Stereoselective synthesis of the C1-C13 fragment of 2,3-dihydrodorrigocin A

Full text of DOI:10.1021/jo050942s

Stereoselective Synthesis of the C1-C13
Fragment of 2,3-Dihydrodorrigocin A
Jean-Yves Le Brazidec,* Charles A. Gilson III, and
Marcus F. Boehm
Departments of Chemistry and Biology,
Conforma Therapeutics Corporation,
9393 Towne Centre Drive, Suite 240,
San Diego, California 92121
jlebrazidec@conformacorp.com
Received May 11, 2005
FIGURE 1. Structures of dorrigocin A and migrastatin A.
SCHEME 1. Retrosynthetic Analysis of the
C1-C13 Fragment of 2,3-Dihydrodorrigocin A
The first synthesis of the C1-C13 fragment of 2,3-dihydro-
dorrigocin A has been achieved from 6-bromohexanoic acid
in 14 linear steps and an overall yield of 2%. The configura-
tions of the stereogenic centers C8, C9, and C10 have been
determined to be the same as for migrastatin.
Dorrigocins A and B along with migrastatins A and B
represent a new class of natural products isolated from
Streptomyces platensis1 (Figure 1). In the context of our
oncology program, we focused our attention on dorrigocin
A, which presented the potential ability2 to block the
activation of the Ras pathway involved in the control of
tumor cell growth, differentiation, migration, and sur-
vival.3
sulfone 4,6 easily available in three steps from 6-bromo-
hexanoic acid, is reacted with the aldehyde 57 in the
presence of KHMDS at low temperature to give the non-
6-enoic acid tert-butyl ester derivative 6 as a 1:1 mixture
of E/Z isomers. Upon heating and treatment with thiophe-
nol and AIBN, the alkene 6 is converted into a 9:1
mixture of isomers amenable to produce, after cleavage
of the TBDPS ether with TBAF and oxidation using the
Dess-Martin reagent, the aldehyde 8.
At this stage, the Evans asymmetric aldol reaction
using the boron enol ether of 9 afforded the product 10
in good yield and with excellent syn/syn selectivity8
(Scheme 3). After protection of the secondary alcohol of
10 as a methoxymethyl ether, the chiral auxiliary was
reduced to give the alcohol 12 in moderate yield.
The alcohol 12 was then oxidized into the aldehyde 13
followed by a coupling reaction with the stabilized
phosphorilidene 14 to generate the diester 15 with
acceptable yield and excellent control of the double bond
stereochemistry. For the next step which required the
chemoselective reduction of an R,â-unsaturated ethyl
ester in the presence of a tert-butyl ester, we first tried
DIBAL at low temperature without success. However,
lithium borohydride in the presence of 1 equiv of metha-
nol9 selectively reduced the ethyl ester to give the alcohol
Njardarson et al.4 have shown that migrastatin A was
able to inhibit cell migration in 4T1 mouse breast tumor
cells. More interestingly, the macrolactone core of mi-
grastatin A was much more potent than the natural
product itself. We hypothesized that the analogous core
structure of dorrigocin may also provide interesting
biological activities and set out to prepare derivative 1
(Scheme 1). As the configuration of the stereogenic
centers of dorrigocins was unknown, we made the hy-
pothesis that the C1-C13 fragment of dorrigocin would
have the same stereochemistry as the migrastatin core.
We embarked on the synthesis of the 2,3-dihydrodor-
rigocin A fragment by a retrosynthetic analysis starting
with the C11-C12 disconnection leading to the retron 2
(Scheme 1). Cleavage of the C9-C10 bond gave rise to
the aldehyde 3, which is now set for an aldol addition
and the subsequent control of two stereogenic centers.
The C6-C7 double bond represents the last disconnection
affording the phenyltetrazole sulfone 4, precursor for a
Julia-Kocien˜ski5 coupling. As depicted in Scheme 2, the
(5) Blakemore, P. R.; Cole, J. C.; Kocien˜ski, P. J.; Morley, A. Synlett
1998, 26-28.
(6) See the Supporting Information for experimental details.
(7) Nicolaou, K. C.; Piscopio, A. D.; Bertinato, P.; Chakraborty, T.
K.; Minowa, N.; Koide, K. Chem. Eur. J. 1995, 318-33.
