pyridine (70 L, 0.865 mmol). The reaction mixture was
stirred at 0 °C for 1 h and warmed to r.t. for 18 h. H2O was added,
the separated aq layer was extracted with CH2Cl2, the combined or-
ganic extracts were washed with H2O, dried, and concentrated. The
residue was purified by flash chromatography (EtOAc hexanes,
2:8) to afford 13 as a colorless solid (113 mg, 44%).
1H NMR (300 MHz, CDCl3): = 0.87 (d, J = 6.5 Hz, 3 H), 0.94 (s,
3 H), 1.10 (s, 3 H), 1.18 (s, 9 H), 1.27 (m, 2 H), 1.42 (dd, J = 14.6,
11.7 Hz, 1 H), 1.75–2.05 (m, 7 H), 2.10 (dd, J = 14.6, 4.2 Hz, 1 H),
2.35 (ddd, J = 15.0, 5.5, 5.5 Hz, 1 H), 2.62 (ddd, J = 11.1, 11.1, 6.5
Hz, 1 H), 3.13 (d, J = 5.1 Hz, 1 H), 3.44 (ABq, JAB = 13.8 Hz,
AB = 18.9 Hz, 2 H), 3.86 (dd, J = 6.4 Hz, 1 H), 3.89 (d, J = 12.0 Hz,
1 H), 4.25 (d, J = 12.0 Hz, 1 H).
1
astereomer as indicated by high field H NMR (>95% de). The
crude product was recrystallized from MeOH to afford colorless
crystals. The mother liquor was concentrated under reduced pres-
sure and purified by flash chromatography (EtOAc hexanes, 2:3)
to furnish a total of 8.82 g (84%) of 11 as a colorless solid; mp 168–
170 °C.
13C NMR (125 MHz, CDCl3): = 18.9, 19.7, 20.7, 26.29, 26.31,
27.1 (3 C), 28.5, 32.6, 33.3, 38.3, 38.8, 44.5, 46.4, 47.6, 48.2, 53.1,
54.6, 58.7, 64.9, 66.4, 173.8, 177.8.
HRMS (EI): m/z calcd for C24H37NO6S (M+), 467.2342; found,
467.2354.
[ ]D22 +161 (c 2.2, CHCl3).
1
IR (neat): 3300, 1676, 1399, 1326 cm .
1H NMR (300 MHz, CDCl3): = 0.91 (d, J = 6.3 Hz, 3 H), 0.97 (s,
3 H), 1.14 (s, 3 H), 1.29–1.48 (m, 3 H), 1.73 (br s, 1 H), 1.82–1.95
(m, 4 H), 1.98–2.13 (m, 4 H), 2.38 (ddd, J = 15.1, 5.5, 5.5 Hz, 1 H),
2.66 (ddd, J = 11.0, 11.0, 6.4 Hz, 1 H), 3.28 (d, J = 5.5 Hz, 1 H),
3.47 (ABq, JAB = 14.0 Hz, AB = 19.3 Hz, 2 H), 3.59 (br d, J = 12.2
Hz, 1 H), 3.72 (br d, J = 12.2 Hz, 1 H), 3.89 (br dd, J = 6.2, 6.2 Hz,
1 H).
13C NMR (75 MHz, CDCl3): = 19.0, 19.8, 20.8, 26.4, 26.6, 28.7,
32.8, 33.2, 38.4, 44.6, 46.8, 47.7, 48.3, 53.2, 54.3, 61.1, 64.0, 65.0,
174.0.
