Application of sulfur ylide mediated epoxidations in the asymmetric synthesis of β-hydroxy-δ-lactones. Synthesis of a mevinic acid analogue and (+)-prelactone B

Article abstract of DOI:10.1016/j.tet.2004.07.044

Catalytic and stoichiometric asymmetric sulfur ylide reactions were employed to prepare alkyl-aryl epoxide intermediates in a convergent manner. These epoxides were utilized in efficient syntheses of the mevinic acid analogue 1 and prelactone B. Graphical abstract.

Full text of DOI:10.1016/j.tet.2004.07.044

Tetrahedron 60 (2004) 9725–9733
Application of sulfur ylide mediated epoxidations in the
asymmetric synthesis of b-hydroxy-d-lactones. Synthesis of a
mevinic acid analogue and (C)-prelactone B
Varinder K. Aggarwal,a, Imhyuck Baea,b and Hee-Yoon Leeb,
*
*
aSchool of Chemistry, Cantock’s Close, University of Bristol, Bristol BS8 1TS, UK
bCenter for Molecular Design and Synthesis (CMDS), Department of Chemistry and School of Molecular Science (BK21),
Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, South Korea
Received 21 June 2004; revised 4 July 2004; accepted 6 July 2004
Available online 21 August 2004
Abstract—Catalytic and stoichiometric asymmetric sulfur ylide reactions were employed to prepare alkyl–aryl epoxide intermediates in a
convergent manner. These epoxides were utilized in efficient syntheses of the mevinic acid analogue 1 and prelactone B.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Our general retrosynthetic analysis of b-hydroxy-d-lactones
A1/A2 is shown in Scheme 1. The target lactone A1/A2
could be generated from the corresponding hydroxy keto-
ester via diastereoselective reduction. The hydroxy keto
ester B could be obtained by sequential Birch reduction and
ozonolysis of epoxide D,6 which itself could potentially be
obtained through our asymmetric sulfur ylide mediated
epoxidation reaction employing sulfide S.2 In this paper we
report two successful syntheses of b-hydroxy-d-lactones
using this synthetic strategy.
The asymmetric synthesis of epoxides from carbonyl
compounds using sulfur ylide intermediates has emerged
as a powerful method for not only creating C–C bonds with
control of asymmetry but also for generating functionality
suitable for further manipulation.1 We have reported an
efficient catalytic asymmetric process for the conversion of
aldehydes into epoxides2 and a complementary stoichio-
metric process for a range of problematic substrates, which
had either given low yields or low selectivities in our
catalytic process.3 The broad substrate scope of the
combined catalytic and stoichiometric processes now allows
the sulfur ylide disconnection to be applied with confidence
in total synthesis. The practicality of these methods have
been demonstrated in the concise synthesis of CDP 840.3
Most studies of asymmetric epoxidation of carbonyl
compounds to date have focused on methodology develop-
ment4 rather than their use, but the power of new
methodology is best illustrated with applications in
synthesis. In this paper, we describe the application of
catalytic and stoichiometric asymmetric sulfur ylide
mediated epoxidation methodology in the synthesis of the
b-hydroxy-d-lactones which are present in a large number
of biologically important molecules (Fig. 1).5
We chose as our first target the b-hydroxy-d-lactone 1.7 This
lactone is a simplified structural analogue of the naturally
occurring potent HMG-CoA reductase inhibitors, compac-
tin and mevinolin.8 Since their discovery, many synthetic
approaches to these compounds as well as analogues have
appeared9 and it has been shown from SAR studies that the
lactone moiety of the mevinic acids is essential for the
biological activity.10
To synthesize lactone 1 we required epoxide 2. In order to
prepare epoxide 2, we decided to employ the stoichio-
metric sulfur ylide reaction since we were aware that
a-unsubstituted aldehydes gave epoxides with low dia-
stereoselectivity (e.g. valeraldehyde, 3:1 trans/cis)2 under
catalytic conditions. Thus, sulfide S was converted into the
required sulfonium salt and treated with 3-cyclohexane
propanal (prepared from commercially available 3-cyclo-
hexyl propanol) in the presence of the EtP2 base. This
furnished the desired epoxide 2 with almost perfect
Keywords: Sulfur ylide; Epoxides; Mevinic acid.
11,3
* Corresponding authors. Tel.: C44-117-9546315; fax: C44-117-9298611
(V.K.A.); e-mail: v.aggarwal@bristol.ac.uk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.044

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V. K. Aggarwal et al. / Tetrahedron 60 (2004) 9725–9733
Figure 1. b-Hydroxy-d-lactone structures in biologically important molecules.
Scheme 1. Retrosynthetic analysis of b-hydroxy-d-lactones A1/A2.
enantioselectivity (99% for trans) and good diastereo-
selectivity (92:8) in 96% yield (Scheme 2). Chiral sulfide S
was recovered in 83% yield.
ethers from which the desired anti product 3 was isolated in
82% yield. Since the diastereomeric ratio of epoxide
isomers correlated well with the ratio of ethers formed, it
is believed that epoxide opening occurred with clean
inversion.
Separation of the cis and trans epoxides was required since
they possess opposite stereochemistry at C2 and if they were
both carried through would erode the enantioselectivity of
the final product. However, all attempts to separate the two
epoxides were unsuccessful. We therefore decided to open
the epoxide with a suitable nucleophile to generate a
separable diastereomeric mixture. Among a variety of
possible nucleophiles, we considered alkoxides because
such functionality could be easily removed during Birch
reduction. Both methanol and i-PrOH were investigated and
the isopropyl ether 3 gave a readily separable diastereo-
meric mixture. Thus, opening of epoxides with i-PrOH in
the presence of catalytic concd H2SO4 gave two separable
Next, Birch reduction was carried out under standard
conditions.12 After a solution of alcohol 3 in NH3 with
10 equiv of Li metal and 5 equiv of i-PrOH was refluxed
for 2 h, diene 4 was generated in 68% yield. Ozonolysis of
diene 4 afforded hydroxy keto ester 5 in moderate yield.
However, the resulting keto ester 5 readily lactonized during
purification on silica gel and decomposed in basic media. To
avoid these problems, the crude material was quickly
filtered through a silica gel pad, and used directly in the next
step. syn Selective reduction of hydroxy keto ester 5 using
NaBH4 in the presence of Et2B(OMe) gave 6 with almost

V. K. Aggarwal et al. / Tetrahedron 60 (2004) 9725–9733
9727
Scheme 2. Total synthesis of a mevinic acid analogue.
perfect diastereoselectivity (O98:2).13 The syn-3,5-di-
hydroxy ester 6 slowly lactonized during purification on
silica gel. We therefore treated the crude material with a few
drops of 1 N HCl and this furnished the desired lactone 1
(42% over 3 steps). This material was identical to that
reported in the literature (mp 70–72 8C, [a]2D0ZC35.6 (cZ
1.0 in CHCl3) [lit.7a: mp 69–70 8C, [a]2D0ZC34.1 (cZ0.85
in CHCl3)]).
and cis isomers. The enantiomeric excesses for the two
isomers were 93 and 70%, respectively.