(8) No other diastereomers were detected on the crude 1H NMR or
during the purification by column chromatography.
(1) Hochlowski, J. E.; Whittern, D. N.; Hill, P.; McAlpine, J. B. J.
Antibiot. 1994, 47, 870-874.
(2) Kadam, S.; McAlpine, J. B. J. Antibiot. 1994, 47, 875-880.
(3) Kloog, Y.; Cox, A. D. Mol. Med. Today 2000, 6, 398-402.
(4) Njardarson, J. T.; Gaul, C.; Shan, D.; Huang, X.-Y.; Danishefsky,
S. J. J. Am. Chem. Soc. 2004, 126, 1038-1040.
10.1021/jo050942s CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/31/2005
8212
J. Org. Chem. 2005, 70, 8212-8215

SCHEME 2. Synthesis of Aldehyde 8
TABLE 1. Chemical Shifts and Coupling Constants of
H8 and H9
SCHEME 3. Synthesis of tert-Butyl Ester 12
dorrigocin A
compound 1
H8
H9
3.54 (dd, J ) 4.1, 8.6 Hz)
3.21 (dd, J ) 4.1, 6.9 Hz)
3.49 (dd, J ) 4.1, 8.6 Hz)
3.17 (dd, J ) 4.2, 7.0 Hz)
firmed to be syn in the compound 12. In addition to
confirming the stereochemistry of the three stereogenic
centers of the C1-C13 fragment of dorrigocin A, the
coupling constants and the chemical shifts of H8 and H9
were compared to the published data (Table 1) for
dorrigocin A.1 The excellent match led us to conclude that
the configurations of the stereogenic centers of dorrigocin
A and migrastatin are the same. Finally, our stereo-
chemistry assignment has been corroborated by the work
of Ju et al. who have recently shown that dorrigocin and
migrastatin were shunt metabolites of isomigrastatin.12
In conclusion, this synthetic effort has led to the
production of an advance fragment of dorrigocin A, for
which the configuration of the three contiguous stereo-
genic centers was assigned. This work contributes to shed
light on a new family of natural products which have
been of interest for synthetic chemists due to their
complexity and their biological activity.
16 with moderate yield (Scheme 4). Finally, the MOM
ether and the tert-butyl ester were cleaved under acidic
conditions to give the C1-C13 fragment of dorrigocin A
with moderate yield.
To confirm the stereochemistry of the stereogenic
centers, the Mosher esters10 of the aldol adduct 10 were
prepared following a literature precedent9 (see the Sup-
porting Information). As the chemical shift differences
were unexpectedly negative and positive on both sides
of carbon 9, this method was considered inconclusive as
reported in some cases.11 We then carried out a fragmen-
tation study of 12 which was first converted into the
dioxane 18 using acidic conditions (Scheme 5).
The small coupling constant between H9 and H10 (2.1
Hz) corresponds to a cis axial-equatorial relative ster-
eochemistry which confirms the syn relationship between
the C9-OH and C10-Me. Second, the treatment of 12
with RuO4 and methyl orthoformate produced a mixture
of anomers 19R and 19â. As the coupling constants
between H8 and H9 (9.3 Hz for 19R and 8.5 Hz for 19â)
are in the range expected for a trans diaxial relative
stereochemistry, the MeO and MOM groups are con-
Experimental Section
(S)-9-(tert-Butyldiphenylsilanyloxy)-8-methoxynon-6-
enoic Acid tert-Butyl Ester 6. To a solution of sulfone 4 (14.0
g, 36.6 mmol) in anhydrous DME at -78 °C was added KHMDS
(88.0 mL, 43.9 mmol, 0.5 M solution in toluene). The resulting
orange solution was stirred for 0.5 h, after which time a solution
of aldehyde 5 (8.00 g, 36.6 mmol) in DME (40 mL) was added
via cannula. The reaction was stirred for 3.0 h during which
time it was allowed to warm to rt. The reaction solution was
then diluted with H2O (100 mL) and extracted with ethyl acetate
(3 × 100 mL). The combined organics were dried (Na2SO4) and
concentrated under reduced pressure. The viscous, orange oil
was purified on a column of silica gel (ethyl acetate/ hexane,
1:4, v/v), affording 13.8 g (76%) of alkene 6 as a colorless oil
consisting of a 6:4 ratio of E/Z isomers. This mixture was
dissolved in benzene (125 mL) and benzenethiol (1.5 mL) and
AIBN (2.98 g, 18.1 mmol) were added whereupon it was refluxed
for 20 h, during which time an additional 3 equiv of AIBN was
added successively. Solvent was removed under reduced pres-
sure, and the resulting viscous, yellow oil was purified by column
chromatography (ethyl acetate/hexane, 1:4, v/v), affording 17.9
g (99%) of 6 as a colorless oil consisting of a 9:1 ratio of E/Z
isomers: 1H NMR (CDCl3, 400 MHz) δ E isomer: 7.68 (m, 4H),
(9) Zhang, W.; Carter, R. G.; Yokochi, A. F. T. J. Org. Chem. 2004,
69, 2569-2572.
