Highly demanding cross-metathesis in the synthesis of the C16-C30 fragment of dolabelide C

Article abstract of DOI:10.1021/jo200466t

A highly demanding cross-metathesis (CM) reaction for the formation of the C24-C25 trisubstituted olefin of dolabelide C has been optimized. A difference in reactivity between the E and Z enone isomers in this reaction was uncovered, and the selection of the Z isomer of the starting enone was critical for the success of the cross-metathesis. Application to the synthesis of the C16-C30 fragment of dolabelide C is reported.

Full text of DOI:10.1021/jo200466t

ARTICLE
pubs.acs.org/joc
Highly Demanding Cross-Metathesis in the Synthesis of the C16ꢀC30
Fragment of Dolabelide C
Marie-Gabrielle Braun,† Aurꢀelie Vincent,† Mehdi Boumediene,† and Jo€elle Prunet*,‡
†Laboratoire de Synthꢁese Organique, CNRS UMR 7652, Ecole Polytechnique, DCSO, F-91128 Palaiseau, France
‡WestCHEM, School of Chemistry, University of Glasgow, Joseph Black Building, University Avenue, Glasgow G12 8QQ, U.K.
S Supporting Information
b
ABSTRACT: A highly demanding cross-metathesis (CM) reaction
for the formation of the C24ꢀC25 trisubstituted olefin of dolabelide
C has been optimized. A difference in reactivity between the E and Z
enone isomers in this reaction was uncovered, and the selection of
the Z isomer of the starting enone was critical for the success of the
cross-metathesis. Application to the synthesis of the C16ꢀC30
fragment of dolabelide C is reported.
’ INTRODUCTION
We thus decided to study this demanding CM on model systems
(Scheme 2). Racemic compound 5a (R = Me) was reacted with
acetate (()-6a9 in the presence of 5 mol % of Grubbs’ second-
generation catalyst G210 (Figure 1). Although the secondary
allylic alcohol 5a is a type II olefin,11 its rate of dimerization is
much faster than the desired CM reaction, and only undesired
homodimer 7a was obtained as a mixture of diastereomers.
The same result was observed with internal olefin 5b (R = Pent),
and CM of the PMB ether of 5a with (()-6a only led to
decomposition.
We then examined CM reactions with the enone analogues of
5a,b, which dimerize significantly more slowly than the corre-
sponding allylic alcohols (Scheme 3). Cross-metathesis of vinyl
ketone 8a with (()-6a only furnished homodimer 9a,12 but CM
of the propenyl ketone 8b (E/Z = 1/1) gave 15% of the desired
product 10b, along with the homodimer of 8b. Use of 4 equiv of
(()-6a suppressed the formation of the homodimer and raised
the yield to 28%.13 This result is consistent with the trend
observed by Grubbs and co-workers for the cross-metathesis
between 2-methyl-1-heptene (which corresponds to compound
(()-6a without the acetate substituent) and ethyl vinyl or ethyl
propenyl ketone, although the presence of the acetate substituent
considerably lowers the yield of the CM reactions in our case. It is
also interesting to note that the E/Z ratio of 10b was higher when
the reaction was performed with 4 equiv of (()-6a.
Dolabelides A and B, two 22-membered-ring lactones, were
isolated in 1995 by Yamada and co-workers from the sea hare
Dolabella auricularia (family Aplysiidae).1 In 1997, Dolabelides
C and D, two similar 24-membered-ring lactones, were also
extracted from this marine organism.2 These polyketides exhibit
cytotoxicity against HeLa-S3 cell lines with IC50 values of 6.3, 1.3,
1.9, and 1.5 μg/mL, respectively. Several groups have published
synthetic approaches to these compounds,3 and the total synth-
esis of dolabelide D has been achieved by Leighton and co-
workers.4
The retrosynthesis we envisioned for dolabelide C is shown in
Scheme 1. Opening the macrocycle and disconnecting the C15ꢀ
C16 bond leads to compounds 1 and 2. These two fragments
would be joined by a B-alkyl Suzuki coupling between the vinyl
iodide at C15 and a borane derived from the iodide at C16. A
Yamaguchi macrolactonization5 would then close the ring. The
order of these two steps could also be reversed if necessary. We
have already reported the synthesis of the C1ꢀC15 fragment,6
and we wish to describe here the completion of the C16ꢀC30
portion of dolabelide C.
In a previous approach to compound 2, we had planned to
construct the trisubstituted C24ꢀC25 double bond by a Wittig
or Julia olefination reaction.7 However, a more flexible route to
this fragment could involve a cross-metathesis (CM) reaction to
install the olefin at C24ꢀC25, allowing the easy formation of
analogues of the target molecule with various side chains
(Scheme 1). Compound 2 would be prepared from allylic alcohol
derivative 3 and gem-disubstituted olefin 4.
Having established that the propenyl ketone was the suitable
functional group for CM, we set to synthesize the metathesis
partners 19a,b required for the synthesis of dolabelide C
(Scheme 4). Homoallylic alcohol 12 is the enantiomer of the
starting compound we used for the C1ꢀC15 portion of dolabe-
lide C and was prepared in the same way by Jacobsen hydrolytic
kinetic resolution (HKR)14 of epoxide (()-11 with complex
’ RESULTS AND DISCUSSION
CM reactions have been employed in numerous syntheses of
natural products for the construction of disubstituted olefins, but
there are very few reports of syntheses of trisubstituted alkenes.8
Received: March 9, 2011
Published: May 02, 2011
r
2011 American Chemical Society
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Scheme 1. Retrosynthesis of Dolabelide C
Scheme 4. Synthesis of Enones 19a,b
Figure 1. Metathesis catalysts.
Scheme 2. CM Reactions with Allylic Alcohol Derivatives
Scheme 3. CM Reactions with Enone Derivatives
(R,R)-[Co], followed by opening of the enantiopure 11 with a
vinyl Grignard reagent.6 Protection of the alcohol as a TBS or
PMB ether gave 13a,b in 91 and 93% yields, respectively, and
subsequent ozonolysis furnished aldehydes 14a,b. The C21 and
C22 stereocenters were installed by an enantioselective Duthaler
crotylation15 of 14a,b with the complex (S,S)-[Ti], which pro-
ceeded in good to excellent selectivity, and the major diastere-
omers 15a,b were isolated in 88 and 80% yields, respectively.16
After protection of the free alcohol, bis -TBS and bis-PMB ethers
16a,b were subjected to oxidative cleavage to give aldehydes
17a,b. These aldehydes were transformed into the corresponding
propenyl ketones 19a,b in two steps. We first employed a 1/1
mixture of (E)- and (Z)-1-bromopropene to make the Grignard
reagent. Use of 5 equiv of this organometallic reagent led to a 3/1
Z/E mixture of alcohols 18a, probably because the Z Grignard
reagent reacts more quickly than the E isomer. Crude alcohols
18a,b were then oxidized to the desired enones 19a,b with
iodoxybenzoic acid (IBX).17 When pure (Z)-1-bromopropene
was used, 19a,b were isolated as 4/1 Z/E mixtures,18 due to
isomerization of the alkene during silica gel chromatography after
the oxidation reaction.
The gem-disubstituted olefin partners 6aꢀc were prepared in
three steps from 1,2-epoxypentane ((()-20) by Jacobsen
HKR14 with (R,R)-[Co], opening of the enantiopure epoxide
20 with isopropenylmagnesium bromide, and suitable protection
of the resulting homoallylic alcohol 21 (Scheme 5).
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Scheme 5. Synthesis of gem-Disubstituted Olefins 6aꢀc
Scheme 6. Synthesis of the C16ꢀC30 Fragment of Dolabe-
lide C
Table 1. Optimization of the CM Reaction
Performing the CM between 19a and 6a at higher temperature
or concentration led to greater amounts of isomerization pro-
duct. In order to counteract this reactivity issue, we prepared the
vinyl ketone equivalent of 19a, but CM with this compound only
led to the homodimer. Cross-metathesis between 19a and 6b
(entries 4 and 5) or between 19b and 6c (entry 7) led to similar
results, showing that this reaction is not sensitive to the alcohol
protecting groups P and P0. The optimum amount of catalyst
appeared to be 30 mol %, as use of 45 mol % gave the same yield
of CM product 22b (entry 5 vs entry 6).
entry
P
P0
x
product
yield, %a
b
1
2
3
TBS
Ac
5
22a
15
30d
26c
39e
We pursued the synthesis of dolabelide C with enone 22b
(Scheme 6). Diasteroselective reduction with L-Selectride3c led
to alcohol 23 as a single diastereomer. Protection of the secondary
alcohol as its MOM ether followed by deprotection of the primary
benzyl ether with Raney nickel21 furnished compound 24. Finally,
transformation of the primary alcohol of 24 into the corresponding
iodide led to the C16ꢀC30 fragment of dolabelide C 25.
In conclusion, we have optimized a demanding CM reaction
between a highly substituted enone and a gem-disubstituted
olefin. In the process, we have uncovered the different behaviors
of the Z and E enone isomers and shown that the latter was
unreactive toward metathesis. We have utilized this reaction for
the synthesis of the C16ꢀC30 portion of dolabelide C. Further
studies toward the synthesis of the target molecule are in progress
and will be reported in due course.
b
4
5
6
TBS
TES
TBS
5
30
45
22b
22c
46
47
7
PMB
30
45
a Refers to the pure E isomer. b Isomerization of 19a to the E olefin.
c Along with 7% of Z isomer of 22a. d Reaction performed with G2
catalyst. e Isolated as a 49% combined yield of a 4/1 mixture of E/Z
isomers.
