A formal total synthesis of epothilone A: Enantioselective preparation of the C1-C6 and C7-C12 fragments

Full text of DOI:10.1021/jo981461u

9580
J . Org. Chem. 1998, 63, 9580-9583
A F or m a l Tota l Syn th esis of Ep oth ilon e A:
En a n tioselective P r ep a r a tion of th e C1-C6
a n d C7-C12 F r a gm en ts1
Richard E. Taylor,* Gabriel M. Galvin,
Kerry A. Hilfiker, and Yue Chen
Department of Chemistry and Biochemistry,
University of Notre Dame, Notre Dame, Indiana 46556
Received J uly 24, 1998
Our continued interest in the anticancer agent pacli-
taxel is driven by the desire to understand the structural
features and spatial arrangement necessary for tubulin
binding2 and stabilization of microtubule dynamics.3 The
recently reported class of natural products, epothilone,
now provides us with compounds structurally distinct
from taxol and taxol analogues but with similar biological
activity. In addition, epothilones have much greater
activity against multi-drug resistant cell lines.4 After
independently determining the relative stereochemistry
of epothilone A we reported our synthetic approach,
Figure 1, which includes a late-stage macrocyclic olefin
metathesis.5 Our initial publication presented an enan-
tioselective preparation of thiazole fragment C and the
successful application of a ring-closing olefin metathesis
reaction to an epothilone model system. Concurrently,
three other synthetic groups reported similar approaches
to epothilone A all of which have culminated in total
synthesis.6-10 Herein we report the details of our inde-
pendent, enantioselective preparation of the ketone frag-
ment B and aldehyde A.
F igu r e 1. Connectivity analysis of desoxy-epothilone A.
PC(which is reusable without significant loss of activity)
provided an efficient route to gram quantities of (R)-2
after purification and deacylation. The enantioselectivity
of the resolution at 47% conversion was determined to
be >20:1 by Mosher ester methodology13 and chiral
capillary gas chromatography (see Experimental Section
for details). The enantiomeric excess was found to be
dependent upon percent conversion (97% ee at 15%
conversion and 92% ee at 48% conversion). The unreacted
alcohol 2 can be easily recycled by a two-step oxidation-
reduction sequence. Acylation of the secondary hydroxyl
occurred readily with bromoacetyl bromide in the pres-
ence of N,N-dimethylaniline to provide ester 3 in excel-
lent yield. Ozonolytic cleavage of the terminal olefin
yielded the necessary Reformatsky precursor which
under exposure to freshly prepared SmI2 provided the
lactone 4 in quantitative yield with >20:1 diastereose-
Ketone B has been prepared from a sequence which is
highlighted by a samarium-mediated Reformatsky reac-
tion11 originally developed by Molander, Scheme 1. The
sequence begins with racemic alcohol 2 readily prepared
in one step from propionaldehyde and 3-methyl-2-bu-
tenylmagnesium chloride. Enzymatic resolution in meth-
yl tert-butyl ether using Altus Biologics12 Chiro-CLEC-
(8) (a) Bertinato, P.; Sorensen, E. J .; Meng, D.; Danishefsky, S. J .
J . Org. Chem. 1996, 61, 8000-8001. (b) Meng, D.; Sorensen, E. J .;
Bertinato, P.; Danishefsky, S. J . J . Org. Chem. 1996, 61, 7998-7999.
(c) Meng, D.; Su, D.-S.; Balog, A.; Bertinato, P.; Sorensen, E. J .;
Danishefsky, S. J .; Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S. B. J .
Am. Chem. Soc. 1997, 119, 2733-2734. (d) Balog, A.; Meng, D.;
Kamenecka, T.; Bertinato, P.; Su, D.-S.; Sorenson, E. J .; Danishefsky,
S. J . Angew. Chem., Int. Ed. Engl. 1996, 35, 2801-2803. (e) Balog, A.;
Bertinato, P.; Su, D.-S.; Meng, D.; Sorensen, E. J .; Danishefsky, S. J .;
Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S. B. Tetrahedron Lett.
