Toward a total synthesis of okilactomycin. 1. A direct, enantiocontrolled route to the western sector

Article abstract of DOI:10.1055/s-2002-28510

A synthesis of the western half of the macrocyclic ring framework of the antitumor antibiotic okilactomycin is described. The strategy employed rests on an efficient synthesis of meso-2,4-dimethylglutaric anhydride and ensuing resolution via reaction with (S)-(-)-α-methylbenzylamine, diborane reduction, and selective crystallization. Following acid-catalyzed cyclization to (2S,4R)-2,4-dimethyl-δ-valerolactone, an acyclic stereocontrol strategy was adopted to achieve chain lengthening with appropriate incorporation of functionality. The sensitive aldehyde 2 was further homologated to β-keto ester 17 in a model reaction sequence performed to simulate its ultimate projected coupling to 3.

Full text of DOI:10.1055/s-2002-28510

888
PAPER
Toward a Total Synthesis of Okilactomycin. 1. A Direct, Enantiocontrolled
Route to the Western Sector
Toward a
Total
e
S
ynthesis
o
o
f
Okilactomycin A. Paquette,* Serge L. Boulet
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
the attention of scientists concerned with human health.
Abstract: A synthesis of the western half of the macrocyclic ring
framework of the antitumor antibiotic okilactomycin is described.
The strategy employed rests on an efficient synthesis of meso-2,4-
dimethylglutaric anhydride and ensuing resolution via reaction with
For the synthetic chemist, the enormous breadth of intri-
cate molecular arrangements provides a proper forum for
the development of new preparative protocols and for the
(S)-( )- -methylbenzylamine, diborane reduction, and selective parallel application of established methodology in new,
crystallization. Following acid-catalyzed cyclization to (2S,4R)-
2,4-dimethyl- -valerolactone, an acyclic stereocontrol strategy was
adopted to achieve chain lengthening with appropriate incorpora-
ed structure, which was originally discovered in the cul-
tion of functionality. The sensitive aldehyde 2 was further homolo-
gated to -keto ester 17 in a model reaction sequence performed to
especially challenging contexts. Such is the case with
okilactomycin (1), an antitumor antibiotic of unprecedent-
ture filtrates of a strain of actinomycetes contained in a
soil sample collected on Zamami Island in the Okinawas.1
simulate its ultimate projected coupling to 3.
The producing organism, strain YP-02908L, was specifi-
cally identified as Streptomyces griseoflavus subsp.
Key words: anhydride, resolution, epoxidation, dithiane, oxidation
zamamiensis subs. nov. Interest in 1 surfaced immediately
as a consequence of its in vitro cytotoxicity against lym-
phoid leukemia L1210 and leukemia P388. In addition,
antimicrobial activity against Gram-positive organisms
was noted.
The remarkable ability of the many species of Streptomy-
ces to elaborate a bewildering array of structurally com-
plex biologically active compounds continues to attract
CO2Me
CO2H
CO2Me
Metathesis
H
H
H
Knoevenagel
Michael
O
H
O
O
H
O
OHC
O
O
O
O
O
TBSO
PMBO
O
H
H
O
OPMB
Knoevenagel
-Michael
1
Metathesis
CO2Me
CO2Me
OTBS
O
H
O
Aldol
OHC
O
O
O
O
O
TBSO
PMBO
O
PMBO
Aldol
2
3
Scheme 1
Synthesis 2002, No. 7, 21 05 2002. Article Identifier:
1437-210X,E;2002,0,07,0888,0894,ftx,en;M05601SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Toward a Total Synthesis of Okilactomycin
889
The polyketide nature of okilactomycin was ascertained to methyl methacrylate afforded triester 5, and hydrolysis/
by a series of 14C labeling experiments.2 The structural decarboxylation gave the diastereomeric pair of diacids.
features and relative stereochemistry of 1 were deter- Direct dehydrative cyclization led to formation of the an-
mined by X-ray crystallographic studies.3 The molecule is hydrides 6 and 7. The relative insolubility of the meso iso-
fundamentally constructed of a 13-membered ring fused mer allowed for its direct isolation by crystallization from
to a cyclohexenecarboxylic acid. The densely oxygenated ethyl acetate in 35% overall yield from 4. Reaction of the
southeastern sector consists of tetrahydro- -pyrone and - pure anhydride 6 with (S)-( )- -methylbenzylamine in
butyrolactone subunits positioned in a manner that gives dichloromethane containing pyridine resulted in ring
rise to a spiro carbon and establishes half of the resident cleavage to generate a mixture of carboxylic acids.9 Re-
stereogenic centers. Although the absolute configuration duction of the acids with the borane-tetrahydrofuran com-
of okilactomycin is unknown, it clearly differs from that plex gave 8 and 9 in good yields. Crystallization of this
present in the related, more densely functionalized conge- product mixture afforded the desired enantiomerically
ners chlorothricolide, kijanolide, and tetronolide either at pure syn-carbinol 9 in a reasonably efficient manner.10
the spiro center or the other cyclohexene substituents.4
We have targeted 1, with proper allowance for accessing
the appropriate enantiomer if ultimately warranted. Our
retrosynthetic strategy for the synthesis of okilactomycin,
Subsequent to this resolution, 9 was heated at 80 °C with
1 M sulfuric acid in THF in order to effect cyclization to
lactone 109 (Scheme 3). A small amount of the open-chain
hydroxy acid accompanies 10. However, dissolution of
this by-product in CDCl3 for several hours suffices to cat-
alyze the ring closure of interest. The reduction of 10 with
DIBAL-H provided the lactol, which was not purified in
outlined in Scheme 1, was envisioned to involve a tandem
Knoevenagel Michael sequence,5 ring-closing metathe-
sis at two sites, and a convergent aldol reaction. In this re-
port, a concise synthesis of aldehyde 2 is detailed. The
advance of Wittig olefination to generate 11. In line with
accompanying paper describes our first-generation at-
precedent,9,11 the oxidation of 11 was difficult, presum-
ably because of the sensitivity of the aldehyde. In our
tempt to craft a close relative of ester 3.6
The quest for 2 began with meso-2,4-dimethylglutaric an- hands, considerable improvement was encountered when
hydride (6). Large quantities of 6 were most readily gen- recourse was made to Swern oxidation conditions.12 The
erated by the sequence given in Scheme 2.7,8 The base- need to isolate the sensitive and volatile aldehyde was al-
catalyzed Michael addition of diethyl methylmalonate (4) leviated when it was discovered that very efficient and E-
selective homologation could be effected by the addition
of ethyl (triphenylphosphoranylidene)acetate to the crude
O
Swern reaction mixture.13 Thus, a separable mixture of
O
homologated , -unsaturated esters was formed in an E:Z
ratio of 48:1 where compound 12 was isolated in 98%
OMe
1. HCl, HOAc
reflux
CO2Et
OMe
yield over the two steps. Importantly, the reduced basicity
of ethyl (triphenylphosphoranylidene)acetate does not in-
duce significant epimerization of the proximal methyl-
bearing center. Following the DIBAL-H reduction of 12,
a set of control experiments demonstrated clearly that the
ensuing Sharpless epoxidation14 proceeded efficiently un-
der catalytic conditions. The beneficial consequence of
this modification is the acquisition of 13 in 92% yield
along with an easier workup protocol.