The CM reactions were performed in the presence of G2 and
HG219 complexes, and the latter catalyst, which gave sligthly
better results, was used for the optimization study. When enone
19a and 4 equiv of olefin 6a were subjected to 5 mol % HG2
catalyst (Figure 1), the only product was the E enone 19a
(Table 1, entry 1). When we increased the amount of catalyst
to 15 mol %, the CM product 22a was obtained as a 4/1 E/Z
mixture, from which the desired E isomer could be isolated in
26% yield and the Z isomer in 7% yield (entry 2). Using 30 mol %
of G2 catalyst further raised the yield to 39%. The isomerized E
enone 19a accounted for the remaining mass balance. When this
enone isomer was submitted to CM with compound 6a, no
reaction occurred, even at concentrations as high as 0.8 M,
proving that it is unreactive toward cross-metathesis.20 We also
attempted slow addition of enone 19a to a mixture of olefin 6a
and catalyst HG2 in refluxing dichloromethane to favor the CM
reaction vs the unwanted isomerization, with no success.
’ EXPERIMENTAL SECTION
General Methods. See ref 22.
2,7-Dimethylocten-4-yl-3,6-diol (7a). Z isomer: 1H NMR
(CDCl3, 400 MHz) δ 5.73ꢀ5.70 (m, 2H), 3.91 (s, 2H), 1.75 (qd, J =
6.8, 13.4 Hz, 2H), 1.45 (s, 2H), 0.94 (d, J = 6.8 Hz, 6H), 0.91 (d, J = 6.9
Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ 132.8, 77.2, 33.8, 18.2, 17.8;
IR (CHCl3, cmꢀ1) 3692, 3610, 2963, 2930, 2873, 2857, 2253, 1937,
1713, 1602, 1467, 1386, 1368, 1262, 1216, 1008; HRMS (EI, m/z) Mþ
þ
1
calcd for C10H20O2 172.1463, found 172.1460. E isomer: H NMR
(CDCl3, 400 MHz) δ 5.68 (dd, J = 1.9, 3.9 Hz, 2H), 3.87 (s, 2H), 1.74
(qd, J = 6.8, 13.4 Hz, 2H), 1.51 (s, 2H), 0.94 (d, J = 6.8 Hz, 6H), 0.90
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(d, J = 6.9 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ 133.1, 77.7, 33.8,
18.2, 18.0; IR (CHCl3, cmꢀ1) 3692, 3610, 2963, 2930, 2873, 2857, 2253,
1937, 1713, 1602, 1467, 1386, 1368, 1262, 1216, 1008; HRMS (EI, m/z)
Mþ calcd for C10H20O2þ 172.1463, found 172.1460.
concentrated in vacuo. The residue was purified by silica gel column
chromatography (98/2 petroleum ether/ether) to afford the protected
alcohol 13a (5.0 g, 91%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ
7.27ꢀ7.34 (m, 5H), 5.81 (ddt, J = 17.6, 10.5, 7.2 Hz, 1H), 5.03 (br d,
J = 16.8 Hz, 1H), 5.02 (br d, J = 10.6 Hz, 1H), 4.50 (s, 2H), 3.69ꢀ3.74 (m,
1H), 3.46 (t, J = 6.6 Hz, 2H), 2.22 (t, J = 6.4 Hz, 2H), 1.58ꢀ1.74 (m, 2H),
1.42ꢀ1.55 (m, 2H), 0.88 (s, 9H), 0.04, 0.04 (2s, 6H); 13C NMR (CDCl3,
100 MHz) δ 138.6, 128.3, 127.6, 127.4, 135.2, 116.7, 72.8, 71.7, 70.5, 41.9,
33.2, 25.9, 25.6, 18.1, ꢀ4.4, ꢀ4.5; IR (CHCl3, cmꢀ1) 3078, 3029, 3023,
3017, 2955, 2930, 2858, 1640, 1496, 1472, 1463, 1454, 1409, 1389, 1362,
1
6,11-Dimethylhexadecen-8-yl-7,10-diol (7b). Z isomer: H
NMR (CDCl3, 400 MHz) δ 5.72ꢀ5.58 (m, 2H), 4.06ꢀ3.91 (m, 2H),
1.65ꢀ1.58 (m, 2H), 1.50ꢀ1.04 (m, 18H), 0.91ꢀ0.85 (m, 12H); 13C
NMR (CDCl3, 100 MHz) δ 133.3, 132.8, 132.5, 131.9, 76.4, 76.3, 76.0,
75.9, 38.9, 38.8, 32.6, 32.3, 32.1, 26.9, 26.8, 22.6, 15.0, 14.5, 14.1; IR
(CHCl3, cmꢀ1) 3691, 3610, 2960, 2930, 2873, 2859, 2248, 1937, 1691,
1669, 1603, 1575, 1539, 1460, 1379,þ1264, 1230, 1217, 1136; HRMS
(EI, m/z) Mþ calcd for C18H36O2 284.2715, found 284.2720. E
1256, 1226, 1215, 1211, 1202, 1092; [R]25 = þ13.6° (c 1.0, CHCl3);
D
HRMS (EI, m/z) Mþ calcd for C20H34O2Siþ 334.2328, found 334.2317.
(R)-7-(Benzyloxy)-4-((4-methoxybenzyl)oxy)hex-1-ene
(13b). tert-Butylammonium iodide (200 mg, 0.54 mmol, 10 wt %) was
added to a stirred suspension of NaH (60% dispersion in mineral oil,
783 mg, 19.6 mmol, 2.2 equiv) in THF (40 mL). After the mixture was
cooled to 0 °C, the alcohol 12 (1.96 g, 8.9 mmol) was added dropwise
and the mixture was stirred at 20 °C for 30 min. PMBBr (2.86 g, 14.4
mmol, 1.6 equiv) was slowly added at 0 °C, and the reaction mixture was
stirred at reflux overnight. The reaction was quenched by careful
addition of water, and the solution was extracted with ether. The com-
bined organic extracts were washed with water and then brine, dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was
purified by silica gel column chromatography (90/10 petroleum ether/
ether) to afford the protected alcohol 13b (2.52 g, 93%) as a colorless
oil: 1H NMR (CDCl3, 400 MHz) δ 7.26ꢀ7.35 (m, 5H), 7.25ꢀ7.27 (m,
2H), 6.85ꢀ6.88 (m, 2H), 5.84 (ddt, J = 17.2, 10.2, 7.1 Hz, 1H),
5.04ꢀ5.11 (m, 2H), 4.50 (d, J = 11.2 Hz, 1H), 4.49 (s, 2H), 4.41 (d,
J = 11.2 Hz, 1H), 3.80 (s, 3H), 3.43ꢀ3.48 (m, 3H), 2.26ꢀ2.38 (m, 2H),
1.56ꢀ1.80 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 159.1, 138.6,
130.9, 129.3, 128.3, 127.6, 127.5, 113.7, 134.9, 116.9, 77.9, 72.8, 70.5,
70.4, 55.3, 38.3, 30.4, 25.7; IR (CHCl3, cmꢀ1) 3006, 2937, 2863,
1640, 1612, 1514, 1465, 1454, 1442, 1362, 1302, 1249, 1174, 1091,
1036; [R]25D = þ15.7° (c 1.0, CHCl3); HRMS (EI, m/z) Mþ calcd for
C22H28O3þ 340.2039, found 340.2032.
1
isomer: H NMR (CDCl3, 400 MHz) δ 5.74ꢀ5.65 (m, 2H), 4.02ꢀ
3.95 (m, 2H), 1.66ꢀ1.57 (m, 2H), 1.52ꢀ1.03 (m, 18H), 0.92ꢀ0.84
(m, 12H); 13C NMR (CDCl3, 100 MHz) δ 133.5, 133.0, 132.8, 132.3,
76.6, 76.4, 76.3, 38.9, 38.8, 32.5, 32.4, 32.1, 26.9, 26.8, 26.7, 22.6, 14.9,
14.6, 14.1; IR (CHCl3, cmꢀ1) 3691, 3610, 2960, 2930, 2873, 2859, 2248,
1937, 1691, 1669, 1603, 1575, 1539, 1460, 1379,þ1264, 1230, 1217,
1136; HRMS (EI, m/z) Mþ calcd for C18H36O2 284.2715, found
284.2720.
(E)-6,9-Dimethyl-8-oxotetradec-6-en-4-yl Acetate (10b).