1997, 38, 4529-4532.
(1) Presented at the 35th National Organic Chemistry Symposium,
J une 22-26, 1997, Trinity University, San Antonio, TX; abstract no.
M71.
(2) Schiff, P. B.; Fant, J .; Horwitz, S. B. Nature 1979, 22, 665.
(3) Wilson, L.; J ordan, M. A. Chem. Biol. 1995, 2, 569.
(4) (a) Bollag, D. M.; McQueney, P. A.; Zhu, J .; Hensens, O.; Koupal,
L.; Liesch, J .; Goetz, M.; Lazarides, E.; Woods, C. M. Cancer Res. 1995,
55, 2325. (b) Hoefle, G.; Bedorf, N.; Gerth, K.; Reichenbach, H. Patent
DE 4138042, 1993. (c) Gerth, K.; Bedorf, N.; Ho¨fle, G.; Irachik, H.;
Reichenbach, H. J . Antib. 1996, 49, 960. (d) Ho¨fle, G.; Bedorf, N.;
Steinmetz, H.; Schomburg, D.; Gerth, K.; Reichenbach, H. Angew.
Chem. 1996, 35, 1567-1569.
(5) Taylor, R. E.; Haley, J . Tetrahedron Lett. 1997, 38, 2061-2064.
(6) For an excellent review of the biology and chemistry of epothilones
(up to February 28, 1998), see: Nicolaou, K. C.; Roschangar, F.;
Vourloumis, D. Angew. Chem., Int. Ed. Engl. 1998, 35, 2014-2045.
Some more recent relevant papers include: (a) Schinzer, D.; Bauer,
A.; Schieber, J . Synlett 1998, 861-864. (b) May, S. A.; Grieco, P. A. J .
Chem. Soc., Chem. Commun. 1998, 1597-1598.
(7) (a) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.;
Roschanger, F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J . I. J .
Am. Chem. Soc. 1997, 119, 7960-7973. (b) Yang, Z.; He, Y.; Vourlou-
mis, D.; Vallberg, H.; Nicolaou, K. C. Angew. Chem. 1997, 36, 170. (c)
Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Yang, Z. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2399-2401. (d) Nicolaou, K. C.;
Winssinger, N.; Pastor, J .; Ninkovic, S.; Sarabia, F.; He, Y.; Vourloumis,
D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel, E. Nature 1997, 387,
268-272. (e) Nicolaou, K. C.; Ninkovic, S.; Sarabia, F.; Vourloumis,
D.; He, Y.; Vallberg, H.; Finlay, M. R. V.; Yang, Z.; J . Am. Chem. Soc.
1997, 119, 7974-7991.
(9) (a) Schinzer, D.; Limberg, A.; Bauer, A.; Bo¨hm O. M.; Cordes,
M. Angew. Chem., Int. Ed. Engl. 1997, 36, 523-524. (b) Schinzer, D.;
Limberg, A.; Bo¨hm O. M. Chem. Eur. J . 1996, 2, 1477-1482.
(10) For other synthetic efforts to epothilone, see: (a) Mulzer, J .;
Mantoulidis, A. Tetrahedron Lett. 1996, 37, 9179-9182. (b) Claus, E.;
Pahl, A.; J ones, P. G.; Meyer, H. H.; Kalesse, M. Tetrahedron Lett.
1997, 38, 1359-1362. (c) De Brabender, J .; Rosset, S.; Bernardinelli,
G. Synlett 1997, 824. (d) Mulzer, J .; Mantoulidis, A. O¨ hler, E.
Tetrahedron Lett. 1997, 38, 7725-7728. (e) Chakraborty, T. K.; Dutta,
S. Tetrahedron Lett. 1998, 39, 101-104. (f) Bijoy, P.; Avery, M. A.
Tetrahedron Lett. 1998, 39, 209-212. (g) Gabriel, T.; Wessjohann, L.