2. Ac2O
3. crystallization
NaOMe
MeOH, rt
CO2Et
CO2Et
CO2Et
4
5
O
O
O
O
O
O
6
7
35% over 3 steps
The optimal conditions for converting 13 into 15 involved
monoprotection of the primary hydroxyl as the p-methox-
ybenzyl ether only subsequent to nucleophilic epoxide
opening with the dithianyl anion15 (Scheme 4). Reversal
of this two-step sequence proved to be less workable for a
number of reasons. For example, PMB-protected 13 was
even more resistant to ring opening than the free alcohol.
Dithiane addition to 13 afforded the desired C-2 adduct 14
which was favored over its C-3 regioisomer in a 9:1 ratio.
Chromatographic separation of the two regioisomers af-
forded 14 in 90% yield. One major issue with this reaction
was that the desired regioadduct could not be separated
from unreacted starting material by column chromatogra-
phy so it was deemed essential to find conditions capable
of driving the reaction to completion (see experimental
section). Following the formation of the tert-butyldimeth-
ylsilyl ether 16, the dithiane functionality was removed by
1.
Ph
py, CH2Cl2
0 °C
NH2,
2. BH3•THF
THF, ether
-20 °C → rt
3. crystallization
HO
O
O
OH
N
Ph
Ph
N
H
H
8
9
29% over 2 steps
Scheme 2
Synthesis 2002, No. 7, 888–894 ISSN 0039-7881 © Thieme Stuttgart · New York

890
L. A. Paquette, S. L. Boulet
PAPER
exposure to iodobenzene bistrifluoroacetate in aqueous Melting points are uncorrected. The column chromatographic sepa-
acetonitrile16 in order to complete the construction of al-
rations were performed with Woelm silica gel (230 400 mesh).
Solvents were reagent grade and in most cases dried prior to use.
dehyde 2.
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. Petro-
leum ether (PE) used has a boiling point range 35–60°C.
With quantities of 2 in hand, its projected coupling to 3
was simulated by treatment with the enolate anion of tert-
butyl acetate and subsequent oxidation of the aldol prod-
uct to give 17. This chemistry proceeded uneventfully.
The stereochemistry assigned to 2 and 17, based on the
synthetic pathway adopted here, finds confirmation in the
NMR spectra of these products, and conforms in the abso-
lute sense to the correlation of 9 and 10 with the prior lit-
erature.9,17
meso-2,4-Dimethylglutaric Anhydride (6)
To a stirred soln of NaOMe (27.0 g, 0.50 mol) in anhyd MeOH (400
mL) was added diethyl methylmalonate [(4), 348 g, 2.00 mol] drop-
wise over 5 10 min. The mixture was stirred at r.t. for 10 min and
methyl methacrylate (200 g, 2.00 mol) was introduced dropwise
over 5 6 h. The mixture was stirred at r.t. for 12–14 h prior to the
addition of HOAc (~15 mL) to bring the pH of the soln to approxi-
mately 7. The volatiles were removed under reduced pressure, the
residue was washed with H2O (750 mL) and the layers were sepa-
rated. The aq phase was extracted with Et2O, the combined organic
extracts were dried and concentrated under reduced pressure to give
5 as a colorless oil (550 g).
O
1. DIBAL-H,
O
H2SO4
88%
9
2. Ph3P=CH2,
THF
THF, 80 °C
90%
89%
The oil was taken up in glacial HOAc (1.7 L) and concd HCl (500
mL), heated at reflux for 25 h, then cooled to r.t. overnight. The
HOAc was removed by distillation under reduced pressure, the re-
sidual H2O was removed by repeated azeotropic distillation with
toluene, and the toluene was removed under reduced pressure. To
the resulting mixture of d,l- and meso-2,4-dimethylglutaric acids
acetic anhydride (500 mL) was added, the soln was heated at reflux
for 90 min, Ac2O was removed by distillation, and the residue was
distilled under high vacuum using an air-cooled condenser to afford
a colorless solid. This material was dissolved in 600 mL of EtOAc
and 400 mL of the solvent was removed by distillation. The soln
was allowed to stand at r.t. for 14 h, in the freezer for 2 h, and in a
–20 °C bath for 90 min to give 147 g of colorless solid. The material
was recrystallized from EtOAc (100 mL) by allowing the soln to
stand at r.t. for 14 h and in the freezer for 2 h to furnish 114.7 g of
colorless solid. This material was recrystallized from EtOAc (50
mL) to give 98.1 g (35%) of 6 as a colorless solid.