The second-generation Grubbs catalyst (15 mg, 3 mol %) was added
to a stirred solution of ketone 8b (100 mg, 0.59 mmol) and protected
allylic alcohol (()-6a (400 mg, 2.34 mmol, 4.00 equiv) in CH2Cl2
(4 mL). The reaction mixture was heated at reflux overnight. The
mixture was then cooled to ambient temperature, concentrated in vacuo,
and directly purified by silica gel chromatography (petroleum ether/
ether 98/2 to 90/10) to afford the desired alkene 10b (48.7 mg, 28%) as
a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 6.08 (s, 1H), 5.10 (tt, J =
7.8, 5.2 Hz, 1H), 2.47 (sextet, J = 6.8 Hz, 1H), 2.38 (dd, J = 13.7, 7.8 Hz,
1H), 2.30 (dd, J = 13.7, 5.3 Hz, 1H), 2.14 (s, 3H), 2.01 (s, 3H),
2.74ꢀ1.26 (m, 12H), 1.05 (d, J = 6.8 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H),
0.87 (t, J = 6.9 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 204.7, 170.4,
153.9, 122.8, 71.5, 47.2, 45.9, 36.3, 33.1, 31.9, 27.0, 22.5, 18.6, 21.1, 19.6,
16.3, 14.0, 13.8; IR (CHCl3, cmꢀ1) 2961, 2930, 2867, 2254, 1727, 1681,
1615, 1460, 1377, 1249; HRMS (EI, m/z) Mþ calcd for C18H32O3
þ
(R)-6-(Benzyloxy)-3-((tert-butyldimethylsilyl)oxy)hexanal
(14a). Ozone was bubbled through a solution of the alkene 13a (3.9 g,
12 mmol) in CH2Cl2 (100 mL) and methanol (25 mL) in the presence
of some drops of pyridine, at ꢀ78 °C for 30 min. After flushing with
oxygen, dimethyl sulfide (5 mL) was added at ꢀ78 °C and the reaction
mixture was stirred overnight at 20 °C. The reaction mixture was
concentrated in vacuo. The residue was purified by silica gel column
chromatography (90/10 petroleum ether/ether) to afford the aldehyde
14a (3.5 g, 90%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 9.81
(t, J = 2.4 Hz, 1H), 7.37ꢀ7.27 (m, 5H), 4.50 (s, 2H), 4.22 (quint, J = 5.6
Hz, 1H), 3.47 (t, J = 5.9 Hz, 2H), 2.52ꢀ2.54 (m, 2H), 1.62ꢀ1.65 (m,
4H), 0.87 (s, 9H), 0.07, 0.05 (2s, 6H); 13C NMR (CDCl3, 100 MHz) δ
202.1, 138.5, 128.3, 127.6, 127.5, 72.9, 70.1, 67.9, 50.8, 34.4, 25.7, 25.6,
18.0, ꢀ4.5, ꢀ4.7; IR (CHCl3, cmꢀ1) 3031, 3022, 3010, 3006, 2956,
2931, 2886, 2858, 1714, 1472, 1463, 1453, 1389, 1362, 1315, 1278, 1257,
296.2352, found 296.2359.
(R)-7-(Benzyloxy)hept-1-en-4-ol (12). To a stirred suspension
of copper(I) iodide (2.38 g, 12.5 mmol, 0.5 equiv) in THF (100 mL)
was added vinylmagnesium bromide (1 M THF solution, 125 mL,
125 mmol, 5.0 equiv) dropwise at ꢀ30 °C. After 30 min, epoxide 1123
(4.8 g, 25 mmol) in THF (25 mL) was slowly added to the mixture. After
it was stirred at ꢀ30 °C for 2 h, the reaction mixture was quenched with
saturated aqueous NH4Cl, filtered, and extracted with ether. The
combined organic extracts were washed with brine, dried over anhy-
drous MgSO4, filtered, and concentrated in vacuo. The residue was
purified by silica gel column chromatography (petroleum ether/ether
80/20) to afford the homoallylic alcohol 12 (5.23 g, 95%) as a colorless
1
oil: H NMR (CDCl3, 400 MHz) δ 7.25ꢀ7.37 (m, 5H), 5.78ꢀ5.89
(m, 1H), 5.12 (br d, J = 16.1 Hz, 1H), 5.12 (br d, J = 11.2 Hz, 1H), 4.52
(s, 2H), 3.63 (m, 1H), 3.52 (t, J = 6.0 Hz, 2H), 2.34 (d, J = 3.9 Hz, 1H),
2.17ꢀ2.31 (m, 2H), 1.71ꢀ1.78 (m, 2H), 1.62ꢀ1.69 (m, 1H), 1.46ꢀ
1.55 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 138.2, 128.4, 127.7,
1230, 1227, 1215, 1211, 1098, 1043; [R]25 = ꢀ2.7° (c 1.5, CHCl3);
D
HRMS (EI, m/z) (M ꢀ tBu)þ calcd for (C15H23O3Si)þ 279.1417,
found 279.1430.
127.6, 138.2, 117.8, 73.0, 70.6, 70.4, 42.0, 34.0, 26.2; IR (CHCl3, cmꢀ1
)
(R)-6-(Benzyloxy)-3-(4-(methoxybenzyl)oxy)hexanal (14b).
Ozone was bubbled through a solution of the alkene 13b (2.52 g, 7.40
mmol) inCH2Cl2 (80mL) andmethanol(20mL) inthepresenceofsome
drops of pyridine, at ꢀ78 °C for 30 min. After flushing with oxygen,
dimethylsulfide (3 mL) wasadded atꢀ78 °C and the reaction mixture was
stirred overnight at 20 °C. The reaction mixture wasconcentrated in vacuo.
The residue was purified by silica gel column chromatography (70/30
petroleum ether/ether) to afford the aldehyde 14b (2.13 g, 84%) as a
3593, 3413, 3080, 3021, 3014, 3009, 2931, 2864, 1640, 1496, 1454, 1364,
1240, 1095, 1028; [R]25D = þ6.8° (c 1.3, CHCl3); HRMS (EI, m/z) Mþ
calcd for C14H20O2þ 220.1463, found 220.1460.
(R)-7-(Benzyloxy)-4-((tert-butyldimethylsilyl)oxy)hex-1-ene
(13a). To a stirred suspension of the alcohol 12 (3.6 g, 16 mmol) in
CH2Cl2 (160 mL) was added imidazole (3.3 g, 49 mmol, 3.0 equiv)
and TBSCl (4.9 g, 33 mmol, 2.0 equiv) at 0 °C. After it was stirred at 20 °C
overnight, the reaction mixture was quenched with saturated aqueous
NH4Cl and extracted with ether. The combined organic extracts were
washed with brine, dried over anhydrous MgSO4, filtered, and
1
colorless oil: H NMR (CDCl3, 400 MHz) δ 9.77 (t, J = 2.1 Hz, 1H),
7.26ꢀ7.32 (m, 5H), 6.85ꢀ6.87 (m, 2H), 6.85ꢀ6.87 (m, 2H), 4.49
(s, 2H), 4.48 (d, J = 11.1 Hz, 1H), 4.41 (d, J = 11.1 Hz, 1H),
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3.93ꢀ3.99 (m, 1H), 3.80 (s, 3H), 3.47 (t, J = 6.1 Hz, 2H), 2.67 (ddd,
J = 16.3, 7.2, 2.6 Hz, 1H), 2.54 (ddd, J = 16.3, 4.8, 1.9 Hz, 1H), 1.66ꢀ1.74
(m, 4H); 13C NMR (CDCl3, 100 MHz) δ 201.6, 159.3, 138.5, 130.2,
129.4, 128.4, 127.6, 127.6, 113.8, 73.6, 72.9, 70.9, 70.0, 55.3, 48.3, 31.0,
25.4; IR (CHCl3, cmꢀ1) 3031, 2936, 2862, 1720, 1606, 1514, 1250, 1173,
3608, 3471, 3067, 3036, 2937, 2868, 2840, 1639, 1613, 1606, 1514, 1464,
1455, 1363, 1303, 1234, 1075, 1035; HRMS (EI, m/z) Mþ calcd for
C25H34O4þ 398.2457, found 398.2456.
(3R,4S,6R)-9-(Benzyloxy)-4,6-bis((tert-butyldimethylsilyl)-
oxy)-3-methylnon-1-ene (16a). To a solution of the alcohol 15a
(982 mg, 2.5 mmol) in CH2Cl2 (25 mL) at ꢀ78 °C was added dropwise
Et3N (1.05 mL, 7.5 mmol, 3.0 equiv) and TBSOTf (1.15 mL, 5 mmol,
2.0 equiv). The reaction mixture was stirred for 1 h at ꢀ78 °C and was
quenched by saturated aqueous NH4Cl. The aqueous phase was
extracted with ether, and the combined organic extracts were washed
with brine, dried over anhydrous MgSO4, filtered, and concentrated in
vacuo. The residue was purified by silica gel column chromatography
(98/2 petroleum ether/ether) to afford the protected alcohol 16a
(1.23 g, 97%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ
7.25ꢀ7.35 (m, 5H), 5.79 (ddd, J = 17.3, 10.7, 7.4 Hz, 1H), 5.01 (br d,
J = 17.3 Hz, 1H), 5.01 (br d, J = 10.7 Hz, 1H), 4.51 (s, 2H), 3.71ꢀ3.76
(m, 2H), 3.46 (t, J = 6.6 Hz, 2H), 3.71ꢀ3.78 (m, 1H), 1.41ꢀ1.70 (m,
6H), 0.98 (d, J = 6.9 Hz, 3H), 0.89, 0.87 (2s, 18H), 0.08, 0.07, 0.04, 0.04
(4s, 12H); 13C NMR (CDCl3, 100 MHz) δ 140.4, 138.6, 128.3, 127.6,
127.5, 114.7, 73.3, 72.8, 70.5, 69.9, 43.4, 41.5, 34.2, 25.9, 25.9, 25.3, 18.1,
18.1, 15.0, ꢀ3.9, ꢀ4.1, ꢀ4.2, ꢀ4.3; IR (CHCl3, cmꢀ1) 3070, 3034,
3028, 3023, 3017, 3005, 2957, 2930, 2886, 2857, 1638, 1586, 1495, 1472,
1463, 1408, 1361, 1257, 1230, 1227, 1219, 1210, 1203, 1188, 1074,
1005; [R]25D = ꢀ6.0° (c 0.9, CHCl3); HRMS (EI, m/z) (M ꢀ tBu)þ
calcd for (C25H45O3Si2)þ 449.2907, found 449.2912.
1096, 1034; [R]25 = ꢀ6.0° (c 1.0, CHCl3); HRMS (EI, m/z) (M ꢀ
D
H2O)þ calcd for (C21H24O3)þ 324.1726, found 324.1719.