Tetrahedron Lett. 1997, 39, 1363-1366. (h) Liu, Z.-Y.; Yu, C.-Y.; Yang,
J .-D. Synlett 1997, 1383-1384. (i) Liu, Z.-Y.; Yu, C.-Y.; Wang, R.-F.;
Li, G. Tetrahedron Lett. 1998, 39, 5261-5264.
(11) (a) Molander, G. A.; Etter, J . B. J . Am. Chem. Soc. 1987, 109,
6556-6558. (b) Molander, G. A.; Etter, J . B.; Harring, L. S.; Thorel,
P.-J . J . Am. Chem. Soc. 1991, 113, 8036-8045.
(12) Altus Biologics Inc., Cambridge, MA.
(13) Dale, J . S.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512-
519.
10.1021/jo981461u CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/18/1998

Notes
J . Org. Chem., Vol. 63, No. 25, 1998 9581
Sch em e 1
Sch em e 3
yield, Scheme 3. Oxidation to the carboxylic acid was
accomplished with sodium chlorite to provide the desired
6-heptenoic acid. The mixed anhydride, generated by
exposure of the acid to pivaloyl chloride, was then treated
with the lithium amide of Evans’ auxiliary to provide the
heptenoyl imide in excellent yield. The sodium enolate
was generated with sodium hexamethyldisilazide at low
temperature which was followed by alkylation with
methyl iodide to provide the imide 6 with a high degree
of diastereocontrol, >20:1. The low temperature condi-
tions presumably generated exclusively the Z-enolate
which based on the steric encumbrance of the neighbor-
ing benzyl substituent directed alkylation to the R-face.
The chiral auxiliary was removed by basic hydrolysis, and
the resulting acid was reduced with lithium aluminum
hydride. Oxidation of the resulting primary alcohol under
Swern conditions provided aldehyde A in excellent yield
with high enantiomeric excess.
Sch em e 2
Herein we have reported practical routes to two
synthetic precursors to epothilone A. Our independent
preparation of each of three precursors (A, B, C) coupled
with the recently published work from the Schinzer
group8 represents a formal total synthesis of epothilone
A. Our effort is now focused on the use of this concise
route for the preparation of analogues, particularly
compounds with altered conformational properties. These
novel compounds have the potential to provide important
information concerning the conformation of the epothilones
while bound to microtubules. The details of these syn-
thetic efforts as well as our independent completion of
the synthesis of the natural product will be presented in
a subsequent publication.
lectivity. The selectivity of this intramolecular condensa-
tion can be rationalized by consideration of the chelated
transition state shown.
The enantioselective preparation of ketone B was com-
pleted by a three-step sequence from lactone 4, Scheme
2. Exposure of the lactone to Red-Al followed by protec-
tion of the resulting triol without purification provided
the alcohol 5. The yields of the reduction step appeared
to be dependent upon reaction scale. Kinetic conditions
(-15 °C) are necessary for the selective acetonide forma-
tion. When the reaction is carried out in refluxing meth-
ylene chloride, exclusive protection of the internal 1,3-
diol occurs. Oxidation of the secondary alcohol with TPAP
then provided the desired ketone B in quantitative yield.
The synthesis of aldehyde A uses the well-precedented
chemistry developed in the Evans’ laboratory.14 Schinzer
has previously reported a similar route to this intermedi-
ate starting from commercially available 6-heptenoic
acid.8 However, the exorbitant cost of 6-heptenoic acid
(>$5000/mol) created a need for a practical, alternative
source of this starting material. Our independent route
was developed starting from 1,7-octadiene (<$50/mol).
