Stereoselective synthesis of C3-C12 dihydropyran portion of antitumor laulimalide using copper-catalyzed oxonium ylide formation-[2,3] shift

Article abstract of DOI:10.1248/cpb.53.989

Copper-catalyzed oxonium ylide formation-[2,3] shift of (5S,7R)-5-allyloxy-1-diazo-8-(p-methoxybenzyloxy)-7-methyl-2-octanone (3) proceeded in tetrahydrofuran-dichloromethane (4 : 1) under reflux with an excellent stereoselectivity (97 : 3) to give (2R,6S

Full text of DOI:10.1248/cpb.53.989

August 2005
Chem. Pharm. Bull. 53(8) 989—994 (2005)
989
Stereoselective Synthesis of C3–C12 Dihydropyran Portion of Antitumor
Laulimalide Using Copper-Catalyzed Oxonium Ylide Formation–[2,3]
Shift
b
Takayuki YAKURA,*,a Wataru MURAMATSU,b and Jun’ichi UENISHI
a Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University; Sugitani, Toyama 930–0194,
Japan: and b Kyoto Pharmaceutical University; Misasagi, Yamashina, Kyoto 607–8412, Japan.
Received April 5, 2005; accepted April 28, 2005; published online May 11, 2005
Copper-catalyzed oxonium ylide formation–[2,3] shift of (5S,7R)-5-allyloxy-1-diazo-8-(p-methoxybenzyloxy)-
7-methyl-2-octanone (3) proceeded in tetrahydrofuran-dichloromethane (4 : 1) under reflux with an excellent
stereoselectivity (97 : 3) to give (2R,6S)-2-allyl-6-[(2R)-3-(p-methoxybenzyloxy)-2-methylpropyl]-3-dihydropyra-
none (2) as a major isomer in 82% yield. The resultant pyranone (2) was converted to the key intermediate (1) of
the Mulzer’s laulimalide synthesis and its derivatives (14, 15).
Key words copper catalyst; oxonium ylide; [2,3] shift; 3-pyranone; laulimalide; antitumor
Tetrahydropyran and dihydropyran rings are structural ondary alcohol (5) in high yield. O-Allylation of 5 was trou-
components of a large number of natural products.1,2) There- blesome. Under usual allylation conditions, such as reaction
fore, considerable attention has recently been directed toward with sodium hydride (NaH) and allyl bromide in THF, no re-
their stereoselective synthesis.3—8) The microtubule-stabiliz- action occurred. Several examinations revealed that treat-
ing agent (ꢀ)-laulimalide,9—18) also known as fijianolide B, ment of 5 with NaH and allyl iodide in the presence of 15-
which was isolated from several sponges (Cacospongia my- crown-5 in THF at room temperature afforded allyl ether (6)
cofijiensis,19) Hyattella sp.,20) Fasciospongia rimosa21)), con- in 96% yield. Deprotection of TBDMS group with
tains 2,6-trans disubstituted 5,6-dihydro-2H-pyran as its tetrabutylammonium fluoride (TBAF), followed by two step-
C5–C9 portion. Stereoselective construction of thermody- oxidation with Dess-Martin periodinane and oxone in
namically less stable 2,6-trans substituted pyrans is one of dimethylformamide (DMF)26) gave carboxylic acid (7) in
most important subjects in synthesis of this attractive antitu- 80% overall yield. Conversion of 7 into a-diazoketone (3)
mor agent and its analogues.
was achieved by the usual procedure,27) formation of mixed
Metal catalyzed carbenoid reactions22,23) have become a acid anhydride with ethyl chloroformate and treatment with
powerful tool for the synthesis of functionalized cyclic com- diazomethane, thereby providing 3 in 85% yield in two steps.
pounds including oxacycles. In 1994, Clark and co-workers
With a-diazoketone (3) in hand, we turned our attention to
reported that a copper-catalyzed reaction of 5-allyoxy-1- cyclization of 3 by the metal catalyzed reaction (Eq. 1).
diazo-2-hexanone predominantly gave 2,6-trans-2-allyl-6-
methy-3-dihydropyranone in good yield.24) This result stimu-
lated us to investigate the metal catalyzed stereoselective
(1)
synthesis of 2,6-trans disubstituted 3-pyranone (2) from a-
diazoketone (3) as a feasible method for synthesis of the
C5–C9 portion of laulimalide and its analogues because 3
Formation of 2,6-disubstituted 3-pyranone using oxonium
would be converted easily into the key intermediate (1) of the ylide formation–[2,3] shift of a-diazoketone has already
Mulzer’s laulimalide synthesis,11,25) as outlined in Chart 1. been examined. Clark and co-workers reported that
Herein, we describe the synthesis of 2 in high yield with ex- copper(II) hexafluoroacetylacetonate [Cu(hfacac)2] catalyzed
cellent stereoselectivity by the copper-catalyzed oxonium the reaction of 5-allyloxy-1-diazohexan-2-one in dichloro-
ylide formation–[2,3] shift of 3 and conversion of 2 into 1 methane to give a 77 : 23 mixture of the corresponding 2,6-
and its derivatives.
trans- and 2,6-cis-2-allyl-6-methyldihydropyran-3-ones in
a-Diazoketone (3) was prepared readily from the known 68% yield.24) Very recently, they reinvestigated the catalyst
alcohol (4)11) as shown in Chart 2. Homoallylic alcohol (4)
was converted to diol by hydroboration–oxidation process
with borane–tetrahydrofuran (THF) complex and subsequent
treatment with hydrogen peroxide and sodium hydroxide.
Then the resulting primary hydroxyl group was protected as
a tert-butyldimethylsilyl (TBDMS) ether to give the sec-
Chart 1
∗ To whom correspondence should be addressed. e-mail: yakura@ms.toyama-mpu.ac.jp
© 2005 Pharmaceutical Society of Japan

990
Vol. 53, No. 8
effect of the same reaction and found that use of copper(II) Cu(hfacac)2 (entry 3). Because of the difficulty of complete
trifluoroacetylacetonate [Cu(tfacac)2] as a catalyst in CH2Cl2 separation of two isomers by column chromatography, we
was more effective than that of Cu(hfacac)2 for the diastere- further investigated reactions of 3 with Cu(tfacac)2 in several
oselectivity to give the ratio of trans : cisꢁ91 : 9.28) For that solvents. A similar reaction of 3 in THF at room temperature
reason, we chose to use mainly Cu(hfacac)2 or Cu(tfacac)2 as for 19 h gave 2 as an essentially single product but the yield
the catalyst in the reaction of 3 (Table 1).
decreased to 56% (entry 4). Although reflux conditions
When 3 was allowed to react with 0.05 equivalent of shortened the reaction time to 3 h, the yield was, unfortu-
Cu(hfacac)2 in CH2Cl2 at room temperature for 1.5 h, the ox- nately, not improved (entry 5). Toluene was not suitable for
onium ylide formation–[2,3] shift proceeded smoothly to this reaction from the standpoint of either yield or stereose-
give the corresponding 3-pyranone in 67% yield as a 80 : 20 lectivity (entry 6). However, in diethyl ether (Et2O) the reac-
mixture of 2,6-trans (2) and 2,6-cis isomers (2ꢀ) (entry 1). tion of 3 with Cu(tfacac)2 under reflux gave an almost satis-
1
The ratio was determined by the H-NMR spectroscopy of factory result (72%, 2 : 2ꢀꢁꢂ95 : 5) (entry 7). In order to im-
the mixture of the diastereomers. Although each pure di- prove both the yield and stereoselectivity, the reactions were
astereomer was obtained by careful silica gel column chro- examined in combination of two solvents, CH2Cl2 giving the
matography of the mixture, repeated chromatography was re- highest yield and THF leading the highest stereoselectivity.
quired for complete separation. Stereochemistries of both the The results are summarized in Table 1 (entries 8—11). The
diastereomers were confirmed by their NOESY spectra; posi- best result was obtained when 3 and Cu(tfacac)2 was allowed
tive NOE effects were observed between H-6 proton and al- to react in 4 : 1 mixture of THF and CH2Cl2 under reflux to
lylic methylene protons at C-2 position of 2,6-trans isomer afford 80% of 2 and 2% of 2ꢀ after single column chromatog-
(2) and between H-2 proton and H-6 proton of 2,6-cis isomer raphy (entry 11).