Ring-opening reactions of the epoxide 7 with a variety of
organometallic reagents was not straightforward. Neither
MeLi nor Grignard reagents furnished the desired product
even with BF3$Et2O. Cuprates and Grignard reagents
(MeMgBr or MeMgCl) with catalytic amount of various
Cu salts under several different conditions were also
examined15 and despite partial success, yields were
capricious and a significant amount of alkene 12 and
unreacted starting epoxide were always observed. In
addition, rearrangement of the epoxide to the corresponding
ketone was occasionally observed. Trimethylaluminum
was also tried16 but in this case, the product was the
undesired syn isomer regardless of the reaction conditions.
Successful ring opening was finally achieved when the
cuprate was employed in the presence of a Lewis acid.17
Most importantly, careful control of the temperature and
stoichiometry of the cuprate were critical to obtain reliable
and reproducible results: 3 equiv of MeLi was slowly added
to a suspension of 3 equiv of CuCN in Et2O at 0 8C. After
30 min at 0 8C, the mixture was cooled to K78 8C and a
solution of epoxide was slowly added to the cuprate
followed by addition of BF3$OEt2. Under the optimized
conditions, the ring-opening reaction of the mixture of
chiral epoxides proceeded smoothly to give alcohol 8 in
In the above synthesis, only one of the two stereogenic
centers created in the epoxide was used, as the other was
destroyed. We were keen to exemplify our methodology
where both stereogenic centers were utilized and therefore
turned our attention to the synthesis of the b-hydroxy-d-
lactone, (C)-prelactone B. This functionalized chiral
d-lactone was first isolated from bafilomycin-producing
Streptomyces griseus by Zeeck and Bindseil in 1993, and it
represents an early metabolite in the biosynthesis of
polyketide antibiotics.14
Since the aryl epoxide required 7 bears branching at the
a-position, we expected that our catalytic process would
furnish the epoxide with good levels of diastereoselectivity.
We therefore began our synthesis by treating isobutyralde-
hyde under our standard catalytic epoxidation conditions
employing 25 mol% of the chiral sulfide S.2 This furnished
the desired epoxide in 50% yield as a 9:1 mixture of trans

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V. K. Aggarwal et al. / Tetrahedron 60 (2004) 9725–9733
Scheme 3. Total synthesis of (C) prelactone B.
61% yield with 93% ee. The trans epoxide was converted
into the anti alcohol 8 while the cis epoxide was largely
untouched (Scheme 3).
when the reduction reaction was quenched with water and
left to stir for an additional 1 h at room temperature, the
anti-dihydroxy ester 11 was converted into (C)-prelactone
B while the minor syn dihydroxy ester remained in solution.
Using a few drops of aqueous 1 N HCl resulted in complete
conversion of the 10:1 mixture of diols into the same
mixture of lactones. The synthetic sample of (C)-prelactone
B (93% ee) was spectroscopically identical to that reported
in the literature (mp 96–98 8C, [a]1D9ZC51.5 (cZ1.0 in
CH3OH) [lit.14b: mp 97–98 8C, [a]1D9ZC62.1 (cZ1.72 in
CH3OH)]). The lower alpha D observed probably reflects
the enantioselectivity obtained in the epoxidation step
(93% ee).
Under identical Birch reduction conditions as used pre-
viously, the desired diene 9 was obtained in only 46% yield
with 42% of over-reduced side-product 13. It was believed
that the presence of the free alcohol in close proximity to the
double bond resulted in further reduction of the diene to the
cylcohexene 13.18 We attempted to suppress unwanted
over-reduction by protecting the free alcohol but this
resulted in considerably slower and lower yielding reac-
tions. Best results were obtained when the reaction was
carried out with 5 equiv of Li and 2 equiv i-PrOH. Under
these conditions, the desired diene 9 was obtained in 84%
yield with negligible amounts of the over-reduced side
product 13.
3. Conclusions
In conclusion, we have successfully synthesized naturally
occurring and biologically important b-hydroxy-d-lactones
from enantiomerically enriched epoxides. These syntheses
demonstrate the utility of enantioselective sulfur ylide
mediated reactions in the convergent preparation of
epoxides and their subsequent diverse applications in
organic synthesis.
After ozonolysis, the hydroxy keto ester 10 was then
reduced to dihydroxy ester 11. Of the several reducing
agents tested, sodium triacetoxyborohydride19 was found to
be optimum giving good yields and selectivities (10:1). As
the resulting dihydroxy ester 11 was unstable on silica gel,
this compound was directly treated with acid. Interestingly,

V. K. Aggarwal et al. / Tetrahedron 60 (2004) 9725–9733
9729
4. Experimental
4.1. General methods
became cloudy. Triethylamine (5.0 mL) was added to the
solution and the solution was warmed to room temperature
slowly. Water (20 mL) was added and the layers were
separated. The aqueous layer was extracted with dichloro-
methane (3!20 mL). The crude mixture was purified by
flash chromatography (EtOAc/hexaneZ1/10). Colorless oil
(500 mg, 89%); RfZ0.50 (EtOAc/hexaneZ1/10); 1H NMR
(300 MHz, CDCl3) 0.80–0.92 (2H, m, CH2), 1.04–1.26 (4H,
m, CH2!2), 1.49 (2H, q, JZ7.5 Hz, CH2CH), 1.57–1.71
(5H, m, CH2!2CCH), 2.40 (2H, dt, JZ2.0, 7.5 Hz,
CH2CHO), 9.73 (1H, t, JZ2.0 Hz, CHO); 13C NMR
(75 MHz, CDCl3) 26.2, 26.4, 29.3, 33.0, 37.2, 41.5, 203.1.
All oxygen or moisture sensitive reactions were carried out
in oven-dried glassware under the positive pressure of
argon. Sensitive liquids and solutions were transferred by
syringe or cannula and introduced through rubber septa
through which a high flow of nitrogen was maintained.
Concentration of solution was accomplished by using a
Buchi rotary evaporator with a water aspirator. This was
generally followed by removal of residual solvents on a
vacuum line held at 0.1–1 Torr. Unless otherwise stated, all
commercial reagents and solvents were used without
additional purification. Chromatography grade hexane and
ethyl acetate were technical grade and distilled before use.
Et2O and THF were distilled from sodium benzophenone
ketyl under nitrogen. Triethylamine was distilled from
sodium. Dichloromethane was distilled from P2O5. Ana-
lytical thin layer chromatography (TLC) was performed on
Merck precoated silica gel 60 F254 plates. Visualization on
TLC was achieved by use of UV light (254 nm), treatment
with acidic anisaldehyde, potassium permanganate, 5%
phosphomolybdic acid in ethanol, or ceric ammonium
molybdate stain followed by heating. Flash column
chromatography was undertaken on silica gel (Merck
Kieselgel 60 F254 400–630 mesh). Proton nuclear magnetic
resonance spectroscopy (1H NMR) was recorded on Bruker
FT AM 400 (400 MHz). Chemical shifts were quoted in
parts per million (ppm) referenced to the appropriate solvent
peak or 0 ppm for TMSCl. The following abbreviations
were used to describe peak patterns when appropriate: brZ
broad, sZsinglet, dZdoublet, tZtriplet, qZquadruplet,
mZmultiplet. Coupling constant, J was reported in Hertz
unit (Hz). Carbon 13 nuclear magnetic resonance spectro-
scopy (13C NMR) was recorded on Brucker FT AM 400
(100 MHz) and was fully decoupled by broad band
decoupling. Chemical shifts were reported in ppm refer-
enced to the center line of a triplet at 77.0 ppm of
chloroform-d. Infrared (IR) spectra were recorded neat in
0.5 mm path length sodium chloride cells on Bruker
EQUINOX 55. Frequencies are given in reciprocal
centimeters (cmK1) and only selected absorbances are
reported. Optical rotations were measured on an Autopol III
of Rudolph instrument or a Perkin–Elmer 241 polarimeter
at598 nm (Na D-line) with a path length of 1 dm.
Concentrations (c) are quoted in g/100 mL. Low resolution
mass spectra (m/z) were recorded on a VG Platform or VG
Prospec with only (MC) and major peaks being reported
with intensities being quoted as percentages of the base
peak. High resolution mass spectra were recorded on a VG
Prospec by using direct insertion probe (DIP) and EI or FAB
method. High performance liquid chromatography (HPLC)
data were obtained by using Agillent with chiralcel OD,
OD-H, OJ or chiralpak AS-H column.
4.1.2. 2-(3-Methoxybenzyl)-3-[(1R)-7,7-dimethyl-2-oxo-
bicyclo[2.2.1]hept-1-yl]-(3S)-2-thionia-bicyclo [2.2.1]-
heptane tetrafluoroborate. To a rapidly stirred solution
of chiral sulfide S (500 mg, 2.0 mmol) and 3-methoxyben-
zyl bromide (420 mL, 3.0 mmol) in dichloromethane (2 mL)
was added silver tetrafluoroborate (778 mg, 4.0 mmol) in
the dark under an argon atmosphere at room temperature.
The reaction stirred for 48 h and 10 mL of CH2Cl2 was
added. Silver bromide precipitate was filtered and the filtrate
was concentrated in vacuo. The residual brown oil was
purified by flash chromatography (0–5% MeOH/CH2Cl2) to
give an off white foam. This was recrystallized from CH2Cl2
and Et2O to give a white precipitate. (572 mg, 77%); RfZ
0.36 (MeOH/CH2Cl2Z1/10); nmax/cmK1 (neat) 2957, 1739,
1587, 1492, 1456, 1267, 1055; mp 168K169 8C; [a]1D9Z
1
K40.0 (cZ1.0 in CH2Cl2); H NMR (400 MHz, CDCl3)
1.08 (3H, s, CH3), 1.18 (3H, s, CH3), 1.29 (2H, d, JZ8.6 Hz,
CH2), 1.60 (2H, m, CH2), 1.87–2.22 (7H, m, 2!CH2C
CHHCOCSCHCHH), 2.54 (1H, ddd, JZ2.6, 5.2, 18.8 Hz,
CHHCO), 2.85 (1H, d, JZ12.9 Hz, SCHCHH), 3.20 (1H, br
s, SCHCH), 3.80 (3H, s, OCH3), 4.11 (1H, d, JZ5.0 Hz,
SCHCH2), 4.39 (1H, d, JZ13.5 Hz, SCHHAr), 4.42 (1H, d,
JZ2.7 Hz, SCHCH), 4.62 (1H, d, JZ13.5 Hz, SCHHAr),
6.88 (1H, dd, JZ2.6, 8.6 Hz, ArH), 6.97 (1H, br s, ArH),
6.99 (1H, d, JZ2.0 Hz, ArH), 7.26 (1H, t, JZ8.2 Hz, ArH);
13C NMR (100 MHz, CDCl3) 19.2, 21.9, 24.4, 26.7, 26.8,
33.3, 41.1, 43.5, 44.1, 45.1, 47.8, 49.9, 55.6, 57.6, 60.1,
68.9, 115.2, 116.2, 122.3, 129.8, 130.7, 160.5, 215.7; m/z
(FAB) 371 (MCKBF4K, 100%), 217 (30), 121 (43), 55 (33);
(Found: MCKBFK4 371.2044 C23H31SO2 requires m/z
371.2045).
4.1.3. 2-(2-Cyclohexylethyl)-3-(3-methoxyphenyl)oxi-
rane (2). To a stirred solution of 2-(3-methoxybenzyl)-3-
[(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]-(3S)-2-
thioniabicyclo-[2.2.1]-heptane tetrafluoroborate (465 mg,
1.0 mmol) in dichloromethane (5.0 mL) was added
N,N,N0,N0,-tetramethyl-N00-[tris(dimethylamino)phos-phor-
alidene]phosphoric triamide ethylimine (415 mL,
1.25 mmol) at K78 8C under argon. After 30 min, 3-cyclo-
hexylpropanal (175 mg, 1.25 mmol) was added to the
solution. After 2 h stirring, the mixture was warmed up to
room temperature and then saturated NaCl solution (10 mL)
was added. The organic layer was separated and the aqueous
layer extracted with EtOAc (3!10 mL). The combined
organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. The crude mixture was purified by
flash chromatography (EtOAc/hexaneZ1/50) to give a
mixture of trans/cisZ92:8 epoxides (249 mg, 96%) and
chiral sulfide (259 mg, 83%); RfZ0.30 (EtOAc/hexaneZ
4.1.1. 3-Cyclohexylpropanal.20 Neat DMSO (1.0 mL,
14 mmol) was added dropwise to a stirred solution of
oxalyl chloride (440 mL, 5.0 mmol) in dichloromethane
(20 mL) at K78 8C under argon atmosphere. After 15 min
3-cyclopropanol (610 mL, 4.0 mmol) was slowly added
while the temperature was maintained at K78 8C. The
solution was stirred for 1 h, during which the solution

9730
V. K. Aggarwal et al. / Tetrahedron 60 (2004) 9725–9733
1/20); nmax/cmK1 (neat) 2923, 1604, 1493, 1455, 1260,
1154, 1047, 891, 782; H NMR (400 MHz, CDCl3) 0.66–
combined organic layers were dried over Na2SO4, filtered
and concentrated in vacuo. The crude mixture was purified
by flash chromatography (EtOAC/hexaneZ1/20) to give a
colorless oil (214 mg, 67%); RfZ0.18 (EtOAc/hexaneZ
1/10); nmax/cmK1 (neat) 3418, 2994, 1696, 1665, 1449,
1
0.80 (cis, 2H, m, CH2), 0.84–0.94 (trans, 2H, m, CH2),
1.04–1.30 (4H, m, CH2!2), 1.30–1.44 (2H, m, CH2), 1.62–
1.74 (7H, m, CH2!3CCH), 2.89 (trans, 1H, dt, JZ2.2,
5.7 Hz, CH(O)CHAr), 3.15 (cis, 1H, dt, JZ4.3, 5.7 Hz,
CH(O)CHAr), 3.57 (trans, 1H, d, JZ2.2 Hz, CH(O)CHAr),
3.78 (trans, 3H, s, OCH3), 3.79 (cis, 3H, s, OCH3), 4.03 (cis,
1H, d, JZ4.3 Hz, CH(O)CHAr), 6.77 (1H, m, ArH), 6.81
(1H, ddd, JZ1.0, 2.4, 8.0 Hz, ArH), 6.85 (1H, m, ArH),
7.23 (1H, t, JZ7.8 Hz, ArH); 13C NMR (100 MHz, CDCl3)
trans isomer: 26.3 (2), 26.6, 29.6, 33.1, 33.3, 33.4, 37.3,
55.2, 58.6, 63.4, 110.4, 113.7, 118.0, 129.4, 139.7, 159.8 cis
isomer: 24.0, 26.1, 26.2, 26.5, 33.0, 33.5, 33.7, 57.5, 59.0,
111.7, 113.2, 118.8, 129.0, 137.4, 159.3; m/z (EI) 260 (MC,
70%), 177 (10), 163 (44), 149 (72), 136 (81), 121 (100), 109
(70), 95 (53), 91 (58), 81 (62), 67 (60), 55 (65); (Found MC
260.1786 C17H24O2 requires m/z 260.1776); Chiracel OD-
H, hexane/i-PrOH (99.5/0.5), 1.0 mL/min, 10 8C, major
9.9 min (2R,3R), minor 10.6 min (2S,3S) for trans isomer and
major 9.2 min (2R,3S), minor 7.0 min (2S,3R) for cis isomer.
1
1390, 1221, 1136; H NMR (400 MHz, C6D6) 0.80–0.95
(2H, m, CH2), 1.05–1.45 (9H, m, CH2!4COH), 1.60–1.75
(5H, m, CH2!2CCH), 1.99 (2H, d, JZ6.3 Hz,
CHOHCH2CHZC), 2.70–2.90 (4H, m,ZCCH2CZ!2),
3.28 (3H, s, OCH3), 3.51 (1H, m, CHOH), 4.44 (1H, br s,
CHZCOCH3), 5.43 (1H, br s, CHZC(CH2)2); 13C NMR
(100 MHz, C6D6) 26.7, 26.8, 27.1, 27.2, 32.3, 33.6, 33.7,
33.8, 35.0, 38.1, 45.9, 53.6, 69.1, 90.2, 121.9, 132.1, 153.4;
m/z (EI) 264 (MC, 20%), 135 (31), 122 (100), 109 (37), 91
(14), 55 (17); (Found MC 264.2090 C17H28O2 requires m/z
264.2089).
4.1.6. 6-(2-Cyclohexylethyl)-4-hydroxy-tetrahydro-
pyran-2-one (1).7a Round-bottomed flask equipped with
CaCl2 drying tube was filled with a solution of (2R)-4-
cyclohexyl-1-(5-methoxycyclohexa-1,4-dienyl)-butan-2-ol
(110 mg, 0.42 mmol) and pyridine (100 mL) in 10 mL of
dichloromethane and 2 mL of methanol at K78 8C. O3 was
bubbled until saturated, at which point blue color was
persisted. The solution was degassed with O2 until blue
color disappeared. Triphenylphosphine (110 mg,
0.42 mmol) was added and stirring continued for 1 h at
room temperature. NaCl solution was added and two layers
were separated. The aqueous layer extracted with dichloro-
methane (3!10 mL). The combined organic layers were
dried (Na2SO4), filtered and concentrated to give the desired
product as a colorless oil, which was used in next step
without further purification; RfZ0.35 (EtOAc/hexaneZ
1/2); nmax/cmK1 (neat) 3421, 2923, 2851, 1747, 1715,
4.1.4. (1S,2R)-4-Cyclohexyl-1-isopropoxy-1-(3-methoxy-
phenyl)butan-2-ol (3). A solution of 2-(2-cyclohexylethyl)-
3-(3-methoxyphenyl)oxirane (260 mg, 1.0 mmol) in i-PrOH
(10 mL) was treated with catalytic amount of conc. H2SO4
at 0 8C. After 30 min, i-PrOH was removed under reduced
pressure in the presence of NaHCO3. The residue was
dissolved with ether, and then after filtration of the mixture,
the filtrate was concentrated in vacuo. The crude mixture
was purified by flash chromatography (EtOAc/hexaneZ
1/10) to give a colorless oil (262 mg, 82%); RfZ0.22
(EtOAc/hexaneZ1/10); nmax/cmK1 (neat) 3568, 2923,
1488, 1453, 1263, 1050; [a]2D0ZC57.4 (cZ1.0 in
1
1
CH3OH); H NMR (400 MHz, CDCl3) 0.82 (2H, m, CH2),
1651, 1448, 1324; H NMR (400 MHz, CDCl3) 0.82–0.95
1.05–1.50 (8H, m, CH2!4), 1.09 (3H, d, JZ6.1 Hz,
CH(CH3)2), 1.13 (3H, d, JZ6.1 Hz, CH(CH3)2), 1.55–
1.70 (5H, m, CH2!3CCH), 1.79 (1H, br s, OH), 3.51 (1H,
septet, JZ6.1 Hz, CH(CH3)2), 3.62 (1H, m, CHOH), 3.78
(3H, s, OCH3), 4.27 (1H, d, JZ5.3 Hz, CHO(i-Pr)), 6.81
(1H, m, ArH), 6.89 (1H, m, ArH), 7.24 (1H, t, JZ8.1 Hz,
ArH); 13C NMR (100 MHz, CDCl3) 21.2, 23.4, 26.4 (2),
26.9, 29.4, 33.2, 33.5 (2), 37.8, 55.2, 69.5, 75.1, 82.0, 113.0,
113.1, 120.1, 129.2, 141.4, 159.6; m/z (FAB) 343 (MCC
Na, 98), 261 (100), 180 (47), 137 (65), 121 (58), 109 (28),
55 (16); (Found MCCNa 343.2251 C20H32O3Na requires
m/z 343.2249); Chiracel OD-H, hexane/i-PrOH (98/2),
0.5 mL/min, 20 8C, major 12.8 min (1S,2R), minor
11.7 min (1R,2S).
(2H, m, CH2), 1.00–1.50 (10H, m, CH2!5), 1.55–1.78
(5H, m, CH2!2CCH), 2.61 (1H, dd, JZ8.8,
17.4 Hz, CHOHCH2CO), 2.70 (1H, dd, JZ3.1, 17.4 Hz,
CHOHCH2CO), 3.46 (2H, s, COCH2CO2CH3), 3.71 (3H, s,
OCH3), 4.00 (1H, m, CHOH); 13C NMR (100 MHz, C6D6)
26.3 (2), 26.6, 33.0, 33.2, 33.3, 33.8, 37.5, 49.6 (2), 52.4,
67.8, 167.3, 203.6; m/z (FAB) 257 (MCCH, 100), 239 (49),
189 (35), 137 (60), 117 (44), 81 (43), 55 (40); (Found MCC
H 257.1750 C14H25O4 requires m/z 257.1753).
To a cooled (K78 8C) solution of resulting (5R)-7-
cyclohexyl-5-hydroxy-3-oxo-heptanoic acid methyl ester
in 5 mL of THF and 1 mL of methanol was added a solution
of diethylmethoxyborane (1.0 M in THF, 420 mL). The
reaction mixture stirred at K78 8C for 15 min and then
sodium borohydride (77 mg, 2.0 mmol) was added in a
portion. The mixture stirred for 2 h and quenched by adding
1 mL of 1 N HCl. Stirring continued 1 h and NaHCO3
solution was added to neutralize the mixture. The aqueous
layer extracted with ethyl acetate (3!5 mL). The combined
organic layer were dried (MgSO4), filtered and concen-
trated. Flash chromatography with EtOAc/hexaneZ1/2
gave the desired product as a white solid (40 mg, 42%);
RfZ0.15 (EtOAc/hexaneZ1/2); mp 70–72 8C [lit.: 69–70
8C]7a; [a]D20ZC35.6 (cZ1.0 in CHCl3) [lit.: [a]2D0ZC34.1
4.1.5. (2R)-4-Cyclohexyl-1-(5-methoxycyclohexa-1,4-di-
enyl)-butan-2-ol (4). Well-dried NH3 over Na was
transferred to a two-neck flask containing Li (69 mg,
10.0 mmol). A solution of (1S,2R)-4-cyclohexyl-1-isopro-
poxy-1-(3-methoxyphenyl)butan-2-ol (385 mg, 1.2 mmol)
in THF (1 mL) was added to the blue NH3 solution via
cannula followed by addition of i-PrOH (500 mL,
6.0 mmol). The mixture was refluxed for 2 h and cooled
to K78 8C, and then treated sequentially with 2 mL of
benzene and 850 mg of ammonium acetate. NH3 was
allowed to evaporate and the residue was partitioned
between brine (10 mL) and ethyl acetate (10 mL). The
mixture was extracted with ethyl acetate (3!10 mL). The
1
(cZ0.85 in CHCl3)]7a; H NMR (300 MHz, CDCl3) 0.75–
0.95 (2H, m, CH2), 1.05–1.95 (16H, m, CH2!7CCHC
OH), 2.60 (1H, ddd, JZ1.5, 3.8, 22.6 Hz, CH2CO2), 2.65

V. K. Aggarwal et al. / Tetrahedron 60 (2004) 9725–9733
9731
(1H, dd, JZ5.0, 22.6 Hz, CH2CO2), 4.36 (1H, m, CHOH),
4.63 (1H, m, CHOCO).
organic phases dried over MgSO4, filtered and concentrated
in vacuo. The crude mixture was purified on silica gel
(Et2O/hexaneZ1/20) to give a desired product with some
unknown impurities. Further purification was carried out by
Kugelrohr distillation (6 Torr, 140 8C) to afford a pure
mixture of trans/cisZ90:10 (190 mg, 50%) as a colorless
oil; RfZ0.30 (Et2O/hexaneZ1/10); nmax/cmK1 (neat) 2963,
4.1.7. m-Methoxybenzaldehyde tosylhydrazone. To a
rapidly stirred suspension of p-toluenesulfonyl hydrazide
(5.7 g, 30.0 mmol) in methanol (20 mL) was added
m-anisaldehyde (3.75 mL, 30 mmol) dropwise. A mildly
exothermic reaction ensued and the hydrazide dissolved.
Within 5–10 min m-methoxybenzaldehyde tosylhydrazone
began to precipitate. After approximately 30 min the
mixture was cooled to 0 8C and the product removed by
filtration, washed with a small quantity of ice-cold
methanol. Recrystallization from methanol gave a white
solid (8.25 g, 90%); nmax/cmK1 (neat) 3463, 3158, 1597,
1327, 1270, 1171, 1064, 899, 665; mp 106–107 8C; 1H
NMR (400 MHz, CDCl3) 2.37 (3H, s, CH3), 3.78 (3H, s,
OCH3), 6.88 (1H, dd, JZ2.5, 8.2 Hz, ArH), 7.08 (1H, d, JZ
7.6 Hz, ArH), 7.12 (1H, s, ArH), 7.22 (1H, t, JZ8.0 Hz,
ArH), 7.28 (2H, d, JZ8.2 Hz, ArH), 7.73 (1H, s, CHZN),
7.86 (2H, d, JZ8.2 Hz, ArH), 8.32 (1H, br s, NH); 13C
NMR (100 MHz CDCl3) 21.6, 55.3, 111.5, 116.7, 120.5,
127.9, 129.6, 129.7, 134.5, 135.2, 144.3, 147.7, 159.7; m/z
(EI) 304 (MC, 20%), 156 (18), 148 (100), 139 (13), 134
(46), 120 (97), 105 (15), 91 (81), 77 (31), 65 (28), 51 (22);
(Found MC 304.0886 C15H16N2O3S requires m/z
304.0882).
1
1604, 1464, 1260, 1046; H NMR (400 MHz, CDCl3) 0.70
(cis, 3H, d, JZ6.7 Hz, CH3), 1.01 (trans, 3H, d, JZ6.8 Hz,
CH3), 1.08 (transCcis, 3H, d, JZ6.8 Hz, CH3), 1.24 (cis,
1H, m, CH(CH3)2), 1.66 (trans, 1H, octet, JZ6.8 Hz,
CH(CH3)2), 2.72 (trans, 1H, dd, JZ2.1, 6.8 Hz, COHCH),
3.63 (trans, 1H, d, JZ2.1 Hz, ArCOH), 2.83 (cis, 1H, dd,
JZ4.4, 9.2 Hz, COHCH), 3.78 (trans, 3H, s, OCH3), 3.79
(cis, 3H, s, OCH3), 4.06 (cis, 1H, d, JZ4.4 Hz, ArCOH),
6.76–6.92 (3H, m, ArH), 7.23 (1H, t, JZ7.9 Hz, ArH); 13C
NMR (100 MHz CDCl3) trans isomer: 18.4, 19.0, 30.9,
55.2, 57.5, 68.3, 110.4, 113.7, 117.9, 129.4, 139.7, 159.8; cis
isomer: 17.9, 19.9, 25.9, 55.2, 57.7, 65.1, 111.7, 112.9,
118.7, 129.0, 137.5, 159.3; m/z (EI); 192 (MC, 79%), 176
(13), 161 (25), 149 (95), 136 (100), 121 (40), 109 (19), 91
(45), 77 (28), 71 (12), 55 (12); (Found MC 192.1152
C12H16O2 requires m/z 192.1150); Chiracel OJ-H, hexane/
i-PrOH (99.5/0.5), 1.0 mL/min, 10 8C, major 12.0 min
(2R,3R), minor 13.1 min (2S,3S) for trans isomer and
major 7.4 min (2R,3S), minor 8.1 min (2S,3R) for cis
isomer.
4.1.8. m-Methoxybenzaldehyde tosylhydrazone sodium
salt. A 1.0 M sodium methoxide solution was prepared by
adding sodium (635 mg, 27.5 mmol) to anhydrous methanol
(27.5 mL) with external cooling. Once all of the metal had
dissolved, m-methoxybenzaldehyde tosylhydrazone (8.25 g,
27 mmol) was added and the mixture stirred until the solid
had dissolved. After stirring for a further 15 min, methanol
was removed under reduced pressure at room temperature to
yield hydrazone salt in quantitative yield. Solid hydrazone
salt was then ground using a pestle and mortar to give a free
flowing powder; nmax/cmK1 (neat) 3459, 2959, 1600, 1237,
4.1.10. (2S,3R)-2-(3-Methoxyphenyl)-4-methyl-pentan-
3-ol (8). To a stirred suspension of CuCN (464 mg,
5.2 mmol) in Et2O (20 mL) was quickly added MeLi
(1.6 M in Et2O, 3.25 mL) at 0 8C. After 20 min the mixture
was cooled to K78 8C. A solution of 2-isopropyl-3-
(3-methoxyphenyl)oxirane (322 mg, 1.73 mmol) in Et2O
(5 mL) was added followed by BF3$Et2O (220 mL,
1.73 mmol). Temperature was raised to room temperature
after 6 h and 50 mL of NH3Cl/NH4OH solution (4/1) was
added. The aqueous layer was washed with ethyl acetate
(3!50 mL) and the combined organic phases were dried
over MgSO4, filtered and concentrated in vacuo. The crude
material was purified by flash chromatography (EtOAc/
hexaneZ1/20) to furnish a pale yellow oil (232 mg, 64%);
RfZ0.25 (EtOAc/hexaneZ1/10); nmax/cmK1 (neat) 3476,
2962, 1602, 1487, 1262; [a]1D7ZK19.1 (cZ1.0 in CH3OH);
1H NMR (400 MHz, CDCl3) 0.92 (3H, d, JZ6.8 Hz,
(CH3)2CH), 1.01 (3H, d, JZ6.8 Hz, (CH3)2CH), 1.20 (1H,
br s, OH), 1.22 (3H, d, JZ7.0 Hz, CH3CHAr), 1.79 (1H,
d-septet, JZ4.2, 6.8 Hz, CH(CH3)2), 2.80 (1H, quintet, JZ
7.2 Hz, CH3CHAr), 3.41 (1H, dd, JZ4.2, 7.6 Hz, COHCH),
3.79 (3H, s, OCH3), 6.80 (3H, m, ArH), 7.22 (1H, t, JZ
7.7 Hz, ArH); 13C NMR (100 MHz CDCl3) 15.2, 18.5, 20.4,
29.9, 43.5, 55.1, 80.3, 111.7, 114.0, 120.5, 129.5, 145.8,
159.7; m/z (EI) 208 (MC, 22%), 165 (12), 136 (100), 121
(63), 104 (14), 91 (11), 77 (8), 55 (9); (Found MC 208.1464.
C13H20O2 requires m/z 208.1463); Chiracel OD-H, hexane/
i-PrOH (95/5), 0.5 mL/min, 20 8C, major 14.8 min (2S,3R),
minor 13.0 min (2R,3S).
1
1129, 1084, 1031, 910; H NMR (400 MHz, (CD3)2SO)
2.27 (3H, s, CH3), 3.71 (3H, s, OCH3), 6.65 (1H, dd, JZ
2.3, 8.1 Hz, ArH), 6.92 (2H, m, ArH), 7.12 (1H, t, JZ
7.2 Hz, ArH), 7.15 (2H, d, JZ8.2 Hz, ArH), 7.54 (1H,
s, CHZN), 7.58 (2H, d, JZ8.2 Hz ArH); 13C NMR
(100 MHz, (CD3)2SO) 20.8, 54.8, 109.5, 111.6, 117.6,
126.5, 128.1, 129.1, 136.2, 138.4, 139.9, 143.9, 159.2; m/z
(FAB) 327 (MCC1, 21%), 201 (100), 176 (17); (Found:
[MCH]C 327.0781 C15H16O3N2SNa requires m/z
327.0779).
4.1.9. 2-Isopropyl-3-(3-methoxyphenyl)oxirane (7). A
round bottomed flask was fitted with chiral sulfide
(125 mg, 0.5 mmol), rhodium(II) acetate dimer (9 mg,
0.02 mmol), benzyl triethylammonium chloride (46 mg,
0.2 mmol), isobutyraldehyde (180 mL, 2.0 mmol) in anhy-
drous acetonitrile (6.0 mL) under nitrogen atmosphere.
m-Methoxybenzaldehyde tosylhydrazone sodium salt
(667 mg, 2.0 mmol) was added and the reaction mixture
was stirred vigorously at room temperature for 10 min, then
at 40 8C. Same amount of m-methoxybenzaldehyde tosyl-
hydrazone sodium salt was added again after 12 and 24 h.
After an additional 12 h stirring, the reaction was quenched
by the addition of water (15 mL). The aqueous layer was
washed with ethyl acetate (3!10 mL) and the combined
4.1.11. (2S,3R)-2-(5-Methoxycyclohexa-1,4-dienyl)-4-
methylpentan-3-ol (9). Well-dried NH3 over Na was
transferred to a two-neck flask containing Li (53 mg,
7.5 mmol). A solution of (2S,3R)-2-(3-methoxyphenyl)-4-
methyl-pentan-3-ol (314 mg, 1.5 mmol) in THF (2 mL) was

9732
V. K. Aggarwal et al. / Tetrahedron 60 (2004) 9725–9733
added to the blue NH3 solution via cannula followed by the
addition of i-PrOH (250 mL, 3.0 mmol). The mixture was
refluxed for 2 h and cooled to K78 8C, and then treated
sequentially with 2 mL of benzene and 850 mg of
ammonium acetate. NH3 was allowed to evaporate and the
residue was partitioned between brine (20 mL) and ethyl
acetate (20 mL). The mixture was extracted with ethyl
acetate (3!20 mL). The combined organic layers were
dried over Na2SO4, filtered and concentrated in vacuo. The
crude mixture was purified by flash chromatography
(EtOAC/hexaneZ1/20) to give a colorless oil (265 mg,
84%); RfZ0.30 (EtOAc/hexaneZ1/10); nmax/cmK1 (neat)
3553, 2962, 1695, 1389, 1221, 1156; [a]1D6ZC14.7 (cZ1.0
in PhH); 1H NMR (400 MHz, C6D6) 0.79 (3H, d, JZ7.1 Hz,
CH3CH), 0.88 (3H, d, JZ6.8 Hz, (CH3)2CH), 1.04 (3H, d,
JZ6.8 Hz, (CH3)2CH), 1.39 (1H, br s, OH), 1.61 (1H,
d-septet, JZ3.2, 6.8 Hz, CH(CH3)2), 2.17 (1H, dq, JZ7.1,
8.8 Hz, CH3CH), 2.69 (2H, m, CH2), 2.79 (2H, m, CH2),
3.13 (1H, dd, JZ3.2, 8.8 Hz, CHOH), 3.27 (3H, s, OCH3),
4.41 (1H, br s, CH2CHZC), 5.40 (1H, br s, CH2CHZ
COCH3); 13C NMR (100 MHz C6D6) 14.6, 15.5, 20.9, 27.0,
28.8, 29.6, 45.1, 53.6, 76.3, 90.1, 121.6, 136.9, 153.6; m/z
(EI) 210 (MC, 21%), 149 (43), 138 (100), 121 (47), 109
(82), 105 (19), 91 (30), 77 (12), 55 (9); (Found MC
210.1619. C13H22O2 requires m/z 210.1620).
dimethyl-3-oxo-heptanoic acid methyl ester (130 mg,
0.64 mmol) in THF (2 mL) was added. Reaction continued
for 3 h, and then temperature was raised to room
temperature. The reaction was quenched by adding water
(5 mL) and two-phase mixture was stirred for an additional
hour. After being neutralized by 20% NaOH solution, the
aqueous layer extracted with ethyl acetate (3!10 mL). The
combined organic layers were dried (MgSO4), filtered and
concentrated. Flash chromatography (EtOAc/hexaneZ1/1)
gave Prelactone B as a white solid (73 mg, 66%); RfZ0.26
(EtOAc/hexaneZ1/1); mp 96–98 8C [lit.: 97–98 8C]14b
;
[a]D19ZC51.5 (cZ1.0 in CH3OH)[lit.: [a]1D9ZC62.1 (cZ
1.72 in CH3OH)]14b; 1H NMR (400 MHz, CDCl3) 0.90 (3H,
d, CH3CH, JZ6.9 Hz), 1.04 (3H, d, JZ6.7 Hz, (CH3)2CH),
1.04 (3H, d, JZ6.7 Hz, (CH3)2CH), 1.73 (1H, d-septet, JZ
2.2, 6.9 Hz, CHCH3), 1.97 (1H, m, CH(CH3)2), 2.02 (1H, br
s., OH), 2.46 (1H, dd, JZ8.1, 17.3 Hz, CHHCO), 2.90 (1H,
dd, JZ5.9, 17.3 Hz, CHHCO), 3.74 (2H, m, CHOHC
OCHCH); 13C NMR (100 MHz CDCl3) 13.6, 14.0, 20.0,
28.9, 38.9, 39.0, 69.8, 86.2, 170.9.
References and notes
4.1.12. (4S,5R)-5-Hydroxy-4,6-dimethyl-3-oxo-heptanoic
acid methyl ester (10). A two-neck flask equipped with
CaCl2 drying tube was filled with a solution of (2S,3R)-2-
(5-methoxycyclohexa-1,4-dienyl)-4-methylpentan-3-ol
(210 mg, 1.0 mmol) and pyridine (100 mL) in 10 mL of
CH2Cl2 and 2 mL of methanol at K78 8C. O3 was bubbled
until saturated, at which point blue color persisted, and then
the solution was degassed with O2 until blue color
disappeared. Triphenyl phosphine (785 mg, 3.0 mmol)
was added and stirring continued for 1 h at room
temperature. After solvent was removed under reduced
pressure, flash chromatography (25% EtOAc in hexane)
gave the desire product as a pale yellow oil (135 mg, 67%);
RfZ0.36 (EtOAc/hexaneZ1/2); nmax/cmK1 (neat) 3525,
2964, 1747, 1713, 1457, 1317, 1159, 996; [a]1D7ZK16.6
(cZ1.0 in CHCl3); 1H NMR (400 MHz, CDCl3) 0.84 (keto
3H, d, JZ6.8 Hz, (CH3)2CH), 0.88 (enol 3H, d, JZ6.7 Hz,
(CH3)2CH), 0.91 (enol, 3H, d, JZ6.7 Hz, (CH3)2CH), 0.92
(keto, 3H, d, JZ6.8 Hz, (CH3)2CH), 1.06 (keto, 3H, d, JZ
7.1 Hz, CHCH3), 1.14 (enol, 3H, d, JZ7.1 Hz, CHCH3),
1.68 (enol, 1H, m, CH(CH3)2), 1.74 (keto, 1H, d-septet, JZ
2.8, 6.8 Hz, CH(CH3)2), 1.90 (enol, 1H, br s, OH), 2.00
(enol, 1H, br s, OH), 2.31 (keto, 1H, d, JZ5.9 Hz, OH), 2.37
(enol, 1H, quintet, JZ7.0 Hz, CHCH3), 2.81 (keto, 1H,
quintet, JZ7.4 Hz, CHCH3), 3.32 (enol, 1H, m, CHOH),
3.45 (keto, 1H, m, CHOH), 3.55 (keto, 2H, d, JZ3.4 Hz,
COCH2), 3.68 (enol, 3H, s, OCH3), 3.69 (keto, 3H, s,
OCH3), 5.03 (enol, 1H, s, COHZCH); 13C NMR (100 MHz
CDCl3) keto: 13.5, 15.0, 19.8, 29.9, 49.1, 49.3, 52.2, 78.1,
167.7, 207.8 enol: 15.5, 16.2, 19.9, 30.8, 42.8, 51.2, 78.3,
89.9, 173.0, 180.3.
1. Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004. ASAP.
2. (a) Aggarwal, V. K.; Alonso, E.; Bae, I.; Hynd, G.; Lydon,
K. M.; Palmer, M. J.; Patel, M.; Porcelloni, M.; Richardson, J.;
Stenson, R. A.; Studley, J. R.; Vasse, J.-L.; Winn, C. L. J. Am.
Chem. Soc. 2003, 125, 10926. (b) Aggarwal, V. K.; Alonso, E.;
Hynd, G.; Lydon, K. M.; Palmer, M. J.; Porcelloni, M.;
Studley, J. R. Angew. Chem., Int. Ed. 2001, 40, 1430.
3. Aggarwal, V. K.; Bae, I.; Lee, H.-Y.; Richardson, J.; Williams,
D. T. Angew. Chem., Int. Ed. 2003, 42, 3274.
4. (a) Furukawa, N.; Sugihara, Y.; Fujihara, H. J. Org. Chem.
1989, 54, 4222. (b) Breau, L.; Durst, T. Tetrahedron:
´
Asymmetry 1991, 2, 367. (c) Solladie-Cavallo, A.; Diep-
Vohuule, A.; Sunjic, V.; Vinkovic, V. Tetrahedron: Asym-
metry 1996, 7, 1783. (d) Li, A.-H.; Dai, L.-X.; Hou, X.-L.;
Huang, Y.-Z.; Li, F.-W. J. Org. Chem. 1996, 61, 489.
(e) Julienne, K.; Metzner, P.; Henyron, V. J. Chem. Soc.,
Perkin Trans. 1 1999, 731. In addition to our own previous
example of applications of sulfur ylides in synthesis (Ref. 3),
´
see also Solladie-Cavallo, A.; Diep-Vohuule, A. J. Org. Chem.
1995, 60, 3494.
5. (a) Echeverri, F.; Arango, V.; Quin˜ones, W.; Torres, F.;
Escobar, G.; Rosero, Y.; Archbold, R. Phytochemistry 2001,
56, 881. (b) Donadio, S.; Staver, M. J.; McAlpine, J. B.;
Swanson, S. J.; Katz, L. Gene 1992, 115, 97. (c) Gunasekera,
S. P. J. Org. Chem. 1990, 55, 4912. (d) Yada, H. Nat. Prod.
Lett. 1993, 2, 221.
6. Evans, D. A.; Gauchet-Prunet, J. A.; Carreira, E. M.; Charette,
A. B. J. Org. Chem. 1991, 56, 741.
7. (a) Bonini, C.; Pucci, P.; Viggiani, L. J. Org. Chem. 1991, 56,
4050. (b) Johnson, W. S.; Kelson, A. B.; Elliott, J. D.
Tetrahedron Lett. 1988, 29, 3757.
8. (a) Endo, A.; Kuroda, M.; Tsujita, Y. J. Antibiot. 1976, 29,
1346. (b) Endo, A.; Kuroda, M.; Tsujita, Y.; Tanzawa, K. Eur.
J. Biochem. 1977, 77, 31.
4.1.13. Prelactone
B
((3R,4S,5R)-3-hydroxy-4,6-
dimethylheptanoic acid-d-lactone).14b Acetic acid
(1.0 mL) was added to a suspension of NaBH(OAc)3
(410 mg, 1.9 mmol) in THF (3 mL) at K78 8C under
argon. After 10 min, a solution of (4S,5R)-5-hydroxy-4,6-
9. Some examples of total synthesis, see: (a) Clive, D. L. J.;
Murthy, K. S. K.; Wee, A. G. H.; Prasad, J. S.; da Silva,
G. V. J.; Majewski, M.; Anderson, P. C.; Evans, C. F.; Haugen,

V. K. Aggarwal et al. / Tetrahedron 60 (2004) 9725–9733
9733
R. D.; Heerze, L. D.; Barrie, J. R. J. Am. Chem. Soc. 1990, 112,
3018. (b) Hagiwara, H.; Nakano, T.; Kon-no, M.; Uda, H.
J. Chem. Soc., Perkin Trans. 1 1995, 777. For a review, see
Rosen, T.; Heathcock, C. H. Tetrahedron 1986, 42, 4909.
Selected recent examples of analogues, see: (c) Ghosh,
A. K.; Lei, H. J. Org. Chem. 2000, 65, 4779.
(d) Bouzbouz, S.; Cossy, J. Tetrahedron Lett. 2000, 41,
3363. (e) Reddy, P. P.; Yen, K.-F.; Uang, B.-J. J. Org.
14. (a) Bindseil, K. U.; Zeeck, A. Helv. Chim. Acta 1993, 76, 150.
(b) Hanefeld, U.; Hooper, A. M.; Staunton, J. Synthesis 1999,
401. (c) Chakraborty, T. K.; Tapadar, S. Tetrahedron Lett.
¨
2003, 44, 2541. (d) Pihko, P. M.; Erkkila, A. Tetrahedron Lett.
2003, 44, 7607. (e) Csaky¨, A. G.; Mba, M.; Plumet, J. Synlett
´
´
2003, 2092. (f) Fournier, L.; Gaudel-Siri, A.; Kocienski,
P. J.; Pons, J.-M. Synlett 2003, 107. (g) Enders, D.; Haas, M.
Synlett 2003, 2182. (h) Dias, L. C.; Steil, L. J.; Vasconcelos,
V. A. Tetrahedron: Asymmetry. 2004, 15, 147.
15. (a) Klunder, J. M.; Posner, G. H. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford;
1991; Vol. 3, pp 223–226 and references therein. (b) Richard,
J. K.; Casy, G. In Organocopper Reagents, Taylor, R. J. K.,
Ed.; Oxford University Press: Oxford, 1994; Chapter 2 and
references therein.
´
Chem. 2002, 67, 1034. (f) Solladie, G.; Bauder, C.; Rossi,
L. J. Org. Chem. 1995, 60, 7774.
10. Stokker, G. E.; Hoffman, W. F.; Alberts, A. W.; Gragoe,
E. J.; Deana, A. A.; Gilfilan, J. L.; Huff, J. W.; Novello, F. C.;
Prugh, J. D.; Smith, R. L.; Willard, A. K. J. Med. Chem. 1985,
28, 347.
11. EtP2ZN,N,N0,N0-tetramethyl-N00-[tris(dimethylamino)-phos-
´
phoranylidene]phosphoric triamide ethylimine (a) Solladie-
Cavallo, A.; Diep-Vohuule, A.; Isarno, T. Angew. Chem., Int.
16. Carde, L.; Davies, D. H.; Roberts, S. M. J. Chem. Soc., Perkin
Trans. 1 2000, 2455.
´
Ed. 1998, 37, 1689. (b) Solladie-Cavallo, A.; Roje, M.; Isarno,
17. Schwink, L.; Knochel, P. Chem. Eur. J. 1998, 4, 950.
18. Cotsaris, E.; Paddon-Row, M. N. J. Chem. Soc., Perkin Trans.
2 1984, 1487.
T.; Sunjic, V.; Vinkovic, V. Eur. J. Org. Chem. 2000, 1077.
(c) Fei, X. S.; Verkade, J. G. Heteroatom Chem. 1999, 10, 538.
12. Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1 and
references therein.
19. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560.
ˇ
13. Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.;
Shapiro, M. J. Tetrahedron Lett. 1987, 28, 155.
20. Stratakis, M.; Nencka, R.; Rabalakos, C.; Adam, W.; Krebs, O.
J. Org. Chem. 2002, 67, 8758.