(10) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092-4096.
(11) Seco, J. M.; Quio`oa´, E.; Riguera, R. Chem. Rev. 2004, 104, 17-
117.
(12) Ju, J.; Lim, S.-K.; Jiang, H.; Shen, B. J. Am. Chem. Soc. 2005,
127, 1622-1623.
J. Org. Chem, Vol. 70, No. 20, 2005 8213

SCHEME 4. Achievement of the Synthesis of the C1-C13 Fragment of 2,3-Dihydrodorrigocin A
1.44 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 199.3, 172.8, 138.0,
122.3, 86.8, 79.9, 56.8, 35.1, 32.1, 28.1, 28.0, 24.4.
SCHEME 5. Fragmentation Study of the
tert-Butyl Ester 12
To a solution of (S)-(+)-4-benzyl-3-propionyl-2-oxazolidinone
(0.83 g, 3.56 mmol) in CH2Cl2 (50 mL) at 0 °C were added dibutyl
borontriflate (3.92 mL, 3.92 mmol; 1.0 M solution in CH2Cl2)
and Hunig’s base (0.55 g, 4.27 mmol). The solution was stirred
at 0 °C for 30 min and then cooled to -78 °C, at which time a
solution of aldehyde 8 (0.92 g, 3.56 mmol) in CH2Cl2 was added
dropwise over 5 min. The reaction was allowed to warm to rt
over 18 h. The solution was quenched with 0.5 mL of H2O2 and
2.0 mL of MeOH and was stirred at rt for an additional 0.5 h.
The resulting solution was absorbed directly onto silica gel (2
g) under reduced pressure and purified by column chromatog-
raphy (ethyl acetate/hexane, 2:3, v/v) to give 1.3 g (74%) of
oxazolidinone 10 as a colorless oil: [R]20D ) +44.8 (c 1.25, CH2-
Cl2); IR (KBr, cm-1) νmax ) 2974, 2935, 1778, 1726, 1697, 1453,
1
1386, 1366, 1208, 1151, 1098, 979; H NMR (CDCl3, 400 MHz)
δ 7.34-7.26 (m, 3H), 7.22-7.20 (m, 2H), 5.75 (dt, J ) 15.5, 6.7
Hz, 1H), 5.32 (dd, J ) 15.5, 9.0 Hz, 1H), 4.65 (m, 1H), 4.19, (m,
2H), 3.90 (m, 2H), 3.45 (dd, J ) 8.9, 6.8 Hz, 1H), 3.32 (dd, J )
7.3, 3.2 Hz, 1H), 3.28 (s, 3H), 2.79 (d, J ) 3.1 Hz, 1H), 2.74 (dd,
J ) 9.8, 8.4 Hz, 1H), 2.22 (t, J ) 7.5 Hz, 2H), 2.11 (q, J ) 6.7
Hz, 2H), 1.6 (m, 2H), 1.43 (m, 2H), 1.43 (s, 9H), 1.24 (d, J ) 6.0
Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 175.3, 172.8, 152.9, 136.8,
135.4, 129.4, 128.8, 127.1, 126.5, 84.7, 79.7, 73.4, 66.0, 55.8, 55.4,
7.39 (m, 6H), 5.65 (dt, J ) 15.5, 6.6 Hz, 1H), 5.28 (dd, J ) 15.4,
7.5 Hz, 1H), 3.72 (m, 1H), 3.61 (m, 2H), 3.29 (s, 3H), 2.21 (t,
J ) 7.3 Hz, 2H), 2.05 (q, J ) 7.2 Hz, 2H), 1.59 (dd, J ) 7.7, 3.99
Hz), 1.43 (s, 9H), 1.40 (m, 2H), 1.04 (s, 9H); Z isomer: 5.60 (br
dt, J ) 11.1, 7.8 Hz, 1H), 5.215 (ddt, J ) 11.0, 9.1, 1.6 Hz, 1H),
3.54 (dd, J ) 10.6, 4.9 Hz, 1H), 3.30 (s, 3H), 2.04-2.01 (m, 1H),
1.96-1.85 (m, 1H), 1.35-1.31 (m, 2H); 13C NMR (CDCl3, 100
MHz) δ 173.1, 135.6, 134.6, 133.8, 129.5, 128.0, 127.6, 83.1, 80.0,
66.7, 56.6, 35.4, 32.0, 28.6, 28.1, 26.8, 24.6, 19.2; HRMS calcd
for C30H44O4Si (M + Na)+ 519.2901, found 519.2910.