(2ꢀ) (Fig. 1). Similar reaction of 3 with Cu(hfacac)2 in THF
The other copper(II) catalyst such as copper(II) triflate
did not proceed to recover the starting material after 27 h gave a complex mixture in both CH2Cl2 and THF. In the case
(entry 2).
of the reaction of 3 with dirhodium(II) tetraacetate, the ratio
Reaction with Cu(tfacac)2 gave better result. Thus, 3 was of 2 and 2ꢀ was reversed (entry 14).
treated with Cu(tfacac)2 in CH2Cl2 at room temperature for
One possible rationalization of the observed stereoselec-
7 h to give the 3-pyranone in quantitative yield, but its stere- tivity in copper-catalyzed reaction of 3 is based on the con-
oselectivity was identical to that of the reaction using sideration of the conformation of oxonium ylide (Fig. 2).28)
The conformer (A) is favored because both the allyl group
and the substituent at C-6 position are accommodated in
Fig. 1
Fig. 2
Chart 2
Table 1. Metal Catalyzed Oxonium Ylide Formation–[2,3] Shift of 3a)
Entry
Catalyst
Solvent
CH2Cl2
THF
CH2Cl2
THF
THF
Toluene
Et2O
THF–CH2Cl2 (1 : 1)
THF–CH2Cl2 (10 : 1)
THF–CH2Cl2 (4 : 1)
THF–CH2Cl2 (4 : 1)
CH2Cl2
Conditions
Yield (%)
trans : cis (2 : 2ꢀ)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Cu(hfacac)2
Cu(hfacac)2
Cu(tfacac)2
Cu(tfacac)2
Cu(tfacac)2
Cu(tfacac)2
Cu(tfacac)2
Cu(tfacac)2
Cu(tfacac)2
Cu(tfacac)2
Cu(tfacac)2
Cu(OTf)2
rt, 1.5 h
rt, 27 h
rt, 7 h
rt, 19 h
Reflux, 3 h
rt, 1.5 h
rt, 27 h
rt, 7 h
67
80 : 20b)
No reaction
Quant
56
50
57
72
98
59
59
82
80 : 20b)
ꢂ99 : 1b)
ꢂ99 : 1b)
85 : 15b)
95 : 5b)
86 : 14b)
97 : 3c)
rt, 8 d
rt, 15 h
Reflux, 4 h
rt, 7 h
rt, 19 h
rt, 24 h
95 : 5b)
97 : 3c)
Complex mixture
Complex mixture
11
45 : 55b)
Cu(OTf)2
Rh2(OAc)4
THF
THF–CH2Cl2 (4 : 1)
a) All the reactions were carried out using 0.05 eq of catalyst. b) Determined by 1H-NMR. c) The ratio was calculated based on the isolated yield of 2 and 2ꢀ.

August 2005
991
Chart 5
in THF at ꢀ80 °C formed less substituted enolate, which was
trapped with N-phenylbis(trifluoromethanesulfon)imide
[PhNTf2]30) to afford vinyl triflate (13). Then 13 was reduced
with tributyltin hydride and lithium chloride in the presence
of tetrakis(triphenylphosphine) palladium31) to yield Mulzer’s
laulimalide intermediate (1) in 88% from 11. Spectroscopic
data of 1, including its optical rotation, were identical to
those of the reported sample.11)
Chart 3
The vinyl triflate (13) was useful for preparation of the 3-
alkyl derivatives of Mulzer’s intermediate (Chart 5). Reaction
of 13 with methylmagnesium chloride in the presence of pal-
ladium(II) acetate and triphenylphosphine provided the cor-
responding 3-methyl derivative (14) in 52% yield from 11. A
similar treatment of 13 with trimethylsilylmethylmagnesium
chloride gave rise to 15 in 40% yield from 11. These deriva-
tives (14, 15) would be used for synthesis of laulimalide ana-
logues, which are expected to show more effective activities
than laulimalide itself.
Chart 4
In conclusion, the reaction of a-diazoketone (3) and a cat-
alytic amount of Cu(tfacac)2 in THF–CH2Cl2 (4 : 1) under re-
flux gave 2,6-trans-3-pyranone (2) in 82% yield as a major
product (97 : 3). The resulting pyranone (2) was converted to
Mulzer’s key intermediate (1) of laulimalide and its deriva-
tives (14, 15).
equatorial positions. The subsequent rearrangement proceeds
in the same side of the allyl group to give 2,6-trans isomer
(2).
Our next subject was conversion of 2 to Mulzer’s lauli-
malide intermediate (1) (Charts 3, 4). The C-3 ketone of 2
was protected as a silyl ether of the corresponding alcohol to Experimental
Melting points are uncorrected. IR spectra were recorded using JASCO
FT/IR-400 and JASCO FT/IR-460 Plus spectrophotometers. H-NMR spec-
avoid isomerization to thermodynamically more stable 2,6-
cis isomers during the transformation. Reduction of 2 with
sodium borohydride in ethanol gave an approximately 5 : 2
mixture of diastereomers of alcohol in 98% yield which was
used in the following steps without separation of two di-
astereomers and was silylated by TBDMS chloride and imi-
dazole in DMF to afford silyl ether 8 in 97% yield. Treat-
ment of 8 with a catalytic amount of osmium tetroxide and
N-methylmorpholine N-oxide (NMO) in THF–water (5 : 1),
then sodium periodate gave rise to aldehyde (9) in 95% over-
all yield. The aldehyde (9) was reduced by NaBH4 to yield
alcohol in 99%, then desilylated with tetrabutylammmonium
fluoride (TBAF) in THF to produce 10 (97%). Selective
monosilylation of 10 followed by oxidation with Dess-Martin
periodinane afforded ketone (11) in 86% in two steps.
1
tra were determined with Varian Unity plus 500 (500 MHz), Varian Inova
Unity XL400 (400 MHz), Varian Gemini 300 (300 MHz), JEOL JNM-
AL300 (300 MHz), and JEOL JNM-FX270 (270 MHz) spectrometers,
tetramethylsilane as an internal standard. 13C-NMR spectra were determined
with Varian Unity plus 500 (125 MHz), Varian Inova Unity XL400
(100 MHz), Varian Gemini 300 (75 MHz), JEOL JNM-AL300 (75 MHz),
and JEOL JNM-FX270 (68 MHz) spectrometers. All 13C-NMR spectra were
determined with complete proton decoupling. High resolution MS were de-
termined with JEOL JMS-GCmate, JEOL JMS-SX102AQQ, and JEOL
JMS-AX505HAD instruments. Optical rotations were measured with
JASCO DIP-360 and JASO DIP-1000 polarimeters. Column chromatogra-
phy was performed on Silica gel 60 (0.063—0.200 mm) (MERCK) and Sil-
ica Gel 60 PF254 (Nacalai Tesque).