(3R,4S,6R)-9-(Benzyloxy)-6-((tert-butyldimethylsilyl)oxy)-
3-methylnon-1-en-4-ol (15a). Crotylmagnesium chloride in THF
(773 μL of a 0.5 M solution, 0.39 mmol, 1.3 equiv) was added dropwise
over 10 min at 0 °C to a solution of cyclopentadienyl[(4S,trans)-2,2-
dimethyl-R,R,R0,R0-tetraphenyl-1,3-dioxolane-4,5-dimethanolato-O,O0]-
titanium chloride (290 mg, 0.48 mmol, 1.6 equiv) in ether (6 mL). After
it was stirred for 3 h at 0 °C, the slightly orange suspension was cooled
to ꢀ78 °C, and aldehyde 14a (100 mg, 0.30 mmol, dissolved in 1 mL of
ether) was added over 2 min. Stirring at ꢀ78 °C was continued for
20 min, and the reaction mixture was then treated with 5 mL of water,
stirred for 12 h at 20 °C, filtered through Celite, and extracted with ether.
The combined organic phases were washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo. The solid residue was
stirred with 15 mL of pentane. Subsequent filtration furnished white
crystalline
(4S,trans)-2,2-dimethyl-R,R,R0,R0-tetraphenyl-1,3-dioxo-
lane-4,5-dimethanol (TADDOL). The residue was purified by silica
gel column chromatography (90/10 petroleum ether/ether) to afford
the alcohol 15a (346 mg, 88%) as a slightly yellow oil. Analysis of the 1H
1
(2R,3S,5R)-8-(Benzyloxy)-3,5-bis((tert-butyldimethylsilyl)-
oxy)-2-methyloctanal (17a). Ozone was bubbled through a solu-
tion of the alkene 16a (1.1 g, 2.2 mmol) in CH2Cl2 (20 mL) and
methanol (5 mL) in the presence of some drops of pyridine, at ꢀ78 °C
for 20 min. After flushing with oxygen, dimethyl sulfide (1 mL) was
added at ꢀ78 °C and the reaction mixture was stirred overnight at 20 °C.
The reaction mixture was concentrated in vacuo. The residue was
purified by silica gel column chromatography (90/10 petroleum
ether/ether) to afford the aldehyde 17a (917 mg, 83%) as a colorless
oil: 1H NMR (CDCl3, 400 MHz) δ 9.74 (d, J = 1.9 Hz, 1H), 7.27ꢀ7.34
(m, 5H), 4.50 (s, 2H), 4.06ꢀ4.10 (m, 1H), 3.82 (qd, J = 7.2, 5.4 Hz, 1H),
3.46 (t, J = 6.6 Hz, 2H), 2.50 (qdd, J = 6.9, 3.2, 1.9 Hz, 1H), 1.51ꢀ1.67
(m, 6H), 1.10 (d, J = 6.9 Hz, 3H), 0.87, 0.88 (2s, 18H), 0.08, 0.07, 0.07,
0.06 (4s, 12H); 13C NMR (CDCl3, 100 MHz) δ 204.4, 138.6, 128.3,
127.6, 127.5, 72.9, 71.3, 70.3, 69.7, 52.1, 43.1, 34.3, 25.9, 25.8, 25.2, 18.0,
18.0, 10.2, ꢀ3.9, ꢀ4.1, ꢀ4.2, ꢀ4.4; IR (CHCl3, cmꢀ1) 3673, 3450,
3029, 3023, 3014, 2955, 2931, 2885, 2858, 2338, 1715, 1603, 1471, 1463,
1362, 1257, 1239, 1235, 1231, 1223, 1219, 1215, 1211, 1207, 1203, 1177,
1087, 1043, 1006; [R]25D = þ16.0° (c 1.2, CHCl3); HRMS (EI, m/z)
(M ꢀ tBu)þ calcd for (C24H43O4Si2)þ 451.2700, found 451.2680.
(2R,3S,5R)-8-(Benzyloxy)-3,5-bis((4-methoxybenzyl)oxy)-
2-methyloctanal (17b). To a solution of the alcohol 15b (1.3 g, 3.3
mmol) and freshly prepared p-methoxybenzyltrichloroacetimidate
(1.8 g, 6.6 mmol, 2.0 equiv) in ether (16 mL) at 20 °C was added
camphorsulfonic acid (77 mg, 0.30 mmol, 0.1 equiv) in ether (1 mL).
The clear solution turned cloudy within 5 min after the addition of acid.
The reaction mixture was stirred for 1 h at 20 °C and was then quenched
with saturated aqueous NaHCO3 and diluted with ether. The combined
organic phases were washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by silica gel column
chromatography (70/30 petroleum ether/ether) to afford the protected
alcohol 16b (1.39 g, 81%) as a colorless oil. Ozone was bubbled through
a solution of 16b (1.39 g, 2.67 mmol) in CH2Cl2 (20 mL) and methanol
(5 mL) in the presence of some drops of pyridine, at ꢀ78 °C for 45 min.
After flushing with oxygen, dimethyl sulfide (2.0 mL) was added at
ꢀ78 °C and the reaction mixture was stirred overnight at 20 °C. The
reaction mixture was concentrated in vacuo. The residue was purified by
silica gel column chromatography (60/40 petroleum ether/ether) to
NMR of the product showed a >98/2 ratio of diastereoisomers: H
NMR (CDCl3, 400 MHz) δ 7.33ꢀ7.26 (m, 5H), 5.79 (ddd, J = 17.0,
11.1, 7.8 Hz, 1H), 5.11 (br d, J = 11.1 Hz, 1H), 5.11 (br d, J = 17.0 Hz,
1H), 4.50 (s, 2H), 4.04ꢀ4.10 (m, 1H), 3.85 (ddt, J = 9.9, 5.0, 2.2 Hz,
1H), 3.52 (t, J = 6.1 Hz, 2H), 3.18 (d, J = 2.2 Hz, 1H), 2.19ꢀ2.27 (m,
1H), 1.59ꢀ1.72 (m, 5H), 1.26ꢀ1.32 (m, 1H), 1.08 (d, J = 6.9 Hz, 3H),
0.89 (s, 9H), 0.09, 0.07 (2s, 6H); 13C NMR (CDCl3, 100 MHz) δ 140.7,
138.5, 128.3, 127.6, 127.5, 115.2, 72.9, 71.3, 71.2, 70.3, 44.1, 38.6, 33.0,
26.0, 25.8, 18.0, 15.7, ꢀ4.6, ꢀ4.7; IR (CHCl3, cmꢀ1) 3672, 3475, 3084,
3068, 3013, 3009, 2954, 2931, 2884, 2859, 1639, 1496, 1471, 1463,
1454, 1434, 1420, 1389, 1362, 1310, 1256, 1095, 1028; [R]25D = ꢀ1.0°
(c 1.0, CHCl3); HRMS (EI, m/z) (M ꢀ tBu)þ calcd for (C19H31O3Si)þ
335.2043, found 335.2044.
(3R,4S,6R)-9-(Benzyloxy)-6-(4-(methoxybenzyl)oxy)-3-
methylnon-1-en-4-ol (15b). Crotylmagnesium chloride in THF
(12.8 mL of a 0.5 M solution, 6.40 mmol, 1.3 equiv) was added dropwise
over 10 min at 0 °C to a solution of cyclopentadienyl[(4S,trans)-2,2-
dimethyl-R,R,R0,R0-tetraphenyl-1,3-dioxolane-4,5-dimethanolato-O,O0]-
titanium chloride (4.51 g, 7.36 mmol, 1.6 equiv) in ether (90 mL). After it
was stirred for 20 min at 0 °C, the slightly orange suspension was cooled
to ꢀ78 °C, andthe aldehyde 14b(1.57 g, 4.6 mmol, dissolvedin10 mLof
ether) was added over 2 min. Stirring at ꢀ78 °C was continued for 4 h.