39.8, 37.6, 35.1, 31.8, 28.2, 28.0, 24.4, 11.1; HRMS for C27H39
-
NO7 (M + Na)+ 512.2619, found 512.2608.
(8S,9S,10R)-11-Hydroxy-8-methoxy-9-methoxymethoxy-
10-methylundec-6-enoic Acid tert-Butyl Ester 12:
(8S,9S,10S)-11-(4-Benzyl-2-oxooxazolidin-3-yl)-8-methoxy-
9-methoxymethoxy-10-methyl-11-oxoundec-6-enoic Acid
tert-Butyl Ester 11. To a solution of the secondary alcohol 10
(3.76 g, 7.64 mmol) in anhydrous DCE (100 mL) at room
temperature were added DMAP (0.28 g, 2.29 mmol), Hunig’s
base (1.48 g, 11.5 mmol), and chloromethylmethyl ether (1.23
g, 15.3 mmol). The reaction was stirred at 60 °C for 20 h. The
reaction solution was diluted with H2O (100 mL), extracted with
CH2Cl2 (3 × 100 mL), dried with Na2SO4, and concentrated
under reduced pressure to give a colorless oil that was purified
on a column of silica gel (ethyl acetate/hexane, 1:1, v/v), affording
3.2 g (79%) of 11 as a colorless oil: 1H NMR (CDCl3, 400 MHz)
δ 7.28 (m, 5H), 5.19 (dt, J ) 15.5, 6.7 Hz, 1H), 5.43 (dd, br, J )
15.5, 8.7 Hz, 1H), 4.71 (dd, J ) 49.6, 6.9 Hz, 2H), 4.55 (m, 1H),
4.16 (m, 2H), 3.92 (m, 2H), 3.59 (dd, J ) 8.6, 6.2 Hz, 1H), 3.33
(dd, J ) 7.4, 3.4 Hz, 1H), 3.34 (s, 3H), 3.18 (s, 3H), 2.73 (dd,
J ) 13.3, 10.0 Hz, 1H), 2.10 (t, J ) 7.6 Hz, 2H), 2.10 (q, J ) 7.1
Hz, 2H), 1.59 (m, 2H), 1.42 (s, 9H), 1.42 (m, 2H), 1.21 (d, J )
6.7 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 174.8, 173.0, 153.1,
136.0, 135.6, 129.4, 128.9, 127.2, 126.5, 98.1, 84.8, 80.6, 79.9,
66.1, 56.2, 56.1, 39.7, 37.8, 35.3, 31.9, 28.4, 28.0, 24.5, 11.4;
HRMS calcd for C14H24O4 (MH)+ 534.3061, found 534.3050.
