Asymmetric aldol reactions using catalytic D(+)-proline: A new, economic and practical approach to a commonly employed C1-C6 keto-acid synthon of the epothilones

Article abstract of DOI:10.1016/j.tet.2003.12.048

A new approach to ketoacid 4, a common C1-C6 fragment used in the total synthesis of epothilones was initiated by direct aldol reaction of acetone with a pivaldehyde-like substance 5, catalyzed with D-proline, leading to a 2,6-diketoalcohol with better than 99% ee. Further intramolecular closure of the diketone 8 followed by oxidation of the silyl protected hydroxycyclohexenone 14 led to the desired product 4. None of the steps have been optimized, yet the overall yield for the four-step process is 31%. The use of commercially available D-proline to construct the chiral center of 4 under very mild reaction conditions provided an economical and practical method for its construction.

Full text of DOI:10.1016/j.tet.2003.12.048

Tetrahedron 60 (2004) 2091–2095
Asymmetric aldol reactions using catalytic D(1)-proline:
a new, economic and practical approach to a commonly employed
C1–C6 keto-acid synthon of the epothilones
Yansong Zhenga and Mitchell A. Averya,b,c
,
*
aDepartment of Medicinal Chemistry, University of Mississippi, University, MS 38677, USA
bNational Center for Natural Products Research, School of Pharmacy, University, MS 38677, USA
cDepartment of Chemistry & Biochemistry, University of Mississippi, University, MS 38677, USA
Received 25 November 2003; revised 19 December 2003; accepted 19 December 2003
Abstract—A new approach to ketoacid 4, a common C1–C6 fragment used in the total synthesis of epothilones was initiated by direct aldol
reaction of acetone with a pivaldehyde-like substance 5, catalyzed with D-proline, leading to a 2,6-diketoalcohol with better than 99% ee.
Further intramolecular closure of the diketone 8 followed by oxidation of the silyl protected hydroxycyclohexenone 14 led to the desired
product 4. None of the steps have been optimized, yet the overall yield for the four-step process is 31%. The use of commercially available
D-proline to construct the chiral center of 4 under very mild reaction conditions provided an economical and practical method for its
construction.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
The key for preparation of the C1–C6 fragment is to
introduce a hydroxyl group at the C-3 position in an
optically pure form. Nicolaou et al. has used Brown’s allyl
isopinocampheyl borane reagent [(þ)-Ipc2B(allyl)] to react
with ketoaldehyde 5 to provide enantiomerically pure
homoallyl alcohol (ee.98%), which was then oxidized to
an alcohol derivative, ketoacid 7 (Scheme 2).3a,e
Since their discovery in 1993,1 epothilones A–D have
evoked a strong interest from the scientific community
because of their taxotere-like anticancer activity.2 One of
the common strategies for total synthesis of epothilones
includes construction of a C1–C6 fragment, for example,
a ketoacid 4, which undergoes aldol condensation with an
aldehyde to set important stereochemical features of the
epothilone architecture (Scheme 1).3–8
Wessjohann et al. obtained the alcohol 7 (92% de, R¼
t-BuMe2Si) by a chromium-Reformatsky reaction of a chiral
N-bromoacyloxazolidinone with the ketoaldehyde 5,
wherein the amide portion of the alcohol was hydrolyzed
to ketoacid.8 We found that the aldol reaction of chiral
N-methylthioacetyloxazolidinones with the ketoaldehyde 5
can furnish the alcohol 7, but the enantioselectivity is
reversed if the boron reagents for forming the boron-enolate
were different. With dibutylboron triflate the desired
S-isomer was obtained in 54% de.9 DeBrabander et al.
reported that aldol reaction of acetylbornanesultam with the
ketoaldehyde 5 can afford the alcohol 7 (R¼t-BuMe2Si)
with 88% de.10 Recently Altmann et al.7 scaled up
Scheme 1.
Scheme 2.
Keywords: Epothilone; C1–C6 Keto-acid synthon; Asymmetric aldol reaction; Proline.
*
Corresponding author. Tel.: þ1-662-915-5879; fax: þ1-662-915-5863; e-mail address: mavery@olemiss.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.12.048