Nitrile 14
To a stirred soln of 11 (300 mg, 0.78 mmol), KCN (114 mg, 1.75
mmol), and tetra-N-butylammonium iodide (433 mg, 1.17 mmol) in
anhyd DMSO (4 mL) at r.t. was added Ti(i-PrO)4 (0.51 mL, 1.73
mmol). The reaction mixture was stirred for 12 h, and Et2O and 5%
H2SO4 were carefully introduced (CAUTION: HCN is evolved;
perform in a well vented hood!). The mixture was stirred vigorously
for 30–45 min to give two clear layers, which were separated. The
aq layer was extracted with Et2O. The combined organic extracts
were washed with brine, dried, and concentrated. The residue was
purified by flash chromatography (EtOAc hexanes, 7:3). The ac-
quired material was absorbed on silica gel and purified a second
time by flash chromatography (EtOAc hexanes, 7:3) to afford 14
(267 mg, 83%) as a colorless solid.
1H NMR (400 MHz, CDCl3): = 0.96 (d, J = 7.5 Hz, 3 H), 0.97 (s,
3 H), 1.15 (s, 3 H), 1.30–1.48 (m, 3 H), 1.61–1.71 (m, 1 H), 1.83–
1.99 (m, 3 H), 2.00–2.21 (m, 5 H), 2.30–2.42 (m, 1 H), 2.50 (br s, 1
H), 2.98–3.11 (m, 2 H), 3.48 (ABq, JAB = 13.8 Hz, AB = 23.3 Hz, 2
H), 3.57 (d, J = 11 Hz, 1 H), 3.86 (d, J = 11 Hz, 1 H), 3.92 (dd,
J = 6.2, 6.2 Hz, 1 H).
HRMS (EI): m/z calcd for C19H29NO5S (M+), 383.1766; found,
383.1775.
Anal. Calcd for C19H29NO5S (383.50): C, 59.51; H, 7.62. Found: C,
59.79; H, 7.68.
O-Benzylation of 11
To a cold (0 °C) stirred soln of 11 (295 mg, 0.77 mmol) in anhyd
THF (7.5 mL) was added anhyd oil-free NaH (28 mg, 0.84 mmol).
The reaction mixture was stirred at 0 °C
13C NMR (75 MHz, CDCl3): = 19.6, 19.9, 20.8, 26.4, 27.4, 28.0,
32.8, 33.5, 37.5, 38.4, 44.6, 47.3, 47.8, 48.5, 53.0, 64.9, 68.2, 71.9,
119.0, 173.4.
HRMS (EI): m/z calcd for C20H31N2O5S (M+1)+, 411.1954; found,
411.1981.
for 10 min, at which point benzyl bromide (125 L, 1.15 mmol) and
tetra-N-butylammonium iodide (140 mg, 0.38 mmol) were intro-
duced and the temperature was allowed to rise to 20 °C. H2O was
added, the separated aq layer was extracted with CH2Cl2, and the
combined organic extracts were dried and concentrated. The residue
was purified by flash chromatography to give 71 mg (20%) of 12 as
a colorless solid.
1H NMR (300 MHz, CDCl3): = 0.91 (d, J = 6.5 Hz, 3 H), 0.97 (s,
3 H), 1.14 (s, 3 H), 1.22–1.45 (m, 2 H), 1.51 (dd, J = 14.8, 11.7 Hz,
1 H), 1.79–2.08 (m, 7 H), 2.19 (dd, J = 14.7, 4.3 Hz, 1 H), 2.37 (ddd,
J = 15, 5.3, 5.3 Hz, 1 H), 2.66 (ddd, J = 11.2, 11.2, 6.5 Hz, 1 H),
3.12 (d, J = 5.2 Hz, 1 H), 3.43 (d, J = 11 Hz, 1 H), 3.46 (ABq,
JAB = 13.8 Hz, AB = 18.0 Hz, 2 H), 3.60 (d, J = 11 Hz, 1 H), 3.89
(dd, J = 6.2, 6.2 Hz, 1 H), 4.54 (ABq, JAB = 12.0 Hz, AB = 11.4 Hz,
2 H), 7.26–7.40 (m, 5 H).
Chloro Sultam 15
A soln of 12 (95 mg, 0.20 mmol) in anhyd CH2Cl2 (2 mL) was
cooled to –78 °C, treated dropwise with TiCl4 (1.0 mL of 1.0 M in
CH2Cl2, 1.0 mmol), stirred at –78 °C for 1.5 h, and allowed to warm
to r.t. After dilution with sat. NH4Cl soln, H2O, and CH2Cl2, the sep-
arated aq phase was extracted with CH2Cl2, and the combined or-
ganic layers were washed with H2O, dried, and concentrated. Flash
chromatographic purification of the residue (EtOAc hexanes, 2:8)
furnished 29 mg (28%) of 15 as a colorless solid.