10
1. Swern
CO2Et
OH
2. Ph3P=CHCO2Et
98%
11
12
1. DIBAL-H
90%
O
OH
2. Ti(i-PrO)4,
(-)-DET, TBHP
4Å MS, CH2Cl2
92%
13
(de = 86%)
Scheme 3
Mp 89.5–92.5 °C (lit.7,9 91.4–92.8 °C).
S
S
RO
S
1. NaH,
PMBCl
81%
OH
S
Li
OPMB
OH
13
2. TBSOTf,
2,6-lutidine
CH2Cl2
THF, DMPU
-20 °C
S
S
90%
95%
15, R = H
16, R = TBS
14
O
1.
TBSO
O
TBSO
O
O
Ot-Bu,
PhI(OCOCF3)2
LDA, THF, -78 °C
H
Ot-Bu
CH3CN, H2O
66%
79%
2. Swern
96%
OPMB
OPMB
2
17
Scheme 4
Synthesis 2002, No. 7, 888–894 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Toward a Total Synthesis of Okilactomycin
891
1H NMR (300 MHz, CDCl3): = 1.36 (d, J = 8 Hz, 6 H), 1.58 (ddd,
J = 15, 15, 15 Hz, 1 H), 2.05 (ddd, J = 15, 6, 6 Hz, 1 H), 2.72 (ddq,
J = 15, 8, 6 Hz, 2 H).
1.0 M in hexanes, 136 mmol) dropwise over 1 h. The soln was
stirred at –78 °C for an additional 4 h and MeOH (15 mL) was in-
troduced dropwise. The mixture was stirred at –78 °C for 15 min,
poured into sat. Rochelle salt soln (600 mL), and vigorously stirred
overnight to give a clear, colorless, biphasic soln. The separated aq
phase was extracted with Et2O. The combined organic extracts were
washed successively with H2O and brine, dried, and concentrated
under reduced pressure to afford 12.83 g (88%) of the lactol, which
was used directly in the next step without further purification.
(2S,4R)-5-Hydroxy-2,4-dimethyl-N-[(S)-1-phenethyl]pentana-
mide (9)
To a stirred soln of (–)-S- -methylbenzylamine (18.63 g, 154
mmol) in anhyd CH2Cl2 (135 mL) was added pyridine (16.2 mL,
200 mmol). The soln was cooled to 0 °C and 6 (19.00 g, 134 mmol)
was added in portions. The soln was stirred at 0 °C for 15–20 min
and allowed to warm to r.t. for 16 h before being poured into ice
cold 10% HCl (130 mL). The separated aq phase was extracted with
CH2Cl2 and the combined organic extracts were washed with 10%
HCl (2 150 mL), dried and concentrated under reduced pressure
to afford a viscous yellow oil.
To a cold (0 °C), mechanically stirred suspension of anhyd methyl-
triphenylphosphonium bromide (89.11 g, 249 mmol) in anhyd THF
(550 mL) was added n-BuLi (148 mL, 1.48 M in hexanes, 219
mmol) dropwise over 25 min to give an orange colored suspension
that was stirred at r.t. for 3 h. A soln of the above lactol (12.83 g) in
anhyd THF (60 mL) was added dropwise via cannula, the resultant
mixture was heated at reflux for 3 h, cooled to r.t., poured into ice
H2O, and stirred overnight. The aq layer was saturated with solid
NaCl and extracted with Et2O PE, 1:1. The combined organic ex-
tracts were washed with brine, dried, and concentrated under re-
duced pressure. The crude oil was distilled (bulb-to-bulb, high
vacuum up to 150 °C) to give 14.08 g of a colorless oil. This mate-
rial was purified by flash chromatography (EtOAc hexanes, 2:8)
and bulb-to-bulb distillation to give 11.07 g [(87%), 76% over 2
steps] of 11 as a colorless oil.
To a cold (–20 °C) stirred soln of BH3 THF (160 mL, 1.0 M in THF,
160 mmol) in anhyd Et2O (160 mL) was added the acquired oil as a
soln in anhyd THF (160 mL) via cannula. Gas evolution was ob-
served. On completion, the soln was stirred at –20 °C for 10–15
min, allowed to warm to r.t. for 1 h, and treated dropwise with a 3:1
mixture of H2O–glycerine (160 mL). The separated aq phase was
extracted with Et2O (5 120 mL), the combined organic extracts
were washed successively with sat. NaHCO3 soln, brine, dried, and
concentrated under reduced pressure. The crude product was puri-
fied by flash chromatography (EtOAc hexanes, 45:55) to remove
the non-polar material and the column was then flushed with EtOAc
to recover the more polar mixture of hydroxy amides. The appropri-
ate fractions were concentrated and the oil thus obtained (30.15 g)
was dissolved in a minimum amount of warm CHCl3 PE, 3:1 and
allowed to crystallize in the freezer for 2.5 d to give 10.77 g of col-
orless crystals. This material was recrystallized from CHCl3 to give
9.55 g (29% from 6) of 9 as a colorless solid.
[ ]D22 +35.2 (c 2.1, CHCl3), [lit.9 –39.4 (c 5.87, CDCl3) for the enan-
tiomer].
1H NMR (300 MHz, CDCl3): = 0.88 (d, J = 6.6 Hz, 3 H), 0.98 (d,
J = 6.7 Hz, 3 H), 1.27–1.42 (m, 2 H), 1.53–1.72 (m, 1 H), 2.13–2.30
(m, 1 H, H–4), 3.30–3.50 (m, 2 H), 4.84–5.00 (m, 2 H), 5.60 (ddd,
J = 17.6, 10.1, 8.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): = 16.3, 16.9, 33.4, 35.5, 40.3, 68.5,
112.8, 114.4.