The reaction mixture was then treated with water, stirred for 12 h at
20 °C, filtered through Celite, and extracted twice with ether. The
combined organic phases were washed with brine, dried over MgSO4,
filtered, and concentrated in vacuo. The solid residue was stirred with
15 mL of pentane. Subsequent filtration furnished white crystalline (4S,
trans)-2,2-dimethyl-R,R,R0,R0-tetraphenyl-1,3-dioxolane-4,5-dimethanol
(TADDOL). The residue was purified by silica gel column chromatog-
raphy (70/30 petroleum ether/ether) to afford the alcohol 15b (1.47 g,
1
80%) as a slightly yellow oil. Analysis of the H NMR of the product
showed a 90/10 ratio of diastereoisomers: 1H NMR (CDCl3, 400 MHz)
δ 7.25ꢀ7.36 (m, 7H), 6.86ꢀ6.88 (m, 2H), 5.81 (ddd, J = 17.0, 10.8, 8.0
Hz, 1H), 5.08 (br d, J = 10.8 Hz, 1H), 5.08 (br d, J = 17.0 Hz, 1H), 4.51 (s,
2H), 4.48ꢀ4.51 (m, 2H), 3.80 (s, 3H), 3.70ꢀ3.78 (m, 2H), 3.48 (t, J =
6.0 Hz, 2H), 2.59 (br s, 1H), 2.15ꢀ2.24 (m, 1H), 1.56ꢀ1.77 (m, 6H),
1.03 (d, J = 6.9 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 159.2, 140.6,
138.6, 130.6, 129.4, 128.3, 127.6, 127.5, 113.8, 115.4, 76.4, 72.9, 71.0,
70.3, 71.4, 55.2, 44.2, 37.3, 30.3, 25.8, 15.9; IR (CHCl3, cmꢀ1) 3670,
1
afford the aldehyde 17b (1.04 g, 75%) as a colorless oil: H NMR
4925
dx.doi.org/10.1021/jo200466t |J. Org. Chem. 2011, 76, 4921–4929

The Journal of Organic Chemistry
ARTICLE
(CDCl3, 400 MHz) δ 9.70 (d, J = 1.6 Hz, 1H), 7.26ꢀ7.35 (m, 5H),
7.16ꢀ7.23 (m, 4H), 6.83ꢀ6.87 (m, 4H), 4.50 (s, 2H), 4.50 (d, J = 11.1
Hz, 1H), 4.47 (d, J = 11.0 Hz, 1H), 4.34 (d, J = 11.0 Hz, 1H), 4.30 (d,
J = 11.1 Hz, 1H), 4.00 (ddd, J = 9.4, 4.7, 2.8 Hz, 1H), 3.78 (s, 6H),
3.66ꢀ3.69 (m, 1H), 3.47 (t, J = 6.9 Hz, 2H), 2.69ꢀ2.76 (m, 1H),
1.50ꢀ1.72 (m, 6H), 1.09 (d, J = 6.7 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 204.0, 159.2, 159.1, 138.6, 130.8, 130.3, 129.3, 129.3, 128.3,
127.6, 127.5, 113.8, 113.8, 75.7, 74.7, 72.9, 71.6, 70.3, 70.1, 55.3, 49.9,
37.5, 30.3, 25.0, 9.1; IR (CHCl3, cmꢀ1) 2955, 2938, 2865, 2840, 1727,
1611, 1513, 1464, 1456, 1361, 1302, 1250, 1174, 1161, 1095, 1035;
HRMS (EI, m/z) Mþ calcd for C32H40O6þ 520.2825, found 520.2810.
(5S,6S,8R)-11-(Benzyloxy)-6,8-bis((tert-butyldimethylsilyl)-
oxy)-5-methylundec-2-en-4-one (19a). A solution of (Z)-1-bro-
mo-1-propene (600 μL, 7.0 mmol, 7 equiv) in THF (7 mL) was added
dropwise to a solution of magnesium (190 mg, 7.7 mmol, 7.7 equiv) and a
few crystals ofI2 in THF (7 mL). The reaction mixture was refluxed for 1 h
and then diluted with ether (7 mL) and cooled to ꢀ78 °C. The aldehyde
17a (509 mg, 1.0 mmol) in THF (1 mL) was added dropwise, and the
mixture was stirred at ꢀ78 °C for 1 h. Saturated aqueous NH4Cl was
added, and the aqueous phase was extracted with ether. The combined
organic extracts were washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The residue was directly used in the
next step without further purification. To a stirred solution of 2-iodoxy-
benzoic acid (840 mg, 3.0 mmol, 3.0 equiv) in DMSO (18 mL) was added
a solution of the alcohol 18a in THF (9 mL) at 20 °C. After the solution
hadbeenstirredovernight, 10mLofwaterand10mLofetherwere added.
The mixture was stirred for 2 h to form a white precipitate, which was then
filtered off. The aqueous phase was extracted with ether. The combined
organic extracts were washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (petroleum ether/ether 95/5) to afford the
two separable diastereomers of the alkene 19a (297 mg, 54% over 2 steps,
Z/E = 4/1) as two yellow oils. Z isomer: 1H NMR (CDCl3, 400 MHz) δ
7.26ꢀ7.34 (m, 5H), 6.15ꢀ6.27(m, 2H), 4.49 (s, 2H), 4.18 (dt, J = 7.2, 3.3
Hz, 1H), 3.79 (m, 1H), 3.44 (t, J = 6.6 Hz, 2H), 2.75 (qd, J = 8.9, 5.4 Hz,
1H), 2.09 (d, J = 5.9 Hz, 3H), 1.58ꢀ1.63 (m, 2H), 1.47ꢀ1.54 (m, 3H),
1.28ꢀ1.34 (m, 1H), 1.05 (d, J = 6.8 Hz, 3H), 0.89, 0.85 (2s, 18H), 0.11,
0.10, 0.05, 0.03 (4s, 12H); 13C NMR (CDCl3, 100 MHz) δ 202.3, 143.5,
138.6, 128.3, 127.6, 127.4, 72.8, 70.5, 70.1, 69.6, 54.1, 41.0, 34.6, 25.9, 25.8,
combined organic extracts were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated invacuo. Theresidue was directly used
in the next step without further purification. To a stirred solution of
2-iodoxybenzoic acid (1.68 g, 6.0 mmol, 3.0 equiv) in DMSO (36 mL)
was added a solution of the alcohol 18b in THF (18 mL) at 20 °C. After
the solution had been stirred overnight, 20 mL of water and 20 mL of
ether were added. The mixture was stirred for 2 h to form a white
precipitate, which was then filtered off. The aqueous phase was extracted
with ether. The combined organic extracts were washed with brine, dried
over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue
was purified byflash chromatography on silica gel (petroleum ether/ether
90/10) to afford the two diastereomers of alkene 19b (639 mg, 57% for 2
steps, Z/E = 4/1) as yellow oils. Z isomer: 1H NMR (CDCl3, 400 MHz)
δ 7.27ꢀ7.35 (m, 5H), 7.17ꢀ7.22 (m, 4H), 6.82ꢀ6.86 (m, 4H),
6.14ꢀ6.30 (m, 2H), 4.50 (s, 2H), 4.44ꢀ4.47 (m, 2H), 4.22ꢀ4.27 (m,
2H), 3.99 (ddd, J = 8.9, 5.8, 3.0 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H),
3.60ꢀ3.66 (m, 1H), 3.47 (br t, J = 5.7 Hz, 2H), 2.96 (quint, J = 6.6 Hz,
1H), 2.09 (d, J = 6.2 Hz, 3H), 1.52ꢀ1.68 (m, 6H), 1.06 (d, J = 6.6 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 203.2, 143.4, 159.1, 159.0, 138.6,
131.0, 130.5, 129.3, 129.1, 128.3, 127.5, 127.5, 127.4, 113.7, 113.6, 76.3,
74.8, 72.8, 71.6, 70.4, 69.9, 55.2, 55.2, 50.3, 36.8, 30.4, 25.2, 16.0, 10.4; IR
(CHCl3, cmꢀ1) 3032, 2957, 2930, 2857, 1709, 1608, 1514, 1464, 1455,
1360, 1315, 1302, 1250, 1233, 1172, 1097, 1034; HRMS (EI, m/z) (M ꢀ
OPMB)þ calcd for (C27H35O5)þ 439.2484, found 439.2493. E isomer:
1H NMR (CDCl3, 400 MHz) δ 7.26ꢀ7.34 (m, 5H), 7.15ꢀ7.22 (m, 4H),
6.81ꢀ6.86 (m, 4H), 6.17ꢀ6.22 (m, 2H), 4.49 (s, 2H), 4.46 (d, J = 11.2
Hz, 1H), 4.43 (d, J = 10.9 Hz, 1H), 4.25 (d, J = 10.9 Hz, 1H), 4.24 (d, J =
11.2 Hz, 1H), 3.94ꢀ3.99 (m, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.62ꢀ3.66
(m, 1H), 3.47 (br t, J = 5.9 Hz, 2H), 3.12 (quint, J = 6.8Hz, 1H), 1.86 (dd,
J = 6.9, 1.6 Hz, 3H), 1.54ꢀ1.68 (m, 6H), 1.06 (d, J = 6.9 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 201.7, 142.6, 159.1, 159.0, 131.2, 131.0,
130.5, 129.4, 129.1, 128.3, 127.5, 127.4, 113.7, 113.6, 76.6, 74.7, 72.8, 71.8,
70.3, 69.7, 55.2, 55.2, 47.5, 36.8, 30.4, 25.2, 18.2, 11.0; IR (CHCl3, cmꢀ1
)
3032, 2957, 2930, 2857, 1709, 1608, 1514, 1464, 1455, 1360, 1315, 1302,
1250, 1233, 1172, 1097, 1034; HRMS (EI, m/z) (M ꢀ OPMB)þ calcd
for (C27H35O5)þ 439.2484, found 439.2498.
(4R)-2-Methylhept-1-en-4-yl Acetate (6a). To a stirred sus-
pension of copper(I) iodide (0.68 g, 3.6 mmol, 0.5 equiv) in THF
(30 mL) was added isopropenylmagnesium bromide (0.5 M THF
solution, 43.2 mL, 21.6 mmol, 3.0 equiv) dropwise at ꢀ30 °C. After
30 min, (R)-1,2-epoxypentane (20;24 0.62 g, 7.2 mmol) in THF (4 mL)
was slowly added to the mixture. After it was stirred at ꢀ30 °C for 2 h,
the reaction mixture was quenched with saturated aqueous NH4Cl and
filtered and the aqueous phase was extracted with ether. The combined
organic extracts were washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The residue was directly used in the
next step without further purification. To a stirred solution of the
previous allylic alcohol 21 with DMAP (1.1 g, 9.0 mmol) in CH2Cl2
(12 mL) at 0 °C was slowly added acetic anhydride (2.9 mL, 30 mmol).
The reaction mixture was warmed to 20 °C and stirred overnight. The
mixture was diluted by addition of ether (60 mL) and quenched with
saturated aqueous NaHCO3. After separation, the aqueous layer was
extracted with ether. The combined organic extracts were washed with
brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo.