13C NMR (75 MHz, CDCl3): = 19.0, 19.8, 20.8, 26.39, 26.42,
28.7, 32.7, 33.5, 38.4, 44.6, 46.7, 47.7, 48.2, 53.2, 54.5, 60.0, 65.0,
73.2, 73.3, 127.7 (2 C), 128.4 (3 C), 138.0, 174.1.
1H NMR (300 MHz, CDCl3): = 0.92 (d, J = 6.5 Hz, 3 H), 0.96 (s,
3 H), 1.14 (s, 3 H), 1.17–1.27 (m, 1 H), 1.28–1.45 (m, 2 H), 1.47–
1.55 (m, 2 H), 1.81–1.97 (m, 3 H), 2.00–2.17 (m, 2 H), 2.28–2.46
(m, 2 H), 2.72 (br s, 1 H), 3.13–3.25 (m, 1 H), 3.31 (d, J = 11 Hz, 1
H), 3.39–3.52 (m, 2 H), 3.66–3.76 (m, 1 H), 3.90 (m, 1 H), 4.20 (m,
Synthesis 2002, No. 7, 895–900 ISSN 0039-7881 © Thieme Stuttgart · New York

900
S. L. Boulet, L. A. Paquette
PAPER
1 H), 4.80 (ABq, JAB = 12.0 Hz, AB = 11.5 Hz, 2 H), 7.26–7.37 (m,
5 H).
13C NMR (75 MHz, CDCl3): = 19.7, 19.9, 20.9, 26.4, 27.4, 32.8,
33.5, 35.2, 38.5, 44.6, 45.3, 47.7, 48.3, 53.2, 59.1, 65.0, 73.2, 73.6,
74.8, 127.8 (2 C), 127.9, 128.5 (2 C), 137.7, 174.5.
HRMS (EI): m/z calcd for C26H36ClNO5S (M+), 509.2003; found,
509.1993.
(4) (a) Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H.; Smith,
R. A. J. J. Am. Chem. Soc. 1990, 112, 4404. (b) Lipshutz,
B. H.; Hackmann, C. J. Org. Chem. 1994, 59, 7437.
(5) Oppolzer, W.; Mills, R. J.; Pachinger, W.; Stevenson, T.
Helv. Chim. Acta 1986, 69, 1542.
(6) (a) Oppolzer, W.; Lienard, P. Helv. Chim. Acta 1992, 75,
2572. (b) Toyota, S.; Akinaga, T.; Kojima, H.; Aki, M.; Oki,
M. J. Am. Chem. Soc. 1996, 118, 11460.
(7) Boulet, S. L.; unpublished findings.
Allyl Silyl Ether 16
(8) Rossi, R.; Carpita, A.; Chini, M. Tetrahedron 1985, 41, 627.
(9) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett.
1989, 30, 5603.
To a stirred soln of allyldimethylsilyl chloride (97 mg, 0.72 mmol),
Et3N (100 L, 0.72 mmol), and DMAP (14 mg, 0.12 mmol) in an-
hyd CH2Cl2 (2 mL) at r.t. was added 11 (1.007 g, 2.62 mmol) via
cannula as a soln in anhyd CH2Cl2 (3 mL). The reaction mixture was
stirred for 4 h, H2O was added, and the separated aq layer was ex-
tracted with CH2Cl2. The combined organic extracts were washed
with H2O, dried, and concentrated. The residue was purified by
flash chromatography (EtOAc hexanes, 2:8) to afford 229 mg
(87%) of 16 as a colorless solid.