Mp 120.5–121 °C (lit.9 mp 120–120.5 °C for ent-9); [ ]D22 –63.4 (c
2.1, CHCl3) (lit.9 +62.2 (c 6.5, CDCl3) for ent-9).
(E)-(4R,6S)-Ethyl 4,6-dimethylocta-2,7-dienoate (12)
1H NMR (300 MHz, CDCl3): = 0.90 (d, J = 6.8 Hz, 3 H), 1.10–
1.25 (m, 1 H), 1.17 (d, J = 6.9 Hz, 3 H), 1.40–1.60 (m, 1 H), 1.48
(d, J = 6.9 Hz, 3 H), 1.80–2.00 (m, 2 H), 2.24–2.38 (m, 1 H), 3.25–
3.43 (m, 2 H), 5.13 (dq, J = 7, 7 Hz, 1 H), 5.70–5.83 (br d, J = 7 Hz,
1 H), 7.20–7.38 (m, 5 H).
13C NMR (75 MHz, CDCl3): = 17.3, 19.3, 21.5, 34.2, 37.4, 39.6,
48.5, 67.3, 126.1 (2 C), 127.3, 128.6 (2 C), 143.2, 175.8.
To a cold (–78 °C) stirred soln of oxalyl chloride (17.0 mL, 195
mmol) in anhyd CH2Cl2 (400 mL) was added dropwise via cannula
a soln of DMSO (27.5 mL, 388 mmol) in anhyd CH2Cl2 (100 mL).
The resultant soln was stirred at –78 °C for 10 min, treated dropwise
with a soln of 11 (8.199 g, 63.95 mmol) in anhyd CH2Cl2 (100 mL),
and stirred at –78 °C for 55 min. Et3N (72.0 mL, 517 mmol) was
added and the soln was stirred at –78 °C for 5 min, allowed to warm
to r.t. for 3 h, and cooled to 0 °C for 30 min. A soln of ethyl (triph-
enylphosphoranylidene)acetate (67.0 g, 192 mmol) in anhyd
CH2Cl2 (150 mL) was introduced via cannula over 15 min. The re-
action mixture was allowed to warm to r.t. for 7 h. H2O and brine
were added, the mixture was stirred overnight, and the separated aq
phase was extracted with Et2O. The combined organic extracts were
washed with H2O, dried, and concentrated under reduced pressure.
The residue was filtered through a plug of silica gel (elution with
EtOAc hexanes, 15:85) and the appropriate nonpolar fractions
were concentrated. NMR analysis of this oil indicated a 48:1 ratio
of E- to Z-unsaturated esters to be present. This oil was further pu-
rified by flash chromatography (EtOAc hexanes, 1:19) and bulb-
to-bulb distillation (85–100 °C/0.2 Torr) to give 12 as a pale yellow
oil (12.30 g, 98% yield over 2 steps).
[ ]D22 –30.8 (c 3.3, CHCl3).
IR (neat): 1722, 1651, 1273, 1223 cm–1.
1H NMR (300 MHz, CDCl3): = 0.96 (d, J = 6.7 Hz, 3 H), 1.01 (d,
J = 6.7 Hz, 3 H), 1.15–1.30 (m, 1 H), 1.26 (t, J = 7.1 Hz, 3 H), 1.32–
1.47 (m, 1 H), 2.10–2.23 (m, 1 H), 2.27–2.42 (m, 1 H), 4.16 (q,
J = 7.1 Hz, 2 H), 4.85–5.02 (m, 2 H), 5.55–5.69 (ddd, J = 17.3, 10.3,
7.8 Hz, 1 H), 5.75 (dd, J = 15.7, 1.1 Hz, 1 H), 6.84 (dd, J = 15.7, 7.8
Hz, 1 H).
(2S,4R)-2,4-Dimethyl- -valerolactone (10)
To a stirred soln of 9 (31.9 g, 128 mmol) in 130 mL of THF was
added 1.0 M H2SO4 (128 mL), and the mixture was heated at 80 °C
for 43 h, cooled to r.t., and saturated with solid ammonium sulfate.
Concd HCl (65 mL) was added to the mixture, the layers were sep-
arated and the aq phase was extracted with Et2O. The combined or-
ganic layers were dried and concentrated under reduced pressure.
The residual oil was dissolved in CHCl3 containing a small amount
of CDCl3 (~2 mL) and allowed to stand at r.t. overnight. The solvent
was removed under reduced pressure and the oil obtained was dis-
tilled (bulb to bulb, high vacuum up to 130 °C) to afford 14.7 g
(90%) of lactone 10 as a colorless low melting solid.
[ ]D22 +35.9 (c 2.2, CHCl3), (lit.17 +41.6 (c 0.1, CDCl3).
1H NMR (300 MHz, CDCl3): = 0.97 (d, J = 6.6 Hz, 3 H), 1.25 (d,
J = 6.9 Hz, 3 H), 1.16–1.42 (m, 1 H), 2.01–2.20 (m, 2 H), 2.44–2.66
(m, 1 H), 3.87 (dd, J = 11.1, 9.1 Hz, 1 H), 4.30 (ddd, J = 11.1, 4.7,
2.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): = 17.0, 17.3, 28.6, 35.3, 36.8, 74.9,
174.4.