(4S,6R)-7-(p-Methoxybenzyloxy)-6-methyl-1,4-heptanediol
A
solu-
tion of borane–THF complex in THF (1.02 M, 17.5 ml, 17.8 mmol) was
added to a solution of (4S,6R)-1-(p-methoxybenzyloxy)-2-methyl-6-hepten-
4-ol11) (3.63 g, 13.7 mmol) in THF (110 ml) at room temperature and the
mixture was stirred at the same temperature overnight. The mixture was
cooled to 0 °C, 3 M NaOH solution (14 ml) and 30% H2O2 solution (14 ml)
were added to the mixture. The reaction was stirred at the same temperature
Application of the Shapiro reaction29) for construction of a
C–C double bond from ketone (11) was examined first. Reac-
tion of 11 with p-toluenesulfonylhydrazine in ethanol in the
presence of concentrated hydrochloric acid gave hydrazone for 10 min and then stirred at room temperature overnight. The mixture was
quenched with sat. Na2S2O3 solution, and extracted with EtOAc. The extract
was washed with H2O and brine, dried (MgSO4), and concentrated. The
residue was chromatographed on silica gel (50% EtOAc in hexane) to give
(12) in 91% yield. Unfortunately, all attempts of 12 to alkene
(1) by treatment with several bases, such as n-butyl lithium,
methyl lithium, etc. gave a complex mixture. However,
alkene formation of 11 via vinyl triflate was successful. Eno-
lization of 11 with lithium hexamethyldisilazide (LHMDS)
(4S,6R)-7-(p-methoxybenzyloxy)-6-methyl-1,4-heptanediol (3.57 g, 92%) as
a colorless oil. 1H-NMR (300 MHz, CDCl3) d: 0.91 (3H, d, Jꢁ7.0 Hz),
1.44—1.74 (6H, m), 1.88—2.01 (1H, m), 3.10 (2H, br s), 3.23 (1H, t,

992
Vol. 53, No. 8
Jꢁ8.8 Hz), 3.39 (1H, dd, Jꢁ9.2, 4.4 Hz), 3.60—3.73 (3H, m), 3.80 (3H, s), (1H, ddd, Jꢁ13.9, 7.6, 5.3 Hz), 1.72—1.83 (1H, m), 1.84—1.99 (2H, m),
4.46 (2H, s), 6.88 (2H, d, Jꢁ8.8 Hz), 7.24 (2H, d, Jꢁ8.8 Hz). 13C-NMR 2.48 (2H, td, Jꢁ7.3, 1.7 Hz), 3.23 (1H, dd, Jꢁ9.0, 6.3 Hz), 3.30 (1H, dd,
(75 MHz, CDCl3) d: 18.7, 29.5, 32.6, 35.7, 44.6, 55.4, 63.3, 70.9, 73.1, 76.6, Jꢁ9.0, 5.9 Hz), 3.41—3.50 (1H, m), 3.80 (3H, s), 3.93 (2H, dt, Jꢁ5.6,
114.0 (2), 129.6 (2), 129.8, 159.5. IR (neat) cmꢀ1: 3600—3100, 1613, 1586, 1.4 Hz), 4.42 (2H, s), 5.13 (1H, ddt, Jꢁ10.3, 1.7, 1.4 Hz), 5.23 (1H, ddt,
1514, 1463. Exact MS m/z: 282.1824 (Calcd for C16H26O4: 282.1831). [a]D25
ꢃ9.9° (cꢁ1.00, CHCl3).
Jꢁ17.2, 1.7, 1.4 Hz), 5.86 (1H, ddt, Jꢁ17.2, 10.3, 5.6 Hz), 6.87 (2H, d,
Jꢁ8.8 Hz), 7.24 (2H, d, Jꢁ8.8 Hz), 9.76 (1H, t, Jꢁ1.7 Hz). 13C-NMR
(68 MHz, CDCl3) d: 17.5, 26.6, 30.1, 38.4, 39.7, 55.2, 69.8, 72.6, 75.6, 75.8,
(2R,4S)-7-(tert-Butyldimethylsilyloxy)-1-(p-methoxybenzyloxy)-2-
methyl-4-heptanol (5) A mixture of (4S,6R)-7-(p-methoxybenzyloxy)-6- 113.7 (2), 116.7, 129.1 (2), 130.7, 135.0, 159.1, 202.4. IR (neat) cmꢀ1
:
methyl-1,4-heptanediol (3.57 g, 12.6 mmol), TBDMSCl (2.28 g, 17.7 mmol),
and imidazole (1.55 g, 22.7 mmol) in DMF (70 ml) was stirred at room tem-
perature overnight. The mixture was poured into H2O and the mixture was
extracted with Et2O. The combined extracts were washed with brine, dried
(MgSO4), and concentrated. The residue was chromatographed on silica gel
(20% EtOAc in hexane) to give 5 (4.66 g, 93%) as a colorless oil. H-NMR
(300 MHz, CDCl3) d: 0.05 (6H, s), 0.89 (9H, s), 0.93 (3H, d, Jꢁ7.0 Hz),
1724, 1612, 1586, 1513, 1463. Exact MS m/z: 320.1992 (Calcd for
C19H28O4: 320.1987). [a]D26 ꢀ5.4° (cꢁ1.00, CHCl3).
(4S,6R)-4-Allyloxy-7-(p-methoxybenzyloxy)-6-methylheptanoic Acid
(7) Oxone (6.09 g, 9.9 mmol) was added to a solution of (4S,6R)-4-allyl-
oxy-7-(p-methoxybenzyloxy)-6-methylheptanal (2.44 g, 7.62 mmol) in DMF
(50 ml) at 0 °C under nitrogen atmosphere and the mixture was stirred at the
same temperature overnight. The mixture was quenched with pH 4.1 buffer,
1
1.34 (1H, ddd, Jꢁ13.9, 6.8, 2.9 Hz), 1.41—1.68 (6H, m), 1.89—2.05 (1H, and extracted with EtOAc. The extract was washed with H2O and brine,
m), 3.27 (1H, dd, Jꢁ9.2, 7.3 Hz), 3.33 (1H, dd, Jꢁ9.2, 5.5 Hz), 3.62—3.70 dried (MgSO4), and concentrated. The residue was chromatographed on sil-
(1H, m), 3.64 (2H, t, Jꢁ6.0 Hz), 3.80 (3H, s), 4.45 (2H, s), 6.87 (2H, d, ica gel (50% EtOAc in hexane) to give 7 (2.43 g, 95%) as a colorless oil. 1H-
Jꢁ8.8 Hz), 7.25 (2H, d, Jꢁ8.8 Hz). 13C-NMR (75 MHz, CDCl3) d: ꢀ5.2 (2),
NMR (300 MHz, CDCl3) d: 0.95 (3H, d, Jꢁ6.6 Hz), 1.18 (1H, ddd, Jꢁ13.9,
18.1, 18.5, 26.1 (3), 29.3, 31.7, 35.3, 43.4, 55.4, 63.6, 70.1, 72.9, 76.5, 113.9 8.3, 5.2 Hz), 1.68 (1H, ddd, Jꢁ13.9, 8.1, 5.5 Hz), 1.83—2.00 (3H, m), 2.43
(2), 129.4 (2), 130.4, 159.3. IR (neat) cmꢀ1: 3600—3100, 1613, 1586, 1513, (2H, t, Jꢁ7.7 Hz), 3.23 (1H, dd, Jꢁ9.2, 6.6 Hz), 3.30 (1H, dd, Jꢁ9.2,
1463. Exact MS m/z: 396.2698 (Calcd for C22H40O4Si: 396.2696). [a]D27
ꢃ5.4° (cꢁ0.63, CHCl3).
5.9 Hz), 3.44—3.53 (1H, m), 3.80 (3H, s), 3.96 (2H, d, Jꢁ5.5 Hz), 4.42 (2H,
s), 5.13 (1H, dd, Jꢁ10.3, 1.1 Hz), 5.24 (1H, ddd, Jꢁ17.3, 3.3, 1.5 Hz), 5.88
(2R,4S)-4-Allyloxy-7-(tert-butyldimethylsilyloxy)-1-(p-methoxybenzyl- (1H, ddt, Jꢁ17.3, 10.3, 5.5 Hz), 6.87 (2H, d, Jꢁ8.8 Hz), 7.24 (2H, d,
oxy)-2-methylheptane (6) After a mixture of 5 (4.66 g, 11.7 mmol), 60%
NaH (939 mg, 23.5 mmol) and 15-crown-5 (2.58 g, 11.7 mmol) in THF
(45 ml) was stirred at 0 °C for 30 min under nitrogen atmosphere, ally iodide
(3.95 g, 23.5 mmol) was added to the mixture at the same temperature. Then
the reaction mixture was stirred at room temperature overnight. The mixture
was quenched with sat. Na2S2O3 solution, and extracted with EtOAc. The
extract was washed with H2O and brine, dried (MgSO4), and concentrated.