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Y. Zheng, M. A. Avery / Tetrahedron 60 (2004) 2091–2095
DeBrabander’s synthesis, and determined the sign of optical
rotation for S-ketoacid 4 should be negative instead of
positive as reported by Nicolaou and DeBrabander’s group,
which was also confirmed by Avery.11 Besides the above
asymmetric aldol reactions, Kalesse et al. has made use of
Sharpless’s asymmetric epoxidation to establish the chiral
center at the hydroxyl carbon (C-3), and furnished the
ketoacid 7 by at least 13 steps from a chiral epoxide.3 In
addition, optical resolution has been used to prepare the
ketoacid 7. Shioji et al. reported that the corresponding
racemic ketoacid tert-butyl ester of 7 can be resolved to its
optical pure S-isomer by lipase.12 Liu et al. treated a racemic
terminal epoxide of a vinyl ketone with Jacobson’s
hydrolytic kinetic resolution to afford its required enantio-
mer, which was transferred to ketoacid 7 by carbomethoxyl-
ation and hydrolysis.6 Here we report that the key C-3 chiral
center connected with 4 could be introduced by the direct
aldol condensation of ketoaldehyde 5 with acetone cata-
lyzed by D-proline. Processing of the terminal methylketone
group to a carboxylic acid was achieved in an unexpected
fashion as outlined below.
such as 7, it could provide an outstanding method for
preparation of ketoacid 5. We found that the 24 h reaction of
D-proline (35 mol%) in DMSO/acetone with ketoaldehyde
514 furnished aldol product 8 in 75% yield and with better
than 99% ee (Mosher ester analysis). In addition, 1.9% of
intramolecular cyclization product 9 was obtained from 8
(Scheme 3).
Silylation of 8 with tert-butyldimethylsilyl triflate
(TBSOTf) afforded protected product 10 in 90% yield.
Transformation of the methyl ketone group of 10 by
selective bromoform reaction would be the most expedient
synthetic route to ketoacid 4. Unfortunately, attempted
bromoform or iodoform reaction of 10 gave only complex
mixtures when 10 was halogenated under basic conditions
(Scheme 4). This is not surprising given the availability of
7 carbonyl a-protons in 10, for which multiple reaction
pathways can be envisioned for 10 under strongly basic
conditions. Alternatively, low temperature kinetic enoliza-
tion of the C1 methyl ketone of 7 or 9 providing an easily
oxidizable silyl enol ether is an approach currently being
investigated.
Nonetheless, it was recognized that the intramolecular aldol
product, hydroxycyclohexenone 9, could be transformed to
ketoacid 4 by oxidative cleavage after its protection with
various groups. For this study, the tert-butyldimethylsilyl
moiety was used affording 10. Results of intramolecular
aldol reaction of 10 are shown in Table 1. When NaOH was
reacted with 10 in H2O/ethanol (1:1), the major product 12
was produced in 50% yield from attack of the D6,7 enolate
on the C-2 ketone followed by b-elimination. Also
produced in 25% yield was the dienone 11, resulting from
attack of the D1,2 enolate on the C-6 ketone followed by two
b-eliminations. Product distributions in the reaction of 10
with amine bases such as pyrrolidine or proline were
dependent on solvent effects. For example, reaction of 10
with 1 equiv. of pyrrolidine in THF gave 56% of the aldol
adduct 13 in addition to 23% of dienone 11. The
2. Results and discussion
In 2000, List et al. found that the reaction of acetone with
branched aldehydes such as isobuytraldehyde in the
presence of L-proline can give very high yields and very
high enantioselectivities of aldol products.13 If List’s
conditions were used to construct the key C-3 chiral center
Scheme 3. (a) 0.35 equiv. D-proline, DMSO–acetone 4:1, rt, 24 h, 75%
yield and .99% ee for 8, 1.9% yield for 9.
Scheme 4. (a) TBSOTf, DIPEA, CH2Cl2, 278 8C to rt, 2.5 h, 90% yield; (b) Br2, NaOH, dioxane, H2O, 0 8C.
Table 1. Products for intramolecular aldol condensation of 10 under different conditions
Entry
Conditions
11 (%)
12 (%)
13 (%)
1
2
3
4
4 equiv. NaOH/H2O/ethanol, 0 8C, 1 h
1 equiv. Pyrrolidine/THF, rt, 72 h
1 equiv. Pyrrolidine/CH3CN, rt, 72 h
0.5 equiv. DL-Proline/DMF, 65 8C, 2 h
25
23
68
53
50
0
9.1
32
0
56
0
0