(2R,4S)-2,4-Dimethyl-5-hexen-1-ol (11)
To a cold (–78 °C) stirred soln of 10 (14.48 g, 113 mmol) in anhyd
CH2Cl2 (115 mL) and PE (115 mL) was added DIBAL-H (136 mL,
Synthesis 2002, No. 7, 888–894 ISSN 0039-7881 © Thieme Stuttgart · New York

892
L. A. Paquette, S. L. Boulet
PAPER
13C NMR (75 MHz, CDCl3): = 14.2, 19.1, 20.2, 34.0, 35.3, 42.7,
60.1, 112.9, 119.4, 144.0, 154.5, 166.9.
HRMS (EI): m/z calcd for C12H20O2 (M+), 196.1463; found,
Diol 14
To a cold (–20 °C) stirred soln of freshly sublimed 1,3-dithiane
(10.88 g, 90.5 mmol) in anhyd THF (180 mL) was added n-BuLi
(70 mL, 1.29 M in hexanes, 90.3 mmol). The mixture was stirred at
–20 °C for 2 h, DMPU (22.8 mL, 182 mmol) was introduced, after
5–10 min a soln of 13 (3.076 g, 18.1 mmol) in anhyd THF (50 mL)
was added via cannula and the mixture was stirred at –10 °C to –15
°C. In a separate flask containing a cold (–20 °C) stirred soln of 1,3-
dithiane (2.17 g, 18.0 mmol) in anhyd THF (35 mL) was treated
with n-BuLi (14 mL, 1.29 M in hexanes 18.0 mmol) the mixture
was stirred at –20 °C for 2 h before being added to the above reac-
tion mixture at –10 °C to –15 °C after an elapsed time of 23 h. The
exact same procedure was repeated and the resultant 2-lithio-1,3-
dithiane soln was added to the reaction mixture after an elapsed time
of 35 h. After 49 h at –10 °C to –15 °C, H2O, Et2O, and 10% HCl
were introduced and the reaction mixture was warmed to r.t. The
separated aq phase was extracted with Et2O, the combined organic
extracts were dried and concentrated, and the residue was purified
by flash chromatography on silica gel (EtOAc hexanes, 2:3). The
appropriate fractions were concentrated and NMR analysis of the
acquired material indicated a 9:1 ratio of diastereomeric diols. Re-
peated flash chromatography (EtOAc hexanes, 35:65) afforded 14
(4.705 g, 90%) as a yellowish solid, mp 63–63.5 °C (from 10:1 hex-
anes–EtOAc)
196.1476.
Anal. Calcd for C12H20O2 (196.29): C, 73.41, H, 10.28. Found: C,
73.51, H, 10.19.
(2R,3R,4R,6S)-2,3-Epoxy-4,6-dimethyloct-7-en-1-ol (13)
To a cold (0 °C) stirred soln of 12 (2.239 g, 11.41 mmol) in anhyd
CH2Cl2 (57 mL) was added DIBAL-H (35 mL, 1.0 M in hexanes,
35 mmol). The mixture was stirred at 0 °C for 45 min prior to the
slow addition of sat. Rochelle salt soln (200 mL). After achieving
r.t., vigorous stirring was maintained overnight. The separated aq
phase was extracted successively with CH2Cl2 and Et2O. The com-
bined organic extracts were washed with brine, dried, and concen-
trated under reduced pressure. The residue was purified by flash
chromatography (EtOAc hexanes, 1:3). The appropriate fractions
were concentrated and the oil thus obtained was distilled (bulb-to-
bulb, 80–100 °C/0.20 Torr) to afford the allylic alcohol (1.578 g,
90%) as a colorless oil.
[ ]D22 –13.7 (c 3.6, CHCl3).
IR (neat): 3321, 1668, 1640, 1374 cm–1.
1H NMR (300 MHz, CDCl3): = 0.96 (d, J = 6.5 Hz, 3 H), 0.97 (d,
J = 6.5 Hz, 3 H), 1.05–1.20 (m, 1 H), 1.25–1.37 (m, 1 H), 2.05–2.25
(m, 2 H), 2.47 (br s, 1 H), 3.45–4.05 (m, 2 H), 4.80–4.95 (m, 2 H),
5.45–5.55 (m, 2 H), 5.63 (ddd, J = 17, 10, 7.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): = 20.1, 20.2, 33.8, 35.7, 43.7, 63.7,
112.3, 127.0, 138.9, 144.7.
[ ]D22 +2.45 (c 2.0, CHCl3).
IR (neat): 3383, 1641, 1454, 1423, 1244 cm–1.
1H NMR (300 MHz, CDCl3): = 0.87 (d, J = 8.5 Hz, 3 H), 0.95–
1.13 (m, 1 H), 1.02 (d, J = 6.7 Hz, 3 H), 1.56–1.92 (m, 3 H), 1.93–
2.01 (m, 1 H), 2.07–2.17 (m, 1 H), 2.18–2.33 (m, 1 H), 2.35–2.65
(br s, 2 H), 2.80–2.98 (m, 4 H), 3.81 (dd, J = 7.2, 4.2 Hz, 1 H), 3.95–
4.07 (m, 2 H), 4.46 (d, J = 7.3 Hz, 1 H), 4.94 (dd, J = 10.3, 1.9 Hz,
1 H), 5.00 (ddd, J = 17.2, 1.9, 0.7 Hz, 1 H), 5.61 (ddd, J = 17.2,
10.3, 8.6 Hz, 1 H).
13C NMR (75 MHz, CDCl3): = 16.0, 22.1, 26.1, 30.7, 30.9, 34.0,
35.9, 39.0, 45.8, 48.2, 61.1, 76.8, 113.5, 144.2.
HRMS (EI): m/z calcd for C14H26O2S2 (M+), 290.1374; found,
HRMS (EI): m/z calcd for C10H18O (M+), 154.1358; found,
154.1370.
Anal. Calcd for C10H18O (154.25): C, 77.87, H, 11.76. Found: C,
78.07, H, 11.61.