1H NMR (300 MHz, CDCl3): = 0.07 (s, 6 H), 0.85 (d, J = 6.4 Hz,
3 H), 0.93 (s, 3 H), 1.09 (s, 3 H), 1.19–1.35 (m, 2 H), 1.40 (dd,
J = 14.4, 11.6 Hz, 1 H), 1.58 (d, J = 8.0 Hz, 2 H), 1.73–2.04 (m, 7
H), 2.05 (dd, J = 14.4, 4.3 Hz, 1 H), 2.31 (ddd, J = 15.0, 5, 5 Hz, 1
H), 2.60 (ddd, J = 11.1, 11.1, 6.5 Hz, 1 H), 3.07 (d, J = 5 Hz, 1 H),
3.43 (ABq, JAB = 13.8 Hz, AB = 18.3 Hz, 2 H), 3.59 (ABq,
JAB = 11.5 Hz, AB = 33.4 Hz, 2 H), 3.84 (dd, J = 6.1, 6.1 Hz, 1 H),
4.77–4.89 (m, 2 H), 5.65–5.81 (m, 1 H).
(10) (a) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114,
5426. (b) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992,
114, 7324. (c) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc.
1993, 115, 3800. (d) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H.
J. Am. Chem. Soc. 1993, 115, 9856. (e) Nguyen, S. T.;
Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1993, 115,
9858. (f) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997,
62, 7310.
(11) (a) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123.
(b) Paquette, L. A.; Efremov, I. J. Am. Chem. Soc. 2001, 123,
4492.
(12) Ackermann, L.; El Tom, D.; Fürstner, A. Tetrahedron 2000,
56, 2195.
(13) (a) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.;
Ko, S. Y.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109,
5765. (b) Crimmins, M. T.; Lever, J. G. Tetrahedron Lett.
1986, 27, 291. (c) Naruta, Y.; Nishigaichi, Y.; Maruyama,
K. Tetrahedron Lett. 1989, 30, 3319. (d) Tanner, D.; He, H.
M. Tetrahedron 1989, 45, 4309. (e) Hamon, D. P. G.;
Massy-Westropp, R. A.; Newton, J. L. Tetrahedron:
Asymmetry 1990, 1, 771.
13C NMR (75 MHz, CDCl3): = –2.6 (2 C), 18.9, 19.7, 20.7, 24.2,
26.28, 26.34, 28.7, 32.6, 33.0, 38.3, 44.5, 46.7, 47.6, 48.1, 53.1,
54.5, 60.8, 64.9, 66.0, 113.7, 133.7, 174.0.
HRMS (EI): m/z calcd for C24H39NO5S SI (M+), 481.2318; found,
481.2322.
(14) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980,
21, 1557.
(15) Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1560.
(16) Reetz, M. T.; Jung, A.; Bölm, C. Tetrahedron 1988, 44,
3889.
(17) Lin, H.-S.; Paquette, L. A. Synth. Commun. 1994, 24, 2503.
(18) (a) Van der Louw, J.; Van der Baan, J. L.; De Kanter, F. J.
J.; Bickelhaupt, F.; Klumpp, G. W. Tetrahedron 1992, 48,
6087. (b) Van der Louw, J.; Van der Baan, J. L.; Out, G. J.
J.; De Kanter, F. J. J.; Bickelhaupt, F.; Klumpp, G. W.
Tetrahedron 1992, 48, 9901.
References and Notes
(1) Paquette, L. A.; Boulet, S. Synthesis 2002, 888.
(2) Oppolzer, W.; Poli, G.; Kingma, A. J.; Starkemann, C.;
Bernardinelli, G. Helv. Chim. Acta 1987, 70, 2201.
(3) Oppolzer, W.; Kingma, A. J. Helv. Chim. Acta 1989, 72,
1337.
Synthesis 2002, No. 7, 895–900 ISSN 0039-7881 © Thieme Stuttgart · New York