The diene was selectively epoxidized using m-CPBA at
0 °C. With careful control of stoichiometry and temper-
ature, the monoepoxide could be obtained in reasonable
yield (76%). The epoxide was subjected to periodic acid-
based oxidative cleavage to provide 6-heptenal in 79%
Exp er im en ta l Section
Gen er a l Meth od s. Chiro-CLEC-PC (dry) enzyme was ob-
tained from Altus Biologics, Cambridge, MA. When appropriate,
reactions were performed under an atmosphere of nitrogen or
argon with flame-dried glassware. Tetrahydrofuran (THF) was
dried by distillation from sodium/benzophenone ketyl. CH2Cl2
was dried by distillation from CaH2. All purchased reagents were
of reagent grade quality and were used without further purifica-
tion. GC analysis was accomplished using a gas chromatograph
with a flame ionization detector.
(R)-Alcoh ol 2. Racemic alcohol 2 (5.00 g, 0.30 mmol) and
vinyl acetate (6.30 mL, 7.81 mmol) were added to a stirring
solution of ChiroCLEC-PC (dry) enzyme (206 mg) in tert-
butyldimethyl ether (30 mL) at room temperature. The progress
of the reaction was monitored via 1H NMR or GC. After 40%
conversion was obtained, the solution was carefully concentrated
and the oil was chromatographed with pentane-Et2O (gradients
(14) Evans, D. A.; Ennis, M. D.; Mathre, D. J . J . Am. Chem. Soc.
1982, 104, 1737-1739.

9582 J . Org. Chem., Vol. 63, No. 25, 1998
Notes
to 3% Et2O) to yield the acetate as a colorless oil (because of
volatility the bulk material was taken directly to the reduction
without complete removal of solvent). This particular sample
was shown to be 93% ee by chiral GC: tR (S)-OAc 6.483 min; tR
(R)-OAc 6.874 min (Cyclodex B column, 30 m length, 0.25 mm
washed with saturated NaHCO3 and brine and then concen-
trated to give a pale yellow oil which was chromatographed with
pentane-Et2O (gradients from 1:1 to 100% Et2O) to yield lactone
4 (∼20:1 mixture of diastereomers) (1.19 g, 98%) as a low-melting
1
pale yellow solid: [R]23 ) +38.7; H NMR (CDCl3) δ 4.39 (dd,
D
i.d., J & W Scientific, Folsom, CA); [R]23 ) + 39.5; 1H NMR
J ) 4.1 Hz, J ) 8.6 Hz, 1H), 3.75 (s, 1 H), 2.85 (dd, J ) 4.8 Hz,
J ) 18.7 Hz, 1 H), 2.60 (dd, J ) 2.4 Hz, J ) 18.7 Hz, 1 H), 1.59
D
(CDCl3) δ 5.80 (dd, J ) 9.8 Hz, J ) 11.5 Hz, 1 H), 4.97 (m, 2 H),
4.71 (dd, J ) 2.5 Hz, J ) 10.8 Hz, 1 H), 2.05 (s, 3 H), 1.56 (m,
1 H), 1.38 (m, 1 H), 0.97 (s, 6H), 0.81 (t, J ) 7.34 Hz, 3H); 13C
NMR (CDCl3) δ 171.10, 144.54, 112.41, 81.00, 40.81, 23.18, 22.75,
20.94, 10.84; HRMS (CI) calcd for [M + H]+, 171.1385, obsd
171.1361; IR (neat) 3085, 2972, 2937, 2879, 1740, 1370, 1240
cm-1. The acetate was dissolved in anhydrous diethyl ether, and
lithium aluminum hydride (0.83 g, 21.8 mmol) was added in
small portions at -20 °C. After 30 min the reaction was carefully
quenched with solid Na2SO4‚10H2O and stirred at room tem-
perature until the white aluminum salts precipitated. The
mixture was filtered, and the salts were washed with additional
diethyl ether. The combined organic washings were carefully
concentrated, and the residue was chromatographed with pen-
tane-Et2O (gradients to 3% Et2O) to yield alcohol (R)-2 as a
colorless oil (because of volatility the bulk material was taken
(m, 2 H), 1.10 (t, J ) 7.3 Hz, 3 H), 1.07 (s, 3 H), 0.94 (s, 3 H); 13
C
NMR (CDCl3) δ 171.09, 84.42, 72.43, 36.64, 36.38, 22.52, 22.06,
18.79, 10.89; HRMS (CI) calcd for [M + H+] 173.1178, obsd
173.1171; IR (neat) 3437, 2970, 2973, 2880, 1710, 1249 cm-1
.