Epoxy Alcohol 13
To a cold (–20 °C) stirred soln of (–)-diethyl tartrate (1.266 g, 6.14
mmol) in anhyd CH2Cl2 (510 mL) was added freshly activated,
dried, and crushed 4 Å molecular sieves (26 g) followed by
Ti(iPrO)4 (1.5 mL, 5.1 mmol), and the mixture was stirred at –20 °C
for 20 min, treated via cannula with a soln of the above alcohol
(7.889 g, 51.14 mmol) in anhyd CH2Cl2 (60 mL), and stirred at –20
°C for 30 min. A cold (–40 °C) soln of tert-butyl hydroperoxide in
CH2Cl2 (29 mL, 5.3 M in CH2Cl2 stored over molecular sieves prior
to the addition, 154 mmol) was added and the mixture was stirred at
–20 °C for 75 min. Neat dimethyl sulfide (15 mL) was added and
the mixture was stirred at –20 °C for 1 h, then warmed to r.t. A 30%
soln (w/v) of NaOH in brine (200 mL) was added and the reaction
mixture was stirred overnight. The separated aq phase was extracted
with Et2O. The combined organic extracts were washed with H2O,
dried and concentrated. The residue was purified by flash chroma-
tography on silica gel (EtOAc hexanes, 2:3) and the appropriate
fractions were concentrated to afford 13 (8.02 g, 92%) as a colorless
oil. High field (500 MHz) 1H NMR analysis indicated a diastereo-
meric ratio of 93:7 (86% de).
[ ]D22 +38.8 (c 2.8, CHCl3) at 86% de.
IR (neat): 3412, 3076, 1641, 1458 cm–1.
1H NMR (300 MHz, CDCl3): = 0.90 (d, J = 6.8 Hz, 3 H), 1.00 (d,
J = 6.7 Hz, 3 H), 1.13–1.25 (m, 1 H), 1.39–1.57 (m, 2 H), 2.08–2.22
(br m, 1 H), 2.23–2.37 (m, 1 H), 2.73 (dd, J = 7.1, 2.3 Hz, 1 H), 2.92
(ddd, J = 4.7, 2.3, 2.3 Hz, 1 H), 3.52–3.63 (m, 1 H), 3.88 (b rd,
J = 12.4 Hz, 1 H), 4.85–5.00 (m, 2 H), 5.61 (ddd, J = 17.2, 10.2, 8.1
Hz, 1 H).
290.1367.
Anal. Calcd for C14H26O2S2 (290.48): C, 57.89, H, 9.02. Found: C,
57.88, H, 9.01.
Dithianyl Alcohol 15
To a cold (0 °C) stirred soln of 14 (4.185 g, 14.4 mmol) in anhyd
DMF (145 mL) was added anhyd, oil-free NaH (692 mg, 28.8
mmol). The reaction mixture was stirred at 0 °C for 1 h, PMB-Cl
(2.2 mL, 16 mmol) was added and agitation was maintained at 0 °C
for 1 h prior to the addition of H2O. The separated aq phase was ex-
tracted with Et2O–hexanes, 1:1. The residue was purified by flash
chromatography by gradually increasing the solvent polarity from
(EtOAc hexanes, 15 40%) to give 15 (4.771 g, 81%) as a color-
less oil and its regioisomer (817 mg, 14%).
15
[ ]D22 –9.9 (c 2.6, CHCl3).
IR (neat): 3486, 1639, 1612, 1514, 1248 cm–1.
1H NMR (300 MHz, CDCl3): = 0.86 (d, J = 6.6 Hz, 3 H), 1.01 (d,
J = 6.7 Hz, 3 H), 1.06–1.13 (m, 1 H), 1.53–1.72 (m, 2 H), 1.73–1.93
(m, 1 H), 2.01–2.15 (m, 2 H), 2.16–2.32 (m, 1 H), 2.80–2.96 (m, 4
H), 3.01 (d, J = 6.4 Hz, 1 H), 3.67–3.89 (m, 3 H), 3.79 (s, 3 H), 4.40
(d, J = 11.3 Hz, 1 H), 4.44 (d, J = 6.5 Hz, 1 H), 4.46 (d, J = 11.3 Hz,
1 H), 4.83–5.04 (m, 2 H), 5.61 (ddd, J = 17.3, 10.1, 8.6 Hz, 1 H),
6.87 (d, J = 8.6 Hz, 2 H), 7.23 (d, J = 8.6 Hz, 2 H).
13C NMR (75 MHz, CDCl3): = 16.2, 22.0, 26.1, 30.5, 30.8, 34.2,
35.9, 38.8, 44.8, 48.4, 55.2, 68.6, 73.3, 76.3, 113.2, 113.8 (2 C),
129.3 (2 C), 129.6, 144.5, 159.3.
13C NMR (75 MHz, CDCl3): = 15.6, 21.1, 32.9, 35.3, 41.1, 57.2,
60.7, 61.9, 113.0, 144.1.
Synthesis 2002, No. 7, 888–894 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Toward a Total Synthesis of Okilactomycin
893
HRMS (EI): m/z calcd for C22H33O3S2 (M+ – 1), 409.1871; found,
HRMS (ES): m/z calcd for C25H42O4SiNa+, 457.2745; found,
409.1859.
457.2734.
Anal. Calcd for C22H34O3S2 (410.63): C, 64.35, H, 8.35. Found: C,
64.23, H, 8.37.