Y. Zheng, M. A. Avery / Tetrahedron 60 (2004) 2091–2095
2093
configuration of 13 was determined by the 2D-NMR
NOESY spectrum.
epothilones initiated by direct aldol reaction of acetone
with a pivaldehyde-like substance 5, catalyzed with D-pro-
line, leading to a diketoalcohol with better than 99% ee.
Further intramolecular closure of the diketone 8 followed by
oxidation of the silyl protected hydroxycyclohexenone 14
led to the desired product. None of the steps have been
optimized, yet the overall yield for the four-step process is
31%. The use of commercially available D-proline to
construct the chiral center of 4 under very mild reaction
conditions provided an economical and practical method for
its construction.
On the other hand, the same reaction conducted in
acetonitrile led to 68% of dienone 11 and only 9.1% of
enone 12. The b-silyloxy group in cyclohexenones readily
undergoes elimination as reported by Corey et al.15 in the
related cyclopentanones. Clearly, ethyl substituted products
(3-ethyl) produced in basic equilibria are capable of dual
b-eliminations because the gem-dimethyl moiety does not
interfere with the second elimination. Those products
(2,3-dimethyl) from the other mode of aldol reaction can
only readily eliminate HOH, and not the silyloxy group. In
acetonitrile, elimination is faster than in THF, as evidenced
by the high yield of the aldol intermediate 13 in THF but not
acetonitrile.
3. Experimental
Reactions requiring anhydrous conditions were performed
with the usual precautions for rigorous exclusion of air and
moisture. Where necessary, chemicals were purified
according to reported procedures.18 For example,
tetrahydrofuran was distilled from sodium benzophenone
ketyl prior to use and could be stored over 4A molecular
sieves to ensure the lowest levels of water. Thin layer
chromatography (TLC) was performed on precoated silica
gel 60 F254 plates from EM reagents and visualized with a
254 nm UV light. Flash chromatography was carried out on
silica gel 60 (E. M. Merck, particle size 0.040–0.063 mm,
With racemic proline in DMF at 65 8C for 2 h (entry 4),
dienone 11 was the major product produced in 53% yield,
while the remaining isolable material was the 2,3-dimethyl
enone 12 (23% yield). Certainly the elevated temperature,
zwitterionic proline and polar solvent were effective in
solvolyzing aldol adducts thus producing the thermo-
dynamic endpoint, dienone 11, over other more sensitive
intermediates leading to 11. From the other manifold, aldol
adduct 12 could not undergo the second elimination due to
the gem-dimethyl group.
1
230–400 mesh ASTM). H NMR and 13C NMR spectra
were recorded on a Bruker DPX 400 at 400 and 100 MHz,
respectively. The chemical shifts were reported in parts per
million (ppm) downfield from tetramethylsilane, and
J-values were in Hz. IR spectra were obtained on an ATI
Mattson FT/IR spectrometer. Mass spectra were recorded
on a Bruker BioApex FTMS system. Optical rotations were
determined on a Rudolph Autopol IV polarimeter. All mps
were uncorrected.
We reasoned that because the hydroxyl group is a poorer
leaving group than a silyloxy group, that intramolecular
aldol reaction of hydroxydiketone 8 in the presence of
pyrrolidine could provide enhanced selectivity for 5b-
hydroxy-2-eneone 9, and suppress formation of undesired
11. Thus, upon treatment of the diketo-alcohol 8 with
pyrrolidine in dichloromethane at ambient temperature,
compound 9 was produced in 76% yield and 41% of