(3S,5R)-Aceton id e 5. To a stirring solution of lactone 4 (1.76
g, 10.2 mmol) in THF (1 mL) at 0 °C was added Red-Al (65% in
toluene) (6.8 mL, 22.5 mmol). The solution was stirred at room
temperature for 24 h. The reaction was quenched with H2O (1
mL), 2 N NaOH (1 mL), and anhydrous Na2SO4 (20 g) and
allowed to stir for 30 min. The solution was then filtered over a
bed of MgSO4 and washed through numerous times with EtOAc,
the organic layers were then concentrated to provide the triol
as a colorless solid (0.96 g, 53%).
2-Methoxypropene (1.35 mL, 13.9 mmol) and PPTS (cat.) were
added to a stirring solution of the triol (0.56 g, 3.23 mmol) in
DMF (10 mL) at -15 °C. The solution was stirred at -15 °C for
48 h, the reaction was quenched with saturated NaHCO3, and
the resulting mixture was extracted with Et2O (5 × 50 mL). The
organic layer was washed with water, dried with MgSO4,
concentrated, and filtered through a bed of silica gel to yield
directly to the acylation without complete removal of solvent):
1
[R]23 ) + 31.7; H NMR (CDCl3) δ 5.82 (dd, J ) 10.9 Hz, J )
D
17.4 Hz, 1 H), 5.06 (m, 2 H), 3.16 (ddd, J ) 1.9 Hz, J ) 4.9 Hz,
J ) 10.3 Hz, 1 H), 1.62 (m, 1 H), 1.45 (d, J ) 5.2 Hz, 1 H), 1.21
(m, 1 H), 1.04 (t, J ) 3.8 Hz, 3 H), 1.04 (s, 6 H); 13C NMR (CDCl3)
δ 145.53, 113.18, 80.02, 41.70, 24.30, 23.14, 22.09, 11.57; HRMS
(CI) calcd for [M + H+] 129.1279, obsd 129.1274; IR (neat) 3459,
the acetonide 5 (0.68 g, 100%) as a pale yellow oil: [R]23
)
D
+31.5; 1H NMR (CDCl3) δ 3.91 (m, 3H), 3.38 (dd, J ) 2.4 Hz, J
) 10.4 Hz, 1 H), 1.75 (m, 1 H), 1.51 (m, 1 H), 1.48 (s, 3 H), 1.38
(s, 3 H), 1.33 (m, 2 H), 0.99 (t, J ) 7.4 Hz, 3 H), 0.90 (s, 3 H),
0.72 (s, 3 H); 13C NMR (CDCl3) δ 98.44, 81.23, 78.00, 60.20, 40.27,
29.78, 25.37, 24.16, 20.67, 19.29, 14.42, 11.20; HRMS (FAB) calcd
3083, 2966, 2876, 1216 cm-1
.
(R)-Br om oa ceta te 3. Dimethylaniline (4 mL, 31 mmol) and
bromoacetyl bromide (2.70, 31.2 mmol) were added slowly to a
stirring solution of alcohol (R)-2 (from above) in Et2O (30 mL)
at 0 °C. The solution became green upon addition of the bro-
moacetyl bromide, and a green precipitate was formed. Stirring
was continued at room temperature for 24 h. After consumption
of (R)-2 (monitored by TLC), the reaction mixture was diluted
with water and extracted three times with diethyl ether. The
organic layer was washed alternate times with NaOH (2 N) and
HCl (2 N) until the aqueous layer was no longer cloudy upon
addition of NaOH. The organic layer was then dried over MgSO4
and concentrated. Chromatography (gradients to 5% Et2O)
yielded bromoacetate 3 (3.23 g, 83% for three steps based upon
for [M + H+] 217.1804, obsd 173.1171; IR (neat) 3448, 2963 cm-1
.