Keto Ester 17
To a cold (0 °C), stirred soln of diisopropylamine (55 L, 0.39
mmol) in anhyd THF (1.3 mL) was added n-BuLi (245 L, 0.326
mmol) and the reaction mixture was stirred at 0 °C for 15 min,
cooled to –78 °C, treated with tert-butyl acetate (70 L, 0.52 mmol)
via syringe, and stirred at –78 °C for 1 h. A soln of 2 (26.3 mg, 0.064
mmol) in anhyd THF (1 mL) was added via cannula and stirring was
maintained at –78 °C for 45 min before the addition of H2O and
Et2O. After return to r.t., the layers were separated, and the aq phase
was extracted with Et2O. The combined organic extracts were dried,
concentrated, and purified by flash chromatography (EtOAc hex-
anes, 1:19) and the appropriate fractions were concentrated to af-
ford a ~1:1 mixture of inseparable –hydroxy esters (28.1 mg, 79%)
as a colorless oil. This material was used directly in the next step.
Dithiane 16
To a stirred soln of 15 (7.245 g, 17.64 mmol) in CH2Cl2 (175 mL)
was added 2,6-lutidine (4.1 mL, 35 mmol). The mixture was cooled
to –25 °C and neat tert–butyldimethylsilyl trifluoromethane-
sulfonate (6.1 mL, 27 mmol) was introduced. The mixture was
stirred at –25 °C for 1 h, treated with sat. NaHCO3 soln (100 mL),
and warmed to r.t. The separated aq phase was extracted successive-
ly with CH2Cl2 and Et2O. The combined organic extracts were
washed with brine and the brine extract was back-extracted with
Et2O. The combined organic extracts were dried and concentrated
under reduced pressure. The residue was purified by flash chroma-
tography (EtOAc hexanes, 1:9) to furnish 16 (8.798 g, 95%) as a
colorless, viscous oil.
A stirred soln of oxalyl chloride (22 L, 0.252 mmol) in anhyd
CH2Cl2 (0.5 mL) was cooled to –78 °C and DMSO (36 L, 0.51
mmol) dissolved in anhyd CH2Cl2 (0.5 mL) was added via cannula.
The reaction mixture was stirred at –78 °C for 10 min and the above
material (28.1 mg, 0.051 mmol) dissolved in anhyd CH2Cl2 (0.5
mL) was introduced via cannula. The reaction mixture was stirred
at –78 °C for 1 h, Et3N (80 L, 0.57 mmol, 11 equiv) was added, and
stirring was maintained at –78 °C for 35 min prior to warming to r.t.
for 30 min and the addition of half-sat. brine (4 mL). The separated
aq layer was extracted with CH2Cl2. The combined organic extracts
were washed once with brine, dried, concentrated, and purified by
flash chromatography (EtOAc–hexanes, 1:9) to afford 17 [25.5 mg
(96%, 76% over 2 steps)] as a colorless oil.
1H NMR (300 MHz, CDCl3): = 0.01 (s, 6 H), 0.88 (s, 9 H), 0.92
(d, J = 6.8 Hz, 3 H), 1.00 (d, J = 6.7 Hz, 3 H), 1.06–1.07 (m, 1 H),
1.50 (s, 9 H), 1.38–1.55 (m, 2 H), 1.67–1.83 (m, 1 H), 2.09–2.25 (m,
1 H), 3.79 (s, 3 H), 3.70–3.87 (m, 4 H), 3.99 (dd, J = 4.6, 2.4 Hz, 1
H), 4.38 (br s, 2 H), 4.84–5.01 (m, 2 H), 5.54 (ddd, J = 17.5, 10.1,
8.5 Hz, 1 H), 6.84 (d, J = 8.7 Hz, 2 H), 7.20 (d, J = 8.6 Hz, 2 H).
[ ]D22 0.1 (c 1.4, CHCl3).
IR (neat): 1641, 1613, 1586, 1513, 1248 cm–1.
1H NMR (300 MHz, CDCl3): = 0.05 (s, 3 H), 0.11 (s, 3 H), 0.87
(d, J = 6.7 Hz, 3 H), 0.88 (s, 9 H), 1.01 (d, J = 6.7 Hz, 3 H), 1.03–
1.11 (m, 1 H), 1.23–1.47 (m, 1 H), 1.60–1.78 (m, 1 H), 1.78–1.94
(m, 1 H), 2.01–2.31 (m, 3 H), 2.73–2.94 (m, 4 H), 3.54–3.74 (m, 2
H), 3.80 (s, 3 H), 3.93–4.01 (m, 1 H), 4.33 (d, J = 5.3 Hz, 1 H), 4.40
(d, J = 11.4 Hz, 1 H), 4.46 (d, J = 11.4 Hz, 1 H), 4.86–5.02 (m, 2 H),
5.59 (ddd, J = 18, 10, 8 Hz, 1 H), 6.87 (d, J = 8.5 Hz, 2 H), 7.29 (d,
J = 8.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): = –4.4, –3.7, 14.2, 18.3, 21.7, 36.1
(3 C), 26.3, 30.8, 31.1, 35.7, 37.1, 39.8, 45.9, 51.6, 55.2, 68.2, 72.6,
74.8, 113.1, 113.6 (2 C), 129.2 (2 C), 130.9, 144.3, 159.0.
HRMS (EI): m/z calcd for C28H48O3S2Si (M+), 524.2814; found,
524.2772.
Anal. Calcd for C28H48O3S2Si (524.89): C, 64.09, H, 9.23. Found:
C, 64.24, H, 9.24.
13C NMR (75 MHz, CDCl3): = –4.3, –4.2, 15.5, 18.3, 21.9, 26.0
(3 C), 26.1, 27.5 (3 C), 35.8, 37.8, 39.3, 49.5, 55.2, 68.0, 72.9, 76.0,
85.9, 113.4, 113.6 (2 C), 129.2 (2 C), 130.2, 143.8, 159.1, 161.9,
195.4.
HRMS (EI): m/z calcd for C31H52O6Si (M+), 548.3533; found,
548.3508.