(8S,9S,10S)-11-(4-Benzyl-2-oxooxazolidin-3-yl)-9-hydroxy-
8-methoxy-10-methyl-11-oxoundec-6-enoic Acid tert-Butyl
Ester 10:
(S)-9-Hydroxy-8-methoxynon-6-enoic Acid tert-Butyl Es-
ter 7. To a solution of tert-butyldiphenylsilyl ether 6 (10.7 g,
21.5 mmol) in CH2Cl2 (250 mL) was added TBAF (32.3 mL, 32.3
mmol; 1.0 M solution in THF). After 3 h, it was washed with
H2O (2 × 100 mL), dried with Na2SO4, and concentrated under
reduced pressure to give a pale yellow oil which was purified on
a column of silica gel (ethyl acetate/hexane, 4:5, v/v), affording
4.5 g (82%) of the alcohol 7: 1H NMR (CDCl3, 400 MHz) δ 5.59
(dt, J ) 15.5, 6.7 Hz, 1H), 5.14 (dd, br, J ) 15.5, 8.0 Hz, 1H),
3.51 (m, 1H), 3.38 (d, 6.3 Hz, 2H), 3.16 (s, 3H), 2.82 (s, br, 1H),
2.07 (t, J ) 7.5, 2H), 1.94 (q, J ) 7.0 Hz, 2H), 1.44 (m, 2H), 1.30
(s, 9H), 1.29 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 172.6, 135.3,
126.7, 82.8, 79.6, 65.1, 55.8, 34.9, 31.6, 28.1, 27.8, 24.2; HRMS
calcd for C14H24O4 (M + Na)+ 281.1723, found 281.1719.
(S)-8-Methoxy-9-oxonon-6-enoic Acid tert-Butyl Ester 8.
To a solution of alcohol 7 (1.48 g, 5.73 mmol) in CH2Cl2 (60 mL)
at room temperature was added Dess-Martin periodinane (2.92
g, 6.88 mmol). The reaction was stirred for 4 h, at which time it
was diluted with H2O (50 mL) and extracted with ethyl acetate
(3 × 50 mL). The dried organics (Na2SO4) were concentrated
under reduced pressure, affording 1.28 g (87%) of aldehyde 8 as
a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 9.50 (d, J ) 1.5
Hz, 1H), 5.88 (dt, J ) 15.5, 6.6 Hz, 1H), 5.32 (dd, br, J ) 15.6,
7.2 Hz, 1H), 4.05 (d, J ) 7.2 Hz, 1H), 3.42 (s, 3H), 2.22 (t, J )
7.3 Hz, 2H), 2.13 (q, J ) 7.4 Hz, 2H), 1.61 (m, 2H), 1.44 (s, 9H),
To a solution of the oxazolidinone 11 (3.10 g, 5.81 mmol) in
anhydrous THF (60 mL) at room temperature was added MeOH
(464 mg, 14.5 mmol) followed by lithium borohydride (7.25 mL,
14.5 mmol; 2.0 M solution in toluene). The reaction was stirred
for 1.5 h whereupon it was quenched with silica gel (2 g). Solvent
removal in vacuo followed by purification on a column of silica
gel (hexane/ethyl acetate, 1:1, v/v) afforded 1.46 g (70%) of alcohol
8214 J. Org. Chem., Vol. 70, No. 20, 2005

12 as a colorless oil: [R]20D ) -2.8 (c 5.0, CH2Cl2); IR (KBr, cm-1
)
(8S,9S,10R)-9,13-Dihydroxy-8-methoxy-10,12-dimethyl-
trideca-6,11-dienoic Acid 1:
νmax ) 3418, 2930, 1754, 1455, 1367, 1151, 1032; 1H NMR
(CDCl3, 400 MHz) δ 5.68 (dt, J ) 15.4, 6.8 Hz, 1H), 5.27 (dd, br,
J ) 15.6, 8.2 Hz, 1H), 4.74 (dd, J ) 32.2, 6.7 Hz, 2H), 3.63 (dd,
J ) 7.46, 3.08 Hz, 1H), 3.48 (t, J ) 6.8 Hz, 2H), 3.39 (s, 3H),
3.22 (s, 3H), 3.16 (t, J ) 6.8 Hz, 1H), 2.18 (t, J ) 7.3 Hz, 2H),
2.16 (q, J ) 7.0 Hz, 2H), 1.83 (m, 1H), 1.55 (m, 2H), 1.40 (s,
9H), 1.39 (m, 2H), 0.78 (d, J ) 6.9 Hz); 13C NMR (CDCl3, 100
MHz) δ 173.0, 135.6, 126.7, 98.8, 84.8, 80.5, 80.0, 64.6, 56.0, 55.8,
36.5, 35.2, 31.9, 28.4, 28.0, 24.5, 10.2; HRMS calcd for C19H36O6
(M + Na)+ 383.2404, found 383.2403.