(S)-Keton e B. A solution of acetonide 5 (6.75 g, 3.12 mmol)
in CH2Cl2 (1.5 mL) with 3 Å MS (cat.) was stirred for 15 min at
room temperature. N-Methylmorpholine N-oxide (0.89 g, 7.02
mmol) and TPAP (cat.) were added, and this mixture was stirred
for 2.5 h until consumption of 5 was complete (monitored by
TLC). The reaction mixture was then filtered through silica gel
with diethyl ether and concentrated to yield ketone B (0.66 g,
99%) as a clear colorless oil: [R]23 ) +10.5; 1H NMR (CDCl3) δ
D
3.93 (m, 3 H), 2.50 (q, J ) 7.2 Hz, 2 H), 1.60 (m, 1 H), 1.40 (s, 3
H), 1.32 (s, 3 H), 1.12 (s, 3 H), 1.06 (s, 3 H), 1.00 (t, J ) 7.1, 3
H); 13C NMR (CDCl3) δ 215.85, 98.34, 73.92, 59.99, 50.56, 31.70,
29.72, 25.27, 21.02, 19.06, 18.97, 7.87; HRMS (CI) calcd for [M
+ H+] 215.1647, obsd 215.1643; IR (neat) 2973, 2940, 2876, 1706,
40% conversion in enzyme resolution) as a yellow oil: [R]23
)
D
+25.8; 1H NMR (CDCl3) δ 5.85 (dd, J ) 11.2 Hz, J ) 17.0 Hz, 1
H), 5.05 (m, 2 H), 4.81 (dd, J ) 2.5 Hz, J ) 10.7 Hz, 1 H), 3.88
(s, 2H) 1.66 (m, 1 H), 1.52 (m, 1 H), 1.05 (s, 6 H), 0.90 (t, J ) 7.3
Hz, 3 H); 13C NMR (CDCl3) δ 167.29, 144.07, 112.92, 83.46, 41.03,
25.94, 23.13, 22.78, 10.80; IR (neat) 3084, 2972, 2879, 1734, 1279
1372, 1198, 1105 cm-1
.
6-Hep ten oic Acid . 1,7-Octadiene (2 mL, 13 mmol) was added
to a stirred solution of sodium acetate (1.1 g, 13.3 mmol) and
m-chloroperbenzoic acid (2.55 g, 12.3 mmol) in methylene
chloride at 0 °C. The mixture was stirred for 2.5 h, and the
reaction was then quenched by the addition of saturated aqueous
solution of sodium bicarbonate (10 mL) and sodium thiosulfate
(1 mL). The aqueous layer was separated and washed with
additional portions of methylene chloride (2 × 25 mL). The
combined organic layers were dried over MgSO4 and concen-
trated in vacuo. The resulting residue was purified by flash
chromatography (silica gel; 15% ether in pentane) to yield the
monoepoxide (1.27 g, 76%). To a THF (3 mL) solution of the
monoepoxide (708 mg, 5.6 mmol) was added a solution of periodic
acid (1.44 g, 6.7 mmol) in water (3 mL) at 0 °C. The mixture
was stirred for 3 h at this temperature and then extracted with
diethyl ether (3 × 30 mL). The combined organic extracts were
washed with saturated aqueous sodium thiosulfate solution (2
× 10 mL) and then dried over MgSO4. Concentration in vacuo
provided 6-heptenal (498 mg, 79%): 1H NMR (CDCl3) δ 9.76 (t,
J ) 1.8 Hz, 1H), 5.79 (m, 1 H), 5.04-4.93 (td, J ) 7.2 Hz, J )
1.8 Hz, 2 H), 2.11-2.03 (m, 2 H), 1.70-1.60 (m, 2 H), 1.48-1.40
(m, 2 H); 13C NMR (CDCl3) δ 202.6, 138.2, 114.8, 43.7, 33.4, 28.3,
21.4; HRMS (FAB) calcd for [M + H+] 113.0966, obsd 113.0966;
IR (neat) 3075, 2927, 1727, 1640 cm-1. 6-Heptenal (56 mg, 0.5
mmol) was dissolved in a mixture of tert-butyl alcohol (10 mL)
and 2-methyl-2-butene (5 mL). To this solution was added, an
aqueous solution of sodium chlorite (225 mg, 2 mmol) and
sodium phosphate (138 mg, 1 mmol) in distilled water (4 mL).