The residue was purified by silica gel chromatography (petroleum ether
and then petroleum ether/ether 98/2) to afford the protected alcohol 6a
(1.20 g, 7.1 mmol, 98%) as a colorless oil: 1H NMR (CDCl3, 400 MHz)
δ 5.04 (dtd, J = 7.3, 6.4, 5.7 Hz, 1H), 4.76 (s, 1H), 4.70 (s, 1H), 2.26 (dd,
J = 13.9, 7.8 Hz, 1H), 2.17 (dd, J = 13.9, 5.3 Hz, 1H), 2.01 (s, 3H), 1.73
(s, 3H), 1.48ꢀ1.53 (m, 2H), 1.25ꢀ1.42 (m, 2H), 0.90 (t, J = 7.3 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 170.7, 141.9, 113.1, 71.9, 42.9,
36.2, 22.4, 21.1, 18.6, 13.9; IR (CHCl3, cmꢀ1) 2963, 2935, 2875, 1728,
1651, 1465, 1376, 1255, 1023; [R]25D = þ6.6° (c 0.5, CHCl3); HRMS
(EI, m/z) Mþ calcd for C10H18O2þ 170.1307, found 170.1303.
25.2, 18.0, 18.0, 16.0, 9.4, ꢀ3.8, ꢀ4.2, ꢀ4.2, ꢀ4.3; IR (CHCl3, cmꢀ1
)
3034, 3028, 3022, 3010, 2957, 2929, 2857, 1688, 1627, 1471, 1463, 1378,
1362, 1258, 1221, 1209, 1203, 1095, 1006; [R]25 = þ3.9° (c 1.5,
D
CHCl3); HRMS (EI, m/z) Mþ calcd for C31H56O4Si2þ 548.3717, found
548.3722. E isomer: 1H NMR (CDCl3, 400 MHz) δ 7.26ꢀ7.34 (m, 5H),
6.87 (dq, J = 15.4, 6.9 Hz, 1H), 6.25 (dq, J = 15.3, 1.5 Hz, 1H), 4.49 (s,
2H), 4.17 (ddd, J = 8.3, 4.3, 2.9 Hz, 1H), 3.75ꢀ3.81 (m, 1H), 3.44 (td, J =
6.5, 1.3 Hz, 2H), 2.90 (qd, J = 6.8, 4.4 Hz, 1H), 1.87 (dd, J = 6.9, 1.5 Hz,
3H), 1.46ꢀ1.62 (m, 5H), 1.30ꢀ1.38 (m, 1H), 1.05 (d, J = 6.8 Hz, 3H),
0.88, 0.84 (2s, 18H), 0.11, 0.10, 0.04, 0.03 (4s, 12H); 13C NMR (CDCl3,
100 MHz) δ 200.7, 142.1, 130.8, 138.6, 128.3, 127.6, 127.4, 72.8, 70.5,
70.2, 69.6, 51.6, 41.0, 34.6, 25.8, 25.8, 25.2, 18.2, 18.0, 18.0, 9.7, ꢀ3.6,
ꢀ4.1, ꢀ4.2, ꢀ4.3; IR(CHCl3, cmꢀ1) 3034, 3028, 3022, 3010, 2957, 2929,
2857, 1688, 1627, 1471, 1463, 1378, 1362, 1258, 1221þ, 1209, 1203, 1095,
1006; HRMS (EI, m/z) Mþ calcd for C31H56O4Si2 548.3717, found
548.3703.
(5S,6S,8R)-11-(Benzyloxy)-6,8-bis((4-methoxybenzyl)oxy)-
5-methylundec-2-en-4-one (19b). A solution of (Z)-1-bromo-1-
propene (850 μL, 10 mmol, 5.0 equiv) in THF (10 mL) was added
dropwise to a solution of magnesium (267 mg, 11 mmol, 5.5 equiv) and a
few crystalsof I2 inTHF (10 mL). Thereaction mixture was refluxed for 1
h and then diluted with ether (5 mL) and cooled to ꢀ78 °C. The
aldehyde 17b (1.04 g, 2.0 mmol) in THF (2 mL) was added dropwise,
and the mixture was stirred at ꢀ78 °C for 1 h. Saturated aqueous NH4Cl
was added and the aqueous phase was extracted with ether. The
4926
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(4R)-2-Methyl-4-((triethylsilyl)oxy)hept-1-ene (6b). To a
stirred suspension of copper(I) iodide (0.68 g, 3.6 mmol, 0.5 equiv)
in THF (30 mL) was added isopropenylmagnesium bromide (0.5 M
THF solution, 43.2 mL, 21.6 mmol, 3 equiv) dropwise at ꢀ30 °C. After
30 min, (R)-1,2-epoxypentane (20;24 0.62 g, 7.2 mmol) in THF (4 mL)
was slowly added to the mixture. After it was stirred at ꢀ30 °C for 2 h,
the reaction mixture was quenched with saturated aqueous NH4Cl and
filtered and the aqueous phase was extracted with ether. The combined
organic extracts were washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The residue was directly used in the
next step without further purification. To a solution of the alcohol 21
in CH2Cl2 (70 mL) at ꢀ78 °C was added dropwise Et3N (3.1 mL,
22 mmol, 3.0 equiv) and TESOTf (3.2 mL, 14 mmol, 2.0 equiv). The
reaction mixture was stirred for 1 h at ꢀ78 °C and was quenched with
saturated aqueous NH4Cl. The mixture was warmed to 20 °C. The
aqueous phase was extracted with ether, and the combined organic
extracts were washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated in vacuo. The residue was purified by silica gel column
chromatography with a gradient of ether in petroleum ether (1/99,
5/95) to afford the product 6b (1.70 g, 99%) as a colorless oil: 1H NMR
(CDCl3, 400 MHz) δ 4.76 (s, 1H), 4.70 (s, 1H), 3.78ꢀ3.84 (m, 1H),
2.14 (dd, J = 13.6, 5.8 Hz, 1H), 2.14 (dd, J = 13.4, 7.0 Hz, 1H), 1.73
(s, 3H), 1.28ꢀ1.45 (m, 4H), 0.96 (t, J = 7.9 Hz, 9H), 0.90 (t, J = 6.8 Hz,
3H), 0.60 (q, J = 7.9 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ 143.0,
112.6, 70.7, 46.3, 39.2, 23.0, 18.6, 14.2, 6.9, 5.2; IR (CHCl3, cmꢀ1) 3034,
3029, 3023, 3013, 2958, 2913, 2876, 1646, 1458, 1416, 1363, 1075,
ether in petroleum ether (2/98, 5/95, 10/90) to afford 32 mg of the E
isomer of 22a (26%) and 8 mg of Z isomer (7%) as two colorless oils. E
isomer: 1H NMR (CDCl3, 400 MHz) δ 7.25ꢀ7.36 (m, 5H), 6.19 (s, 1H),
5.06ꢀ5.09 (m, 1H), 4.50 (s, 2H), 4.10 (dt, J = 8.0, 4.0Hz, 1H), 3.79ꢀ3.82
(m, 1H), 3.45 (t, J = 6.4 Hz, 2H), 2.68 (qd, J = 6.9, 4.6 Hz, 1H), 2.41 (dd,
J = 13.6, 7.0 Hz, 1H), 2.28 (dd, J = 13.6, 6.2 Hz, 1H), 2.14 (s, 3H), 2.03 (s,
3H), 1.24ꢀ1.65 (m, 10H), 1.05 (d, J = 6.9 Hz, 3H), 0.91 (t, J = 7.3 Hz,
3H), 0.88, 0.84 (2s, 18H), 0.11, 0.10, 0.04, 0.04 (4s, 12H); 13C NMR
(CDCl3, 100 MHz) δ 201.7, 170.5, 154.2, 138.6, 128.3, 127.6, 127.4,
125.4, 72.8, 71.7, 70.6, 70.4, 69.6, 54.1, 46.1, 41.5, 36.1, 34.4, 25.9,
25.2, 21.2, 19.8, 18.5, 18.1, 18.0, 13.8, 10.5, ꢀ3.9, ꢀ4.1, ꢀ4.2, ꢀ4.2; IR
(CHCl3, cmꢀ1) 2930, 2957, 2857, 1728, 1683, 1614, 1495, 1471, 1463,
1377, 1363, 1256, 1219, 1093, 1027, 1006; [R]25 = þ13.0° (c 0.5,
D
CHCl3); HRMS (EI, m/z) Mþ calcd for C38H68O6Si2þ 676.4555, found
676.4567. Z isomer: 1H NMR (CDCl3, 400 MHz) δ 7.25ꢀ7.36 (m, 5H),
6.22 (s, 1H), 5.08ꢀ5.12 (m, 1H), 4.50 (s, 2H), 4.16 (dt, J = 7.6, 3.4 Hz,
1H), 3.79ꢀ3.82 (m, 1H), 3.45 (t, J = 6.4 Hz, 2H), 3.04 (dd, J = 13.1, 8.4
Hz, 1H), 2.76 (dd, J = 13.1, 4.4 Hz, 1H), 2.70 (qd, J = 6.9, 4.3 Hz, 1H),
1.99 (s, 3H), 1.91 (s, 3H), 1.18ꢀ1.60 (m, 10H), 1.04 (d, J = 6.9 Hz, 3H),
0.85ꢀ0.91 (m, 21H), 0.11, 0.10, 0.06, 0.04 (4s, 12H); 13C NMR (CDCl3,
100 MHz) 201.0, 170.7, 154.8, 138.7, 128.4, 127.6, 127.5, 125.8, 73.1,
72.9, 70.5, 70.3, 69.7, 54.2, 41.1, 38.0, 36.6, 34.5, 26.0, 25.9, 25.3, 21.3, 18.7,
18.1, 18.0,14.1, 9.9, ꢀ3.6, ꢀ4.1, ꢀ4.2, ꢀ4.2.