(8S,9S,10R)-13-Hydroxy-8-methoxy-9-methoxymethoxy-
10,12-dimethyltrideca-6,11-dienoic Acid tert-Butyl Ester
16. To a solution of the diester 15 (0.076 g, 0.172 mmol) in THF
(2.5 mL) at room temperature was added MeOH (0.017 mL,
0.430 mmol) followed by LiBH4 (0.22 mL, 0.430 mmol, 2.0 M
solution in toluene). The reaction was stirred for 6 h, whereupon
it was quenched with silica gel (0.5 g). Purification of the
resulting slurry by column chromatography (ethyl acetate/
hexane, 2:3, v/v) provided 0.033 g (48%) of alcohol 16 as a
colorless oil: 1H NMR (CDCl3, 400 MHz) δ 5.60 (dt, J ) 15.4,
6.7 Hz, 1H), 5.27 (dd, br, J ) 15.8, 7.9 Hz, 1H), 4.58 (d, J ) 6.8
Hz, 1H), 4.65 (d, J ) 6.8 Hz, 1H), 3.89 (s, 3H), 3.46 (dd, J ) 8.2,
2.4 Hz, 1H), 3.33 (s, 3H), 3.18 (t, J ) 5.3 Hz, 1H), 3.13 (s, 3H),
2.69 (m, 1H), 2.33 (s, br, 1H), 2.14 (t, J ) 7.3 Hz, 2H), 2.02 (q,
J ) 7.0 Hz, 2H), 1.59 (d, J ) 0.9 Hz, 3H), 1.51 (m, 2H), 1.35 (s,
9H), 1.34 (m, 2H), 0.90 (d, J ) 6.8 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 172.8, 134.6, 134.1, 128.8, 127.7, 98.2, 84.8, 83.4,
79.8, 68.4, 56.0, 55.8, 35.1, 33.6, 31.8, 28.4, 27.9, 24.4, 15.6, 13.6;
HRMS calcd for C22H40O6 (M + Na)+ 423.2717, found 423.2713.
To a 5:2 solution of THF/[HCl] (0.5 mL) at room temperature
was added the ester 16, and the mixture was stirred for 20 h
whereupon it was quenched with saturated aqueous NaHCO3
(2.0 mL), washed with ethyl acetate (2 × 4.0 mL), and reacidified
with 1 N HCl to pH ) 4. The aqueous layer was then extracted
with ethyl acetate (2 × 4.0 mL), dried with Na2SO4, and
concentrated under reduce pressure. The resulting oil was
further purified by flash chromatography (acetone/hexane, 1:1,
v/v) to give 3.4 mg (34%) of the title compound 1 as a colorless
(8S,9S,10R)-8-Methoxy-9-methoxymethoxy-10,12-dimeth-
yltrideca-6,11-dienedioic Acid 13-tert-Butyl Ester 1-Ethyl
Ester 15:
(8S,9S,10R)-8-Methoxy-9-methoxymethoxy-10-methyl-
11-oxoundec-6-enoic Acid tert-Butyl Ester 13. To a solution
of alcohol 12 (1.46 g, 4.05 mmol) in CH2Cl2 (50 mL) was added
DMP (2.03 g, 4.80 mmol). After 1 h, the solvent was removed in
vacuo. Purification of the oily white solid by silica gel chroma-
tography (1:1 hexane/ethyl acetate) gave 1.25 g (86%) of aldehyde
13 as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 9.74 (s, 1H),
6.70 (dd, J ) 10.7, 1.4 Hz, 1H), 5.68 (dt, J ) 15.5, 6.8 Hz, 1H),
5.32 (dd, br, J ) 15.6, 8.2 Hz, 1H), 4.70 (dd, J ) 32.0, 6.9 Hz,
2H), 3.91 (t, J ) 4.57, 1H), 3.58 (dd, J ) 8.3, 5.07, 1H), 3.31 (s,
3H), 3.18 (s, 3H), 2.57 (m, 1H), 2.18 (t, J ) 7.5, 2H), 2.08 (q,
J ) 7.5, 2H), 1.55 (m, 2H), 1.41 (s, 9H), 1.40 (m, 2H), 1.04 (d,
J ) 6.9 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 202.8, 172.9,
136.1, 126.5, 97.6, 82.6, 80.6, 80.0, 56.2, 55.9, 48.2, 35.3, 32.0,
28.4, 28.1, 24.5, 8.72; HRMS calcd for C19H34O6 (M + Na)+
381.2247, found 381.2240; HRMS calcd for C19H34O6 (M + Na)+
381.2247, found 381.2240.