The residue was chromatographed on silica gel (10% EtOAc in hexane) to
Jꢁ8.8 Hz). 13C-NMR (68 MHz, CDCl3) d: 17.6, 29.1, 30.2 (2), 38.3, 55.3,
69.9, 72.6, 75.6, 75.8, 113.7 (2), 116.7, 129.0 (2), 130.7, 134.9, 135.0,
158.9. IR (neat) cmꢀ1: 3100—2800, 1709, 1647, 1612, 1585, 1514, 1463.
Exact MS m/z: 336.1928 (Calcd for C19H28O5: 336.1937). [a]D26 ꢀ1.1°
(cꢁ1.00, CHCl3).
(5S,7R)-5-Allyloxy-1-diazo-8-(p-methoxybenzyloxy)-7-methyl-2-oc-
tanone (3) According to the reported procedure,27) a mixture of 7 (403 mg,
1.20 mmol) in THF (10 ml) and Et3N (145 mg, 1.44 mmol) was stirred at
give 6 (4.92 mg, 96%) as a colorless oil. 1H-NMR (300 MHz, CDCl3) d: 0 °C. After 20 min ClCO2Et (143 mg, 1.32 mmol) was added and the mixture
0.04 (6H, s), 0.89 (9H, s), 0.95 (3H, d, Jꢁ6.6 Hz), 1.12—1.31 (1H, m),
1.49—1.67 (4H, m), 1.91—2.04 (1H, m), 3.20 (1H, dd, Jꢁ9.2, 7.0 Hz), 3.32
stirred for further 30 min at the same temperature. Then a solution of CH2N2
in Et2O was added at the same temperature until a strong yellow color per-
(1H, dd, Jꢁ9.2, 5.5 Hz), 3.39—3.44 (1H, m), 3.58—3.63 (2H, m), 3.80 (3H, sisted. The mixture was allowed to warm to room temperature and stirred
s), 3.90 (1H, ddt, Jꢁ12.5, 5.9, 1.5 Hz), 4.00 (1H, ddt, Jꢁ12.5, 5.5, 1.5 Hz), overnight. The excess of CH2N2 was destroyed by the addition of few drops
4.42 (2H, s), 5.12 (1H, dq, Jꢁ10.3, 1.3 Hz), 5.23 (1H, dq, Jꢁ17.3, 1.7 Hz), of AcOH. The mixture was diluted with H2O, and extracted with Et2O. The
5.89 (1H, ddt, Jꢁ17.3, 10.3, 5.7 Hz), 6.87 (2H, d, Jꢁ8.4 Hz), 7.26 (2H, d, organic layer was washed with saturated aqueous NaHCO3 solution, satu-
Jꢁ8.4 Hz). 13C-NMR (75 MHz, CDCl3) d: ꢀ5.1 (2), 17.5, 18.5, 26.1 (3), rated aqueous NH4Cl solution and brine, and dried (MgSO4) and concen-
28.6, 30.2, 30.6, 38.7, 55.4, 63.4, 69.8, 72.7, 76.1, 76.7, 113.8 (2), 116.5, trated. The residue was chromatographed on silica gel (30% EtOAc in
129.2 (2), 131.0, 135.7, 159.2. IR (neat) cmꢀ1: 1613, 1586, 1514, 1463.
hexane) to give 3 (365 mg, 85% in 2 steps) as a colorless oil. 1H-NMR
Exact FAB-MS m/z: 437.3094 (Calcd for C25H45O4Si: 437.3087). [a]D21 (270 MHz, C6D6) d: 0.98 (3H, d, Jꢁ7.0 Hz), 1.10 (1H, ddd, Jꢁ13.9, 8.0,
ꢃ6.5° (cꢁ1.00, CHCl3).
4.8 Hz), 1.60—2.12 (6H, m), 3.21 (2H, dd, Jꢁ5.9, 2.9 Hz), 3.27—3.52 (1H,
m), 3.32 (3H, s), 3.78 (1H, ddt, Jꢁ12.8, 5.5, 1.5 Hz), 3.85 (1H, ddt, Jꢁ12.8,
5.1, 1.5 Hz), 4.18 (1H, s), 4.35 (2H, s), 5.03 (1H, ddt, Jꢁ10.3, 1.8, 1.5 Hz),
5.24 (1H, ddt, Jꢁ16.9, 1.8, 1.5 Hz), 5.85 (1H, dddd, Jꢁ16.9, 10.3, 5.5,
5.1 Hz), 6.82 (2H, d, Jꢁ8.6 Hz), 7.25 (2H, d, Jꢁ8.6 Hz). 13C-NMR
(68 MHz, C6D6) d: 17.9, 29.3, 30.7, 38.7 (2), 54.9, 69.6, 73.0, 75.9, 76.0,
114.1 (2), 115.6, 129.4 (2), 131.4, 136.0, 159.6, 181.3, 193.4. IR (neat)
cmꢀ1: 2103, 1734, 1644, 1365. Exact FAB-MS m/z: 361.2110 (Calcd for
(4S,6R)-4-Allyloxy-7-(p-methoxybenzyloxy)-6-methyl-1-heptanol
A
solution of TBAF in THF (1.0 M, 5.2 ml, 5.2 mmol) was added to a solution
of 6 (1.90 g, 4.33 mmol) in THF (30 ml) at room temperature and the mix-
ture was stirred at the same temperature overnight. The mixture was
quenched with sat. NH4Cl solution, and extracted with EtOAc. The extract
was washed with H2O and brine, dried (MgSO4), and concentrated. The
residue was chromatographed on silica gel (30% EtOAc in hexane) to give
(4S,6R)-4-allyloxy-7-(p-methoxybenzyloxy)-6-methyl-1-heptanol
(1.31 g, C20H29N2O4: 361.2127). [a]D25 ꢀ2.6° (cꢁ1.00, CHCl3).
Copper-Catalyzed Oxonium Ylide Formation–[2,3] shift of 3 A so-
93%) as a colorless oil. 1H-NMR (300 MHz, CDCl3) d: 0.95 (3H, d,
Jꢁ6.8 Hz), 1.15—1.29 (1H, m), 1.53—1.72 (5H, m), 1.88—2.04 (1H, m), lution of 3 (45 mg, 0.125 mmol) and Cu(tfacac)2 (2.3 mg, 0.0063 mmol)
1.95 (1H, br s), 3.22 (1H, dd, Jꢁ9.1, 6.5 Hz), 3.31 (1H, dd, Jꢁ9.1, 5.8 Hz), in THF and CH2Cl2 (4 : 1, 2 ml) was refluxed for 4 h. The mixture
3.42—3.51 (1H, m), 3.62 (2H, td, Jꢁ5.7, 1.5 Hz), 3.80 (3H, s), 3.94 (1H,
was quenched with sat. EDTA solution, and extracted with Et2O. The
dddd, Jꢁ12.5, 5.7, 1.7, 1.3 Hz), 4.00 (1H, dddd, Jꢁ12.5, 5.7, 1.7, 1.3 Hz), extract was washed with H2O and brine, dried (MgSO4), and concentrated.
4.42 (2H, s), 5.14 (1H, ddt, Jꢁ10.3, 1.5, 1.3 Hz), 5.24 (1H, dtd, Jꢁ17.3, 1.7, The residue was chromatographed on silica gel (10% EtOAc in hexane).