(4R,9S,10S,12R,E)-15-(Benzyloxy)-10,12-bis((tert-butyldi-
methylsilyl)oxy)-4-((triethylsilyl)oxy)-6,9-dimethylpentadec-
6-en-8-one (22b). The HoveydaꢀGrubbs second-generation catalyst
(51 mg, 45 mol %) was added to a stirred solution of enone 19a (100 mg,
0.18 mmol) and alkene 6b (218 mg, 0.90 mmol, 5.0 equiv) in degassed
CH2Cl2 (1 mL) under argon. The reaction mixture was heated at reflux
for 3 days. The mixture was then cooled to 20 °C, concentrated in vacuo,
and directly purified by silica gel column chromatography with a gradient
of ether in petroleum ether (1/99, 3/97, 5/95) to afford E isomer 22b
(47%, 64 mg) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ
7.26ꢀ7.34 (m, 5H), 6.16 (s, 1H), 4.49 (s, 2H), 4.10ꢀ4.15 (m, 1H),
3.78ꢀ3.906 (m, 2H), 3.44 (t, J = 6.4 Hz, 2H), 2.66ꢀ2.74 (m, 1H), 2.34
(dd, J = 12.8, 5.3 Hz, 1H), 2.22 (dd, J = 12.8, 7.8 Hz, 1H), 2.12 (s, 3H),
1.26ꢀ1.63 (m, 10H), 1.04 (dd, J = 6.9, 1.6 Hz, 3H), 0.96 (t, J = 7.9 Hz,
9H), 0.89 (m, 21H), 0.64 (q, J = 7.9 Hz, 6H), 0.10, 0.07, 0.05 (3s, 12H);
13C NMR (CDCl3, 100 MHz) δ 201.6, 156.0, 138.7, 128.3, 127.6,
127.4, 125.2, 72.8, 70.6, 70.6, 70.5, 69.7, 54.2, 50.1, 41.2, 39.2, 34.6,
25.9, 25.9, 25.3, 20.2, 18.5, 18.0, 18.0, 14.1, 10.0, 6.9, 5.1, ꢀ4.3, ꢀ4.2; IR
(CHCl3, cmꢀ1) 3010, 2958, 2932, 2878, 2858, 1722, 1679, 1608, 1472,
1463, 1412, 1379, 1257, 1238, 1092, 1035; [R]25D =þ11.5° (c1.0, CHCl3);
HRMS (EI, m/z) Mþ calcd for C40H80O5Si3þ 750.5470, found 750.5473.
(4R,9S,10S,12R,E)-15-(Benzyloxy)-4-((tert-butyldimethyl-
silyl)oxy)-10,12-bis((4-methoxybenzyl)oxy)-6,9-dimethyl-
pentadec-6-en-8-one (22c). The HoveydaꢀGrubbs second-gen-
eration catalyst (34 mg, 30 mol %) was added to a stirred solution of the
enone 19b (101 mg, 0.18 mmol) and the alkene 6c (218 mg, 0.18 mmol,
5 equiv) in degassed CH2Cl2 (1 mL) under argon. The reaction mixture
was heated at reflux for 3 days. The mixture was then cooled to 20 °C,
concentrated in vacuo, and directly purified by silica gel column
chromatography with a gradient of ether in petroleum ether (2/98,
10/90, 80/:20) to afford E isomer 22c (61 mg, 45%) as a colorless oil
(slightly contaminated by the Z isomer): 1H NMR (CDCl3, 400 MHz)
δ 7.26ꢀ7.34 (m, 5H), 7.15ꢀ7.21 (m, 4H), 6.80ꢀ6.85 (m, 4H), 6.11 (s,
1H), 4.48 (s, 2H), 4.42ꢀ4.46 (m, 2H), 4.23ꢀ4.27 (m, 2H), 3.94ꢀ3.98
(m, 1H), 3.81ꢀ3.86 (m, 1H), 3.77, 3.76 (2s, 6H), 3.62ꢀ3.65 (m, 1H),
3.45 (br t, J = 5.9 Hz, 2H), 2.86ꢀ2.93 (m, 1H), 2.27 (dd, J = 12.9, 6.0 Hz,
1H), 2.19 (dd, J = 12.9, 6.7 Hz, 1H), 2.12 (d, J = 0.9 Hz, 3H), 1.54ꢀ1.66
(m, 6H), 1.39ꢀ1.54 (m, 4H), 1.05 (d, J = 7.0 Hz, 3H), 0.88ꢀ0.90 (m,
12H), 0.04, 0.02 (2s, 6H); 13C NMR (CDCl3, 100 MHz) δ 202.4, 156.6,
159.0, 159.0, 141.9, 138.7, 132.3, 129.3, 129.1, 128.3, 127.6, 127.5, 125.5,
113.8, 113.7, 74.9, 72.8, 71.7, 70.7, 70.5, 69.9, 55.2, 50.7, 49.6, 39.3, 30.6,
1005; [R]25 = þ5.4° (c 2.0, CHCl3); HRMS (EI, m/z) (M ꢀ Et)þ
D
calcd for (C12H25OSi)þ 213.1675, found 213.1682.
(4R)-4-((tert-Butyldimethylsilyl)oxy)-2-methylhept-1-ene
(6c). To a stirred suspension of copper(I) iodide (0.68 g, 3.6 mmol,
0.5 equiv) in THF (30 mL) was added isopropenylmagnesium bromide
(0.5 M THF solution, 43.2 mL, 21.6 mmol, 3.0 equiv) dropwise at
ꢀ30 °C. After 30 min, (R)-1,2-epoxypentane (20;24 0.62 g, 7.2 mmol) in
THF (4 mL) was slowly added to the mixture. After it was stirred at
ꢀ30 °C for 2 h, the reaction mixture was quenched with saturated
aqueous NH4Cl and filtered and the aqueous phase was extracted with
ether. The combined organic extracts were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was
directly used in the next step without further purification. To a solution
of the alcohol 21 in CH2Cl2 (70 mL) at ꢀ78 °C were added dropwise
Et3N (3.1 mL, 22 mmol, 3.0 equiv) and TBSOTf (3.3 mL, 14 mmol,
2.0 equiv). The reaction mixture was stirred for 1 h at ꢀ78 °C and was
quenched with saturated aqueous NH4Cl. The mixture was warmed to
20 °C. The aqueous phase was extracted with ether, and the combined
organic extracts were washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The residue was purified by silica
gel column chromatography with a gradient of ether in petroleum ether
(1/99, 5/95) to afford the product 6c (1.70 g, 98%) as a colorless oil: 1H
NMR (CDCl3, 400 MHz) δ 4.76 (s, 1H), 4.72 (s, 1H), 3.77ꢀ3.83 (m,
1H), 2.20 (dd, J = 13.5, 5.8 Hz, 1H), 2.13 (dd, J = 13.5, 6.8 Hz, 1H), 1.73
(s, 3H), 1.35ꢀ1.42 (m, 4H), 0.88ꢀ0.90 (m, 12H), 0.05 (s, 6H); 13C
NMR (CDCl3, 100 MHz) δ 143.0, 112.7, 70.8, 46.2, 39.2, 25.9, 23.0,
18.6, 18.1, 14.2, ꢀ4.4, ꢀ4.5; IR (CHCl3, cmꢀ1) 2959, 2931, 2858, 1472,
1463, 1376, 1362, 1255, 1125, 1107, 1088, 1039, 1006; [R]25D = þ13.2°
(c 2.0, CHCl3); HRMS (EI, m/z) Mþ calcd for C14H30OSiþ 242.2066,
found 242.2057.
(1R,6S,7S,9R)-12-(Benzyloxy)-7,9-bis((tert-butyldimethyl-
silyl)oxy)-3,6-dimethyl-5-oxo-1-propyldodec-3-enyl Acetate
(22a). The HoveydaꢀGrubbs second-generation catalyst (17 mg,
15 mol %) was added to a stirred solution of enone 19a (100 mg, 0.18
mmol) and acetate 6a (153 mg, 0.90 mmol, 5.0 equiv) in degassed
CH2Cl2 (1 mL) underargon. Thereactionmixture washeatedatrefluxfor
3 days. The mixture was then cooled to 20 °C, concentrated in vacuo, and
directly purified by silica gel column chromatography with a gradient of
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ARTICLE
25.9, 25.3, 22.3, 20.3, 18.4, 18.1, 14.2, 11.1, ꢀ4.4, ꢀ4.5; IR (CHCl3, cmꢀ1
)
in THF (300 μL) at 20 °C, followed by the addition of imidazole
(2.3 mg, 34 μmol, 2.5 equiv) and Ph3P (8 mg, 30 μmol, 2.2 equiv). The
reaction mixture was cooled to 0 °C, and I2 (7 mg, 27 μmol, 2.0 equiv)
was added. The reaction mixture was stirred for 45 min, concentrated,
and purified by flash chromatography (99/1 petroleum ether/ether) to
afford the primary iodide 25 (8 mg, 72%): 1H NMR (CDCl3, 400 MHz)
δ 4.98 (br d, J = 9.6 Hz, 1H), 4.62 (d, J = 6.4 Hz, 1H), 4.43 (d, J = 6.4 Hz,
1H), 4.11ꢀ4.17 (m, 2H), 3.81ꢀ3.90 (m, 2H), 3.35 (s, 3H), 3.16ꢀ3.21
(m, 2H), 2.27 (dd, J = 13.2, 4.4 Hz, 1H), 2.17 (dd, J = 13.3, 8.3 Hz, 1H),
1.69 (s, 3H), 1.28ꢀ1.93 (m, 11H), 0.97 (t, J = 7.9 Hz, 9H), 0.90, 0.88
(2s, 18H), 0.87 (t, J = 6.7 Hz, 3H), 0.77 (d, J = 7.1 Hz, 3H), 0.61 (q, J =
7.9 Hz, 6H), 0.09, 0.09, 0.08, 0.07 (4s, 12H); 13C NMR (CDCl3, 100
MHz) δ 137.7, 127.1, 93.4, 73.3, 70.7, 70.4, 69.5, 55.7, 48.3, 44.0, 39.9,
39.2, 38.7, 29.1, 26.0, 18.4, 18.1, 18.1, 17.4, 14.2, 10.9, 7.3, 6.9, 5.1, ꢀ3.9,
ꢀ4.0, ꢀ4.2, ꢀ4.2; IR (CHCl3, cmꢀ1) 3690, 3623, 3397, 2957, 2932,
2884, 2858, 1664, 1602, 1471, 1463, 1412, 1387, 1362, 1256, 1144, 1086,
2958, 2932, 2877, 2858, 1731, 1679, 1603, 1496, 1471, 1463, 1412, 1379,
1362, 1257, 1095, 1072, 1040; HRMS (EI, m/z) Mþ calcdfor C46H68O7S-
i
þ 760.4734, found 760.4730.