oil: [R]20 ) +1.3 (c 5.0, CH2Cl2); IR (KBr, cm-1) νmax ) 2932,
D
To a solution of aldehyde 13 (0.44 g, 0.994 mmol) in 1,2-
dichloroethane (10 mL) at room temperature was added carb-
ethoxyethylidene triphenylphosphorane (1.08 g, 2.98 mmol). The
resulting yellow solution was heated to 60 °C for 18 h, at which
time TLC showed only partial conversion to the diester 15. More
carbethoxyethylidenetriphenylphosphorane (1.08 g, 2.98 mmol)
was added, and reaction was stirred for an additional 18 h at
60 °C whereupon it was concentrated under reduced pressure
and by flash chromatography (ethyl acetate/hexane, 1:4, v/v) to
afford 0.29 g (66%) of diester 15 as a colorless oil: [R]20D ) +5.4
(c 1.0, CH2Cl2); IR (KBr, cm-1) νmax ) 2974, 2935, 1730,1706,
1649, 1453, 1367, 1252, 1151, 1026; 1H NMR (CDCl3, 400 MHz)
δ 6.70 (dd, J ) 10.7, 1.4 Hz, 1H), 5.68 (dt, J ) 15.5, 6.8 Hz, 1H),
5.32 (dd, br, J ) 15.6, 8.2 Hz, 1H), 4.70 (dd, J ) 32.0, 6.9 Hz,
2H), 4.18 (q, J ) 7.11 Hz, 2H), 3.48 (dd, J ) 8.18, 4.86 Hz, 1H),
3.98 (s, 3H), 3.33 (t, J ) 6.3 Hz, 1H), 3.19 (s, 3H), 2.85 (m, 1H),
2.20 (t, J ) 7.3 Hz, 2H), 2.08 (q, J ) 7.2 Hz, 2H), 1.82 (d, J )
2.3 Hz), 1.57 (m, 2H), 1.42 (s, 9H), 1.41 (m, 2H), 1.25 (t, J ) 7.1
Hz, 3H), 1.03 (d, J ) 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
δ 173.0, 168.3, 144.4, 135.2, 127.5, 127.0, 98.3, 83.7, 80.0, 60.5,
56.3, 35.3, 35.0, 32.0, 28.5, 28.1, 24.6, 15.0, 14.3, 12.5; HRMS
calcd for C24H42O7 (M + Na)+ 465.2823, found 465.2822.
1731, 1454, 1371, 1241, 1155, 1109; 1H NMR (CD3OD), 400 MHz)
δ 5.71 (dt, J ) 15.4, 6.7 Hz, 1H), 5.45 (dd, br, J ) 15.5, 8.6 Hz,
1H), 5.29 (dq, J ) 10.0, 1.3 Hz, 1H), 3.92 (s, br, 2H), 3.49 (dd,
J ) 8.6, 4.1 Hz, 1H), 3.19 (s, 3H), 3.17 (dd, J ) 7.0, 4.2 Hz, 1H),
2.71 (m, 1H), 2.29 (t, J ) 7.3 Hz, 2H), 2.12 (q, J ) 7.0 Hz, 2H),
1.67 (d, J ) 1.3 Hz, 3H), 1.62 (m, 2H), 1.45 (m, 2H), 0.97 (d,
J ) 6.7 Hz, 3H); 13C NMR (CD3OD, 100 MHz) δ 177.6, 138.4,
136.8, 130.0, 129.5, 84.7, 79.2, 68.9, 66.3, 35.8, 34.8, 33.1, 29.8,
25.6, 16.3, 14.0; HRMS calcd for C16H28O5 (M + Na)+ 323.1829,
found 323.1827.
Acknowledgment. We thank Dr. Marco Biamonte
for his help in running NMR experiments and assigning
the protons of some advance intermediates in the
synthesis.
Supporting Information Available: Experimental pro-
cedures, HRMS, and 1H and 13C NMR spectra for 4, 6-8, 10-
14, and 16-19. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO050942S
J. Org. Chem, Vol. 70, No. 20, 2005 8215