1.5 Hz), 5.89 (1H, ddt, Jꢁ17.3, 10.3, 5.7 Hz), 6.87 (2H, d, Jꢁ8.6 Hz), 7.25
The first fraction gave (2S,6S)-2-allyl-6-[(2R)-3-{p-methoxybenzyloxy}-2-
1
(2H, d, Jꢁ8.6 Hz). 13C-NMR (75 MHz, CDCl3) d: 17.7, 28.5, 30.3, 30.8, methylpropyl]tetrahydropyran-3-one (2ꢄ) (1 mg, 2%) as a colorless oil. H-
38.4, 55.4, 63.2, 69.9, 72.7, 75.9, 76.8, 113.9 (2), 116.9, 129.3 (2), 130.9, NMR (400 MHz, C6D6) d: 0.98 (3H, d, Jꢁ6.8 Hz), 1.07 (1H, ddd, Jꢁ13.9,
135.3, 159.2. IR (neat) cmꢀ1: 3600—3100, 1613, 1586, 1514, 1462. Exact 9.0, 3.7 Hz), 1.31—1.47 (2H, m), 1.65 (1H, ddd, Jꢁ13.9, 9.3, 4.9 Hz),
MS m/z: 322.2140 (Calcd for C19H30O4: 322.2144). [a]D22 ꢃ1.2° (cꢁ1.00, 1.83—1.93 (1H, m), 2.06—2.15 (1H, m), 2.21 (1H, ddd, Jꢁ15.7, 5.4,
CHCl3).
(4S,6R)-4-Allyloxy-7-(p-methoxybenzyloxy)-6-methylheptanal
3.8 Hz), 2.41—2.49 (1H, m), 2.69—2.76 (1H, m), 3.16 (1H, dd, Jꢁ8.8,
6.2 Hz), 3.25 (1H, dd, Jꢁ8.8, 5.9 Hz), 3.30—3.37 (1H, m), 3.31 (3H, d,
A
mixture of (4S,6R)-4-allyloxy-7-(p-methoxybenzyloxy)-6-methyl-1-heptanol Jꢁ0.9 Hz), 3.44 (1H, dd, Jꢁ8.2, 4.0 Hz), 4.36 (2H, s), 5.05 (1H, ddt,
(2.70 g, 8.37 mmol) and Dess-Martin periodinane (4.26 g, 10.0 mmol) in
CH2Cl2 (60 ml) was stirred at room temperature for 1 h. The mixture was
quenched with sat. Na2S2O3 solution, and extracted with EtOAc. The extract
was washed with saturated aqueous NaHCO3 solution, H2O, and brine, dried
(MgSO4), and concentrated. The residue was chromatographed on silica gel
Jꢁ10.3, 2.1, 1.1 Hz), 5.12 (1H, ddt, Jꢁ17.1, 2.1, 1.5 Hz), 5.97 (1H, ddt,
Jꢁ17.1, 10.3, 6.9 Hz), 6.82 (2H, d, Jꢁ8.8 Hz), 7.24 (2H, d, Jꢁ8.8 Hz). 13C-
NMR (100 MHz, C6D6) d: 17.2, 30.6, 32.7, 34.5, 37.6, 39.9, 54.7, 72.8,
74.1, 75.8, 82.5, 114.0 (2), 117.0, 129.3 (2), 131.3, 134.9, 159.7, 206.6. IR
(neat) cmꢀ1: 1740, 1612, 1586, 1514, 1462. Exact MS m/z: 332.1993 (Calcd
(10% EtOAc in hexane) to give (4S,6R)-4-allyloxy-7-(p-methoxybenzyl- for C20H28O4: 332.1987). [a]D27 ꢃ17.3° (cꢁ0.33, CHCl3). The second
oxy)-6-methylheptanal (2.44 g, 91%) as a colorless oil. 1H-NMR (270 MHz,
CDCl3) d: 0.95 (3H, d, Jꢁ6.6 Hz), 1.17 (1H, ddd, Jꢁ13.9, 8.2, 5.0 Hz), 1.68 propyl]tetrahydropyran-3-one (2) (33 mg, 80%) as a colorless oil. H-NMR
fraction gave (2R,6S)-2-allyl-6-[(2R)-3-{p-methoxybenzyloxy}-2-methyl-
1

August 2005
993
(500 MHz, C6D6) d: 0.90—1.00 (1H, m), 0.98 (3H, d, Jꢁ6.8 Hz), 1.18— s), 0.061 (3H. s), 0.89 (9H, s), 0.92 (15/7H, d, Jꢁ7.0 Hz), 0.93 (6/7H, d,
1.28 (1H, m), 1.38—1.47 (1H, m), 1.68 (1H, ddd, Jꢁ14.1, 9.8, 4.3 Hz), Jꢁ6.6 Hz), 0.94—1.01 (1H, m), 1.20—1.32 (1H, m), 1.55—2.30 (7H, m),
2.00—2.23 (3H, m), 2.35—2.43 (2H, m), 3.17 (1H, dd, Jꢁ9.0, 6.4 Hz), 3.23
(1H, dd, Jꢁ9.0. 6.0 Hz), 3.30 (3H, s), 3.66 (1H, tt, Jꢁ9.8, 3.8 Hz), 3.93 (1H,
2.60—2.66 (5/7H, m), 2.99—3.04 (2/7H, m), 3.19—3.38 (2H, m), 3.73—
3.96 (5H, m), 3.80 (3H, s), 4.43 (10/7H, s), 4.45 (4/7H, s), 6.87 (2H, d,
dd, Jꢁ9.0, 4.7 Hz), 4.35 (2H, s), 5.03—5.07 (2H, m), 5.81 (1H, ddt, Jꢁ17.0, Jꢁ8.5 Hz), 7.25 (2H, d, Jꢁ8.5 Hz). 13C-NMR (68 MHz, CDCl3) d for the
10.3, 6.9 Hz), 6.81 (2H, d, Jꢁ8.7 Hz), 7.23 (2H, d, Jꢁ8.7 Hz). 13C-NMR major isomer: ꢀ4.9, ꢀ4.7, 16.8, 18.1, 25.8 (3), 27.6, 28.6, 29.9, 30.1, 37.8,
(125 MHz, C6D6) d: 17.3, 30.4, 30.6, 34.8, 35.9, 39.1, 55.0, 68.1, 73.0, 76.1, 55.3, 61.0, 67.2, 68.9, 72.6, 73.8, 75.7, 113.7 (2), 129.2 (2), 130.7, 159.1. IR
78.8, 114.1 (2), 117.3, 129.4 (2), 131.4, 134.6, 159.7, 208.8. IR (neat) cmꢀ1
:
(neat) cmꢀ1: 3700—3100, 1613, 1586, 1514, 1463. Exact MS m/z: 452.2950
1724, 1612, 1586, 1512. Exact MS m/z: 332.1981 (Calcd for C20H28O4: (Calcd for C25H44O5Si: 452.2958).
332.1988). [a]D28 ꢃ97.2° (cꢁ1.00, CHCl3).