(5R,9R,10R,11S,13R,E)-13-(3-(Benzyloxy)propyl)-11-((tert-
butyldimethylsilyl)oxy)-2,2,3,3,7,10,15,15,16,16-decamethyl-
5-propyl-4,14-dioxa-3,15-disilaheptadec-7-en-9-ol (23). To a
solution of E ketone 22b (50 mg, 0.067 mmol) in THF (2 mL) was
added L-Selectride (1 M in THF, 120 μL, 0.12 mmol, 1.8 equiv). After it
was stirred for 5 h at ꢀ78 °C, the reaction mixture was quenched by
successive addition of methanol and saturated aqueous NH4Cl. The
aqueous phase was extracted with ether, and the combined organic
extracts were washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated in vacuo. The residue was purified by silica gel column
chromatography with a gradient of ether in petroleum ether (2/98, 5/
95) to afford the secondary alcohol 23 (36 mg, 71%) as a colorless oil as a
1034; [R]25 = ꢀ22.0° (c 0.5, CHCl3); HRMS (EI, m/z) (M ꢀ I)þ
1
single diastereomer: H NMR (CDCl3, 400 MHz) δ 7.26ꢀ7.34 (m,
D
calcd for (C37H79O5Si3)þ 682.5735, found 682.5739.
5H), 5.19 (br d, J = 8.8 Hz, 1H), 4.51 (s, 2H), 4.10ꢀ4.16 (m, 2H),
3.79ꢀ3.86 (m, 2H), 3.47 (t, J = 6.4 Hz, 2H), 2.23 (dd, J = 13.2, 5.3 Hz,
1H), 2.15 (dd, J = 13.2, 7.9 Hz, 1H), 1.84 (br s, 1H), 1.69 (s, 3H),
1.24ꢀ1.74 (m, 11H), 0.96 (t, J = 7.9 Hz, 9H), 0.89 (m, 21H), 0.73 (d, J =
6.9 Hz, 3H), 0.60 (q, J = 7.9 Hz, 6H), 0.09, 0.08, 0.07 (3s, 12H); 13C
NMR (CDCl3, 100 MHz) δ 138.7, 128.3, 127.6, 127.4, 135.8, 129.9,
72.9, 71.2, 70.8, 70.6, 70.6, 70.5, 48.3, 45.5, 41.0, 39.0, 34.9, 26.0, 25.9,
25.4, 18.4, 18.1, 18.1, 17.4, 14.2, 10.9, 6.9, 5.2, ꢀ3.9, ꢀ4.1, ꢀ4.2, ꢀ4.2; IR
(CHCl3, cmꢀ1) 3616, 3478, 2958, 2932, 2877, 2858, 1685, 1610, 1471,
’ ASSOCIATED CONTENT
1
S
Supporting Information.
Figures giving H and 13C
b
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
1463, 1413, 1379, 1362, 1256, 1073; [R]25 = þ4.5° (c 1.5, CHCl3);
D
HRMS (EI, m/z) Mþ calcd for C42H82O5Si3þ 750.5470, found 750.5473.
(4R,6S,7R,8R,12R)-4,6-Bis((tert-butyldimethylsilyl)oxy)-8-
(methoxymethoxy)-7,10-dimethyl-12-(triethylsilyloxy)-
pentadec-9-en-1-ol (24). The secondary alcohol 23 (63 mg,
84 μmmol) was dissolved in DCE (420 μL) followed by the addition
of diisopropylethylamine (150 μL, 840 μmol, 10 equiv) and MOMCl
(32 μL, 420 μmol, 5.0 equiv) at 20 °C. After it was stirred for 5 h at
50 °C, the reaction mixture was quenched with successive addition of
ether and 10% aqueous HCl solution. The aqueous phase was extracted
with ether, and the combined organic extracts were washed with brine,
dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography with a gradient
of ether in petroleum ether (5/95, 10/90) to afford the desired
protected alcohol (57 mg, 85%) as a slightly yellow oil. A solution of
the preceding benzyl ether (20 mg, 25 μmmol) and an excess of Raney
nickel in absolute ethanol (1 mL) was stirred at 20 °C under 1 atm of H2.
After the reaction was complete, the catalyst was removed by filtration
and the solution concentrated in vacuo. The residue was purified by
silica gel column chromatography with a gradient of ether in petro-
leum ether (10/90, 20/80) to afford the protected alcohol 24 (14 mg,
Corresponding Author
*E-mail: joelle.prunet@glasgow.ac.uk.
’ ACKNOWLEDGMENT
Financial support was provided by the CNRS, the Ecole
Polytechnique, and the University of Glasgow.
’ REFERENCES
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(5) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
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1
77%) as a colorless oil: H NMR (CDCl3, 400 MHz) δ 4.98 (br d,
J = 9.6 Hz, 1H), 4.62 (d, J = 6.5 Hz, 1H), 4.42 (d, J = 6.5 Hz, 1H),
4.10ꢀ4.17 (m, 2H), 3.88ꢀ3.93 (m, 1H), 3.80ꢀ3.85 (m, 1H),
3.58ꢀ3.66 (m, 2H), 3.34 (s, 3H), 2.27 (dd, J = 13.2, 4.6 Hz, 1H),
2.17 (dd, J = 13.2, 8.3 Hz, 1H), 1.78ꢀ1.86 (m, 1H), 1.63 (s, 3H),
1.26ꢀ1.73 (m, 10H), 0.96 (t, J = 7.9 Hz, 9H), 0.89 (m, 21H), 0.76 (d, J =
7.1 Hz, 3H), 0.60 (q, J = 7.9 Hz, 6H), 0.09, 0.08, 0.07 (3s, 12H); 13C
NMR (CDCl3, 100 MHz) δ 137.6, 127.1, 93.4, 73.4, 70.7, 70.5, 70.3,
63.2, 55.7, 48.3, 44.0, 39.4, 38.7, 34.7, 28.1, 26.0, 18.4, 18.2, 18.1, 17.4,
14.2, 10.9, 7.0, 5.1, ꢀ3.9, ꢀ4.1, ꢀ4.2, ꢀ4.3; IR (CHCl3, cmꢀ1) 3690,
3623, 3397, 2957, 2932, 2884, 2858, 1664, 1602, 1471, 1463, 1412, 1387,
1362, 1256, 1144, 1086, 1034; [R]25D = ꢀ25.0° (c 0.5, CHCl3); HRMS
(EI, m/z) Mþ calcd for C37H80O6Si3þ 704.5263, found 704.5191.
(5R,9R,10R,11S,13R)-11-((tert-Butyldimethylsilyl)oxy)-3,3-
diethyl-13-(3-iodopropyl)-9-(methoxymethoxy)-7,10,15,15,
16,16-hexamethyl-5-propyl-4,14-dioxa-3,15-disilaheptadec-
7-ene (25). The primary alcohol 24 (10 mg, 13.6 μmmol) was stirred
(6) Vincent, A.; Prunet, J. Synlett 2006, 2269.
(7) For the synthesis of the C16ꢀC24 portion of dolabelide C, see:
(a) Grimaud, L.; de Mesmay, R.; Prunet, J. Org. Lett. 2002, 4, 419. For
the synthesis of model C21ꢀC24 or C21ꢀC26 fragments of dolabelide
C, see: (b) Grimaud, L.; Rotulo, D.; Ros-Perez, R.; Guitry-Azam, L.;
Prunet, J. Tetrahedron Lett. 2002, 43, 7477. (c) Rotulo-Sims, D.; Prunet,
J. Org. Lett. 2007, 9, 4147. (d) Oriez, R.; Prunet, J. Tetrahedron Lett.
2010, 52, 256. (e) Gamba-Sanchez, D.; Prunet, J. J. Org. Chem. 2010,
75, 3129.
(8) For reviews on the application of CM in the synthesis of natural
products, see: (a) Prunet, J. Curr. Top. Med. Chem. 2005, 5, 1559.
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(b) Prunet, J.; Grimaud, L. Metathesis in Natural Product Synthesis;
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(9) Prepared in the same fashion as enantiopure 6a from racemic
epoxide (()-20; see Scheme 5.
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(16) The configuration of the newly formed stereocenters at C21
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(18) The reason for trying to synthesize the Z enone as a single
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