The reaction mixture was then stirred vigorously for 30 min at
cm-1
.
(3S,2R)-La cton e 4. Ozone was bubbled into a stirring solu-
tion of bromoacetate 3 (2.91 g, 11.7 mmol) in CH2Cl2 (140 mL)
at -78 °C until the solution became blue and 3 was consumed
(by TLC). Nitrogen was then bubbled through the solution until
the blue color dissipated. The reaction was quenched with
trimethylphospite (3.6 g, 29 mmol), and the reaction was stirred
at room temperature for 24 h. The solution was concentrated
and chromatographed with pentane-diethyl ether (gradients to
20% Et2O) to yield the intermediate aldehyde (2.75 g, 94%) as a
clear pale yellow oil: [R]23D ) +20.9; 1H NMR (CDCl3) δ 9.53 (s,
1 H), 5.13 (dd, J ) 3.2 Hz, J ) 9.9 Hz, 1 H), 3.83 (s, 2 H), 1.60
(m, 2 H), 1.10 (s, 1 H), 1.09 (s, 1 H), 0.92 (t, J ) 7.1 Hz, 3 H); 13
C
NMR (CDCl3) δ 203.35, 167.03, 79.64, 50.16, 25.43, 22.96, 18.56,
17.84, 10.50; HRMS (FAB) calcd for [M + H+] 251.0283, obsd
251.0297; IR (neat) 2975, 2880, 1731, 1277 cm-1. A solution of
the aldehyde (1.77 g, 7.05 mmol) in THF (3 mL) was added
slowly to a stirring solution of freshly prepared11 SmI2 in THF
(153 mL, 15.3 mmol) at 0 °C. The solution was titrated with
additional SmI2 until a deep blue color persisted. The solution
was stirred for 5 min until consumption of the aldehyde was
complete (monitored by TLC). The reaction was quenched with
oxygen, and the mixture was concentrated to a green-yellow
solid, dissolved in EtOAc, and separated with water and
NaHCO3. The aqueous layer was washed two additional times
with EtOAc. An insoluble material was isolated by filtration,
dissolved in 1 N HCl (100 mL), and extracted with additional
portions of ethyl acetate. The combined organic layers were

Notes
J . Org. Chem., Vol. 63, No. 25, 1998 9583
room temperature. The mixture was then diluted with ethyl
acetate (80 mL) and washed with water (2 × 10 mL). The
combined aqueous layers were washed with additional portions
of ethyl acetate, and the combined organic extracts were dried
with MgSO4 and concentrated in vacuo. The crude material was
purified by chromatography (silica gel, 5% diethyl ether in
hexane) to provide 6-hepenoic acid as a colorless oil (38 mg, 60%).
is a recipient of a National Science Foundation Early
Career Award.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 2-5 and ketone B (10 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
Ack n ow led gm en t. Altus Biologics is thanked for a
generous gift of Chiro-CLEC-PC. We gratefully acknowl-
edge support from the University of Notre Dame. R.E.T.
J O981461U