Diol 10 A solution of TBAF in THF (1.0 M, 0.63 ml, 0.63 mmol) was
Reduction of 2 A mixture of 2 (200 mg, 0.602 mmol) and NaBH4 added to a solution of the alcohol (237 mg, 0.524 mmol) in THF (5 ml) at
(27 mg, 0.722 mmol) in EtOH (6 ml) was stirred at room temperature
overnight. The mixture was quenched with sat. NH4Cl solution, and ex-
tracted with EtOAc. The extract was washed with brine, dried (MgSO4), and
concentrated. The residue was chromatographed on silica gel (50% EtOAc
in hexane) to give a mixture of (2R,3R,6S)- and (2R,3S,6S)-2-allyl-6-[(2R)-
room temperature and the mixture was stirred at the same temperature
overnight. The mixture was quenched with sat. NH4Cl solution, and ex-
tracted with EtOAc. The extract was washed with H2O and brine, dried
(MgSO4), and concentrated. The residue was chromatographed on silica gel
1
(50% EtOAc in hexane) to give 10 (172 mg, 97%) as a colorless oil. H-
3-(p-methoxybenzyloxy)-2-methylpropyl]tetrahydropyran-3-ol
(197 mg, NMR (270 MHz, CDCl3) d: 0.85—2.30 (9H, m), 0.92 (15/7H, d, Jꢁ7.0 Hz),
98%) as a colorless oil. 1H-NMR (270 MHz, CDCl3) d: 0.93 (6/7H, d, 0.93 (6/7H, d, Jꢁ7.0 Hz), 2.29 (2H, br s), 3.15—3.33 (2H, m), 3.56—3.98
Jꢁ6.6 Hz), 0.94 (15/7H, d, Jꢁ6.6 Hz), 0.98—1.09 (1H, m), 1.23—1.33 (1H, (5H, m), 3.81 (3H, s), 4.45 (2H, s), 6.88 (2H, d, Jꢁ8.8 Hz), 7.25 (2H, d,
m), 1.53—2.01 (5H, m), 2.22—2.44 (2H, m), 3.19—3.33 (2H, m), 3.68— Jꢁ8.8 Hz). 13C-NMR (68 MHz, CDCl3) d for the major isomer: 16.6, 26.7
3.78 (2H, m), 3.80 (3H, s), 3.82—4.04 (1H, m), 4.43 (2H, s), 5.01—5.16 (2), 29.9, 33.0, 34.9, 55.3, 60.0, 67.6, 69.1, 70.3, 72.7, 75.6, 113.7 (2), 129.3
(2H, m), 5.82 (1H, ddt, Jꢁ17.1, 10.1, 7.0 Hz), 6.87 (2H, d, Jꢁ8.6 Hz), 7.25
(2H, d, Jꢁ8.6 Hz). 13C-NMR (68 MHz, CDCl3) d for the major isomer: 16.7,
26.7 (2), 29.8, 33.6, 35.7, 55.3, 67.1, 68.4, 72.49, 72.51, 75.9, 113.7 (2),
(2), 130.4, 171.4. IR (neat) cmꢀ1: 3700—3100, 1613, 1586, 1514, 1462.
Exact MS m/z: 338.2083 (Calcd for C19H30O5: 338.2093).
Monosilylation of 10 A mixture of 10 (95 mg, 0.281 mmol), TBDMSCl
116.8, 129.0 (2), 130.9, 135.1, 159.0. IR (neat) cmꢀ1: 3700—3100, 1613, (51 mg, 0.337 mmol), and imidazole (38 mg, 0.561 mmol) in DMF (3 ml)
1586, 1514, 1462. Exact MS m/z: 334.2165 (Calcd for C20H30O4: 334.2144).
Conversion into 8 A mixture of the alcohol (195 mg, 0.583 mmol),
TBDMSCl (149 mg, 0.991 mmol), and imidazole (119 mg, 1.75 mmol) in
DMF (5.5 ml) was stirred at room temperature overnight. The mixture was
poured into H2O and the mixture was extracted with Et2O. The combined ex- (116 mg, 91%) as a colorless oil. H-NMR (270 MHz, CDCl3) d: 0.07 (6H,
tracts were washed with brine, dried (MgSO4), and concentrated. The
was stirred at room temperature for 10 min. The mixture was poured into
H2O and the mixture was extracted with Et2O. The combined extracts were
washed with brine, dried (MgSO4), and concentrated. The residue was chro-
matographed on silica gel (20% EtOAc in hexane) to give the silyl ether
1
s), 0.89 (9H, s), 0.93 (6/7H, d, Jꢁ7.3 Hz), 0.94 (15/7H, d, Jꢁ6.6 Hz), 1.06
(1H, ddd, Jꢁ13.9, 9.5, 4.4 Hz), 1.25—2.00 (8H, m), 2.84 (1H, br s), 3.23
residue was chromatographed on silica gel (10% EtOAc in hexane) to give 8
1
(254 mg, 97%) as a colorless oil. H-NMR (300 MHz, CDCl3) d: 0.04 (3H, (1H, dd, Jꢁ9.2, 6.2 Hz), 3.30 (1H, dd, Jꢁ9.2, 5.9 Hz), 3.62—3.86 (5H, m),
s), 0.05 (3H, s), 0.88 (45/7H, s), 0.89 (18/7H, s), 0.92 (15/7H, d, Jꢁ6.6 Hz),
3.80 (3H, s), 4.42 (2H, s), 6.87 (2H, d, Jꢁ8.4 Hz), 7.24 (2H, d, Jꢁ8.4 Hz).
0.95 (6/7H, d, Jꢁ6.6 Hz), 1.07 (1H, d, Jꢁ13.9, 9.5, 3.3 Hz), 1.22—1.34 (1H, 13C-NMR (68 MHz, CDCl3) d for the major isomer: ꢀ5.5 (2), 16.7, 18.2,
m), 1.52—1.78 (4H, m), 1.91—2.03 (1H, m), 2.25—2.33 (1H, m), 2.45— 25.8 (3), 26.8, 27.0, 29.9, 32.2, 36.5, 55.2, 60.2, 67.1, 68.0, 71.4, 72.5, 75.9,
2.54 (1H, m), 3.17—3.36 (4/7H, m), 3.19 (5/7H, dd, Jꢁ9.2, 6.8 Hz), 3.30
113.6 (2), 128.98 (2), 129.04, 159.0. IR (neat) cmꢀ1: 3600—3100, 1613,
(5/7H, dd, Jꢁ9.2, 5.9 Hz), 3.61—3.68 (2/7H, m), 3.65 (5/7H, tt, Jꢁ9.7, 1586, 1514, 1462. Exact FAB-MS m/z: 453.3040 (Calcd for C25H45O5Si:
2.9 Hz), 3.75—3.98 (2H, m), 3.80 (3H, s), 4.43 (10/7H, s), 4.44 (4/7H, s), 453.3036).
5.03 (1H, ddt, Jꢁ10.3, 2.1, 1.2 Hz), 5.09 (1H, ddt, Jꢁ17.2, 2.1, 1.6 Hz),
(2R,6S)-2-[2-(tert-Butyldimethylsilyloxyethyl)-6-[(2R)-3-(p-methoxy-
5.85 (1H, ddt, Jꢁ17.2, 10.3, 6.9 Hz), 6.87 (2H, d, Jꢁ8.8 Hz), 7.24 (2H, d, benzyloxy)-2-methylpropyl]tetrahydropyran-3-one (11) A mixture of
Jꢁ8.8 Hz). 13C-NMR (68 MHz, CDCl3) d for the major isomer: ꢀ4.8, ꢀ4.7, the silyl ether (196 mg, 0.433 mmol) and Dess-Martin periodinane (220 mg,
16.9, 25.80 (3), 25.85, 27.8, 29.8, 29.9, 30.3, 39.1, 55.2, 65.9, 68.8, 72.5, 0.52 mmol) in CH2Cl2 (60 ml) was stirred at room temperature overnight.
75.8, 76.0, 113.7 (2), 116.0, 129.1 (2), 135.7, 136.1, 159.0. IR (neat) cmꢀ1
:
The mixture was quenched with sat. Na2S2O3 solution, and extracted with
1613, 1586, 1514, 1463. Exact MS m/z: 448.3032 (Calcd for C26H44O4Si: EtOAc. The extract was washed with saturated aqueous NaHCO3 solution,
448.3009).
H2O, and brine, dried (MgSO4), and concentrated. The residue was chro-
matographed on silica gel (20% EtOAc in hexane) to 11 (185 mg, 95%) as a
colorless oil. 1H-NMR (270 MHz, CDCl3) d: 0.04 (6H, s), 0.88 (9H, s), 0.98
(3H, d, Jꢁ6.6 Hz), 1.19—1.30 (1H, m), 1.71—2.13 (5H, m), 1.77 (1H, ddd,
Jꢁ13.9, 9.6, 4.3 Hz), 2.40—2.60 (2H, m), 3.26 (1H, dd, Jꢁ9.0, 6.1 Hz),
3.32 (1H, dd, Jꢁ9.0, 6.1 Hz), 3.68—3.73 (2H, m), 3.81 (3H, s), 3.95—4.06
(1H, m), 4.17 (1H, dd, Jꢁ8.7, 4.8 Hz), 4.43 (2H, s), 6.87 (2H, d, Jꢁ8.6 Hz),
7.25 (2H, d, Jꢁ8.6 Hz). 13C-NMR (68 MHz, CDCl3) d: ꢀ5.4 (2), 16.8, 18.3,
25.9 (3), 30.0 (2), 33.0, 35.7, 38.8, 55.3, 58.9, 67.9, 72.6, 75.7, 75.8, 113.7
(2), 129.1 (2), 130.8, 159.1, 211.9. IR (neat) cmꢀ1: 1725, 1613, 1586, 1514,
1464. Exact MS m/z: 450.2788 (Calcd for C25H42O5Si: 450.2802). [a]D27
ꢃ62.9° (cꢁ1.00, CHCl3).