Aldehyde 2
To a cold (0 °C), stirred soln of 16 (102 mg, 0.19 mmol) in CH3CN–
H2O (2 mL, 9:1) was added bis(trifluoroacetoxy)iodobenzene (190
mg, 0.442 mmol). The reaction mixture was stirred at 0 °C for 5
min, sat. NaHCO3 soln (2 mL) and Et2O were added, and the mix-
ture was warmed to r.t. The separated aq layer was extracted with
Et2O. The combined organic extracts were washed with sat.
NaHCO3 soln, dried, and concentrated under reduced pressure. The
residue was purified by flash chromatography (EtOAc hexanes,
1:1 ) to afford 68 mg of a clear oil. However, NMR analysis of the
oil thus obtained indicated that small amounts of 16 remained. The
above procedure was repeated using ~100 mg of bis(trifluoroace-
toxy)iodobenzene. After work up and flash chromatography as
above, there was isolated 52 mg (66%) of 2 as a colorless oil.
References and Notes
(1) Imai, H.; Suzuki, K.; Morioka, M.; Numasaki, Y.; Kadota,
S.; Nagai, K.; Sato, T.; Iwanami, M.; Saito, T. J. Antibiot.
1987, 40, 1475.
(2) Imai, H.; Nakagawa, A.; Omura, S. J. Antibiot. 1989, 42,
1321.
(3) Imai, H.; Kaniwa, H.; Tokunaga, T.; Fujita, S.; Furuya, T.;
Matsumoto, H.; Shimizu, M. J. Antibiot. 1987, 40, 1483.
(4) (a) Chlorothricolide: Muntwyler, R.; Keller-Scheirlein, W.
Helv. Chim. Acta 1972, 55, 2071. (b) See also: Brufani, M.;
Cerrini, S.; Fedeli, W.; Mazza, F.; Muntwyler, R. Helv.
Chim. Acta 1972, 55, 2094. (c) Kijanimicin: Mallams, A.
K.; Puar, M. S.; Rossman, R. R.; McPhail, A. T.;
Macfarlane, R. D.; Stephens, R. L. J. Chem. Soc., Perkin
Trans. 1 1983, 1497. (d) Tetronolide: Hirayama, N.; Kasai,
M.; Shirahata, K.; Ohashi, Y.; Sasada, Y. Bull. Chem. Soc.
Jpn. 1982, 55, 2984.
[ ]D22 –4.9 (c 1.18, CHCl3).
IR (neat): 1728, 1614, 1514, 1463, 1360, 1250 cm–1.
1H NMR (300 MHz, CDCl3): = –0.02 (s, 3 H), 0.04 (s, 3 H), 0.86
(s, 9 H), 0.89 (d, J = 6.9 Hz, 3 H), 0.98 (dd, J = 6.7 Hz, 3 H), 1.02–
1.08 (m, 1 H), 1.50–1.75 (m, 1 H), 2.06–2.24 (m, 1 H), 2.63–2.78
(m, 1 H), 3.70 (dd, J = 9.7, 4.7 Hz, 1 H), 3.80 (s, 3 H), 3.85 (dd,
J = 9.7, 8.6 Hz, 1 H), 3.99 (t, J = 4.7 Hz, 1 H), 4.43 (br s, 2 H), 4.87–
4.98 (m, 2 H), 5.50 (ddd, J = 17.2, 10.1, 8.6 Hz, 1 H), 6.87 (d,
J = 8.6 Hz, 2 H), 7.23 (d, J = 8.6 Hz, 2 H), 9.79 (d, J = 2.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): = –4.6, –4.3, 15.3, 18.2, 21.9, 25.9
(3 C), 35.9, 36.1, 39.3, 55.2, 55.3, 66.4, 73.0, 74.1, 113.4, 113.8 (2
C), 129.3 (2 C), 130.1, 143.8, 159.3, 204.2.
(5) Midland, S. L.; Keen, N. T.; Sims, J. J.; Midland, M. M.;
Stayton, M. M.; Burton, V.; Smith, M. J.; Mazzola, E. P.;
Graham, K. J.; Clardy, J. J. Org. Chem. 1993, 58, 2950.
(6) Boulet, S. L.; Paquette, L. A. Synthesis 2002, 895.
Synthesis 2002, No. 7, 888–894 ISSN 0039-7881 © Thieme Stuttgart · New York

894
L. A. Paquette, S. L. Boulet
PAPER
(11) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639.
(12) Compare Anderson, J. C.; Ley, S. V.; Marsden, S. P.
Tetrahedron Lett. 1994, 35, 2087.
(13) Ireland, R. E.; Norbeck, B. W. J. Org. Chem. 1985, 50, 2198.
(14) Behrens, C. H.; Sharpless, K. B. Aldrichimica Acta 1983, 16,
67.
(15) Lipshutz, B. H.; Kotsuki, H.; Lew, W. Tetrahedron Lett.
1986, 27, 4825.
(16) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
(17) Andrus, M. B.; Li, W.; Keyes, R. F. J. Org. Chem. 1997, 62,
5542.
(7) Allinger, N. L. J. Am. Chem. Soc. 1959, 81, 232; we thank
Prof. Satoru Masamune for providing us with more specific
details of the Allinger procedure.
(8) Stork, G.; Nair, V. J. Am. Chem. Soc. 1979, 101, 1315.
(9) Hoffmann, R. W.; Zeiss, H. J.; Ladner, W.; Tabche, S.
Chem. Ber. 1982, 115, 2357.
(10) Subsequent to the completion of this phase of our study,
Deng and co-workers: Chen, Y.; Tian, S.-K.; Deng, L. J. Am.
Chem. Soc. 2000, 122, 9542 reported on a very attractive
alternative means for the desymmetrization of prochiral
cyclic anhydrides. We had no subsequent occasion to
evaluate the Deng protocol.
Synthesis 2002, No. 7, 888–894 ISSN 0039-7881 © Thieme Stuttgart · New York