Oxidative Cleavage of the Terminal Alkene of 8 An aqueous solution
of OsO4 (4%, 0.36 ml, 0.0562 mmol) and NMO (132 mg, 1.12 mmol) were
added to a solution of 8 (252 mg, 0.562 mmol) in THF–H2O (5 : 1, 6 ml) at
0 °C, then the mixture was stirred at room temperature for 1.5 h. The mix-
ture was diluted with EtOAc and washed with H2O and brine, dried
(MgSO4), and concentrated to give the crude diol. A mixture of the crude
diol and NaIO4 (141 mg, 0.659 mmol) in THF–H2O (5 : 1, 6 ml) was stirred
at room temperature overnight. The mixture was quenched with sat. Na2S2O3
solution, and extracted with EtOAc. The extract was washed with saturated
aqueous NaHCO3 solution, H2O, and brine, dried (MgSO4), and concen-
trated. The residue was chromatographed on silica gel (20% EtOAc in
hexane) to give 9 (240 mg, 95%) as a colorless oil. 1H-NMR (270 MHz,
CDCl3) d: 0.04 (3H, s), 0.06 (3H, s), 0.87 (9H, s), 0.89 (3H, d, Jꢁ7.3 Hz),
(2R,6S)-6-[2-(tert-Butyldimethylsilyloxy)ethyl]-2-[(2R)-3-(p-methoxy-
benzyloxy)-2-methylpropyl]-5,6-dihydro-2H-pyran (1) According to the
1.10 (1H, ddd, Jꢁ13.9, 9.5, 3.3 Hz), 1.23—1.38 (1H, m), 1.50—1.95 (5H, reported procedure,30) a solution of LHMDS in THF (1.0 M, 0.72 ml,
m), 2.69 (2H, dd, Jꢁ7.3, 2.6 Hz), 3.17—3.39 (2H, m), 3.55—3.65 (1H, m), 0.72 mmol) was added to a solution of 11 (54 mg, 0.12 mmol) in THF (1 ml)
3.80 (3H, s), 3.80—3.95 (2H, m), 4.41 (2H, s), 6.87 (2H, d, Jꢁ8.8 Hz), 7.24
at ꢀ80 °C under nitrogen atmosphere and the mixture was stirred at the
same temperature for 1.5 h. After solution of PhNTf2 (129 mg,
(2H, d, Jꢁ8.8 Hz), 9.70—9.73 (2/7H, m), 9.74 (5/7H, t, Jꢁ2.6 Hz). 13C-
a
NMR (68 MHz, CDCl3) d for the major isomer: ꢀ4.9, ꢀ4.7, 16.7, 18.0, 0.361 mmol) in THF (1.5 ml) was added to the cold mixture, the resultant
25.8 (3), 27.8, 29.8, 30.0, 38.9, 41.2, 55.2, 66.8, 68.2, 71.7, 72.5, 75.8, 113.7 mixture was allowed to warm up to 0 °C and then stirred at 0 °C for 28 h.
(2), 129.1 (2), 130.1, 159.0, 201.4. IR (neat) cmꢀ1: 1728, 1613, 1586, 1514, The mixture was quenched with sat. NH4Cl solution, and extracted with
1463. Exact MS m/z: 450.2823 (Calcd for C25H42O5Si: 450.2802).
Et2O. The extract was washed with H2O and brine, dried (MgSO4), and con-
centrated to give 13 which was used in the next step without purification.
According to the reported procedure,31) the crude 13 was diluted THF (1 ml)
Reduction of Aldehyde 9 A mixture of 9 (239 mg, 0.53 mmol) and
NaBH4 (24 mg, 0.636 mmol) in EtOH (6 ml) was stirred at room temperature
overnight. The mixture was quenched with sat. NH4Cl solution, and ex-
tracted with EtOAc. The extract was washed with brine, dried (MgSO4), and
concentrated. The residue was chromatographed on silica gel (30% EtOAc
in hexane) to give a mixture of the diastereomers of the primary alcohol
and this mixture was added to
a solution of Pd(PPh3)4 (2.7 mg,
0.00234 mmol) and LiCl (41 mg, 0.967 mmol) in THF (0.5 ml) at room tem-
perature under nitrogen atmosphere. Then Bu3SnH (38 mg, 0.132 mmol) was
added to the resultant mixture at the same temperature. After stirred for
(237 mg, 99%) as a colorless oil. 1H-NMR (270 MHz, CDCl3) d: 0.056 (3H, 1.5 h, the mixture was diluted with Et2O and washed with H2O and brine,

994
Vol. 53, No. 8
dried (MgSO4), and concentrated. The residue was chromatographed on sil-
ica gel (2.5% EtOAc in hexane) to give 111) (46 mg, 88%) as a colorless oil.
1H-NMR (270 MHz, CDCl3) d: 0.06 (6H, s), 0.89 (9H, s), 0.95 (3H, d,
Jꢁ6.9 Hz), 1.10—1.38 (1H, m), 1.57—1.74 (2H, m), 1.76—1.89 (1H, m),
1.90—1.97 (2H, m), 1.99—2.14 (1H, m), 3.23 (1H, dd, Jꢁ9.1, 6.8 Hz), 3.34
(1H, dd, Jꢁ9.1, 5.8 Hz), 3.66—3.81 (3H, m), 3.80 (3H, s), 4.30—4.37 (1H,
m), 4.43 (2H, s), 5.65—5.72 (1H, m), 5.75—5.84 (1H, m), 6.87 (2H, d,
Jꢁ8.7 Hz), 7.25 (2H, d, Jꢁ8.7 Hz). 13C-NMR (68 MHz, CDCl3) d: ꢀ5.33,
ꢀ5.30, 16.9, 18.3, 26.0 (3), 29.6, 31.5, 36.9, 39.6, 55.3, 59.9, 64.9, 69.4,
3) Elliott M. C., J. Chem. Soc., Perkin Trans. 1, 1998, 4175—4200
(1998).
4) Elliott M. C., J. Chem. Soc., Perkin Trans. 1, 2000, 1291—1318
(2000).
5) Elliott M. C., Williams E., J. Chem. Soc., Perkin Trans. 1, 2001,
2303—2340 (2001).
6) Al-Mutairi E. H., Crosby S. R., Darzi J., Harding J. R., Hughes R. A.,
King C. D., Simpson T. J., Smith R. W., Willis C. L., Chem. Commun.,
2001, 835—836 (2001).
7) Díez D., Moro R. F., Lumeras W., Rodríguez L., Marcos I. S., Basabe
P., Escarcena R., Urones J. G., Synthesis, 2002, 175—184 (2002).
8) Chakraborty T. K., Reddy V. R., Reddy T. J., Tetrahedron, 59, 8613—
8622 (2003).
9) For a review, see: Mulzer J., Öhler E., Chem. Rev., 103, 3753—3786
(2003).
72.5, 76.0, 113.7 (2), 124.0, 129.0 (2), 130.0, 131.0, 159.0. IR (neat) cmꢀ1
:
2955, 2927, 2855, 1613, 1586, 1514, 1464, 1249, 1181, 1039. Exact MS
m/z: 434.2878 (Calcd for C25H42O4Si: 434.2852). [a]D26 ꢀ28.0° (cꢁ0.50,
CHCl3) {lit.11) [a]D20 ꢀ28.9° (cꢁ1.27, CHCl3)}.
(2R,6S)-6-[2-(tert-Butyldimethylsilyloxy)ethyl]-2-[(2R)-3-(p-methoxy-
benzyloxy)-2-methylpropyl]-5-methyl-5,6-dihydro-2H-pyran (14) A so-
lution of 13, which was prepared from 11 (29 mg, 0.00643 mmol), LHMDS
(1 M in THF, 0.4 ml, 0.40 mmol) and PhNTf2 (69 mg, 0.193 mmol) according
10) For a total synthesis, see: Ghosh A. K., Wang Y., Kim J. T., J. Org.
Chem., 66, 8973—8982 (2001). Also see, refs. 11—18.
to the procedure described in the preparation of 1, in THF (0.5 ml) was 11) Ahmed A., Hoegenauer E. K., Enev V. S., Hanbauer M., Kaehlig H.,
added to a solution of Pd(OAc)2 (1.5 mg, 0.00666 mmol) and PPh3 (5.2 mg, Öhler E., Mulzer J., J. Org. Chem., 68, 3026—3042 (2003).
0.02 mmol) in THF (0.5 ml) at room temperature under nitrogen atmosphere. 12) Paterson I., De Savi C., Tudge M., Org. Lett., 3, 3149—3152 (2001).
After subsequent addition of MeMgCl in THF (3 M, 0.06 ml, 0.18 mmol), the
mixture was stirred for 30 min. The mixture was quenched with sat. NH4Cl
13) Wender P. A., Hegde S. G., Hubbard R. D., Zhang L., J. Am. Chem.
Soc., 124, 4956—4957 (2002).
solution, and extracted with Et2O. The extract was washed with brine, dried 14) Crimmins M. T., Stanton M. G., Allwein S. P., J. Am. Chem. Soc., 124,
(MgSO4), and concentrated. The residue was chromatographed on silica gel 5958—5959 (2002).
(2.5% EtOAc in hexane) to give 14 (15 mg, 52%) as a colorless oil. 1H-NMR 15) Nelson S. G., Cheung W. S., Kassick A. J., Hilfiker M. A., J. Am.
(270 MHz, CDCl3) d: 0.06 (6H, s), 0.90 (9H, s), 0.95 (3H, d, Jꢁ6.6 Hz), Chem. Soc., 124, 13654—13655 (2002).
1.00—1.62 (2H, m), 1.62 (3H, s), 1.73—1.81 (2H, m), 1.88—1.91 (2H, m), 16) Williams D. R., Mi L., Mullins R. J., Stites R. E., Tetrahedron Lett.,
1.97—2.13 (1H, m), 3.23 (1H, dd, Jꢁ9.1, 6.8 Hz), 3.34 (1H, dd, Jꢁ9.1, 43, 4841—4844 (2002).
5.8 Hz), 3.65—3.81 (3H, m), 3.80 (3H, s), 4.06—4.14 (1H, m), 4.43 (2H, s), 17) Gallagher B. M., Jr., Fang F. G., Johannes C. W., Pesant M., Tremblay
5.45—5.49 (1H, m), 6.87 (2H, d, Jꢁ8.6 Hz), 7.25 (2H, d, Jꢁ8.6 Hz). 13C-
NMR (68 MHz, CDCl3) d: ꢀ5.3 (2), 14.1, 16.9, 19.8, 26.0 (3), 29.7, 32.0,
M. R., Zhao H., Akasaka K., Li X., Liu J., Littlefield B. A., Bioorg.
Med. Chem. Lett., 14, 575—579 (2004).
34.5, 39.8, 55.3, 60.1, 64.2, 72.5, 73.0, 76.0, 113.7 (2), 119.4, 129.0 (2), 18) Uenishi J., Ohmi M., Angew. Chem. Int. Ed., 44, 2756—2760 (2005).
130.9, 135.7, 159.0. IR (neat) cmꢀ1: 1613, 1587, 1514, 1463. Exact MS m/z: 19) Quiñoà E., Kakou Y., Crews P., J. Org. Chem., 53, 3642—3644 (1988).
448.3042 (Calcd for C26H44O4Si: 448.3009). [a]D22 ꢀ7.4° (cꢁ0.40, CHCl3).
(2R,6S)-6-[2-(tert-Butyldimethylsilyloxy)ethyl]-2-[(2R)-3-(p-methoxy-
20) Corley D. G., Herb R., Moore R. E., Scheuer P. J., Paul V. J., J. Org.
Chem., 53, 3644—3646 (1988).
benzyloxy)-2-methylpropyl]-5-(trimethylsilylmethyl)-5,6-dihydro-2H- 21) Jefford C. W., Bernardinelli G., Tanaka J., Higa T., Tetrahedron Lett.,
pyran (15) According to a procedure similar to that described for the 37, 159—162 (1996).
preparation of 14, treatment of 13, prepared from 11 (30 mg, 0.00666 mmol) 22) Doyle M. P., McKervey M. A., Ye T., “Modern Catalytic Methods for
with LHMDS (1 M in THF, 0.4 ml, 0.40 mmol), PhNTf2 (57 mg, 0.16 mmol),
with Pd(OAc)2 (1.5 mg, 0.00666 mmol), PPh3 (5.2 mg, 0.02 mmol), and
TMSCH2MgCl (1 M in THF, 0.2 ml, 0.20 mmol) gave 15 (14 mg, 40%) as a
colorless oil. 1H-NMR (270 MHz, CDCl3) d: 0.02 (9H, s), 0.06 (6H, s), 0.90
Organic Synthesis with Diazo Compounds,” John Wiley & Sons, New
York, 1998.
23) For a recent review, see: Merlic C. A., Zechman A. L., Synthesis,
2003, 1137—1156 (2003).
(9H, s), 0.94 (3H, d, Jꢁ6.9 Hz), 1.11—1.71 (4H, m), 1.73—1.83 (2H, m), 24) Clark J. S., Whitlock G. A., Tetrahedron Lett., 35, 6381—6382 (1994).
1.89—1.94 (2H, m), 1.99—2.10 (1H, m), 3.22 (1H, dd, Jꢁ9.2, 6.9 Hz), 3.33 25) Mulzer J., Hanbauer M., Tetrahedron Lett., 43, 3381—3383 (2002).
(1H, dd, Jꢁ9.2, 5.6 Hz), 3.66—3.81 (3H, m), 3.80 (3H, s), 4.05—4.11 (1H, 26) Travis B. R., Sivakumar M., Hollist G. O., Borhan B., Org. Lett., 5,
m), 4.43 (2H, s), 5.28—5.31 (1H, m), 6.87 (2H, d, Jꢁ8.6 Hz), 7.25 (2H, d, 1031—1034 (2003).
Jꢁ8.6 Hz). 13C-NMR (68 MHz, CDCl3) d: ꢀ5.3, ꢀ5.2, ꢀ1.1 (3), 16.9, 18.4, 27) Yakura T., Tanaka T., Ikeda M., Uenishi J., Chem. Pharm. Bull., 51,
22.7, 26.0 (3), 29.7, 32.0, 34.4, 39.8, 55.3, 60.2, 63.9, 72.5, 72.7, 76.0, 113.7 471—473 (2003).
(2), 116.9, 129.0 (2), 129.6, 137.5, 159.0. IR (neat) cmꢀ1: 1614, 1587, 1514, 28) Clark J. S., Whitlock G., Jiang S., Onyia N., Chem. Commun., 2003,
1464. Exact MS m/z: 520.3394 (Calcd for C29H52O4Si2: 520.3404). [a]D21
ꢀ5.9° (cꢁ0.27, CHCl3).
2578—2579 (2003).
29) Shapiro R. H., Heath M. J., J. Am. Chem. Soc., 89, 5734—5735
(1967).
References and Notes
30) McMurry J. E., Scott W. J., Tetrahedron Lett., 24, 979—982 (1983).
31) Scott W. J., Crisp G. T., Stille J. K., J. Am. Chem. Soc., 106, 4630—
4632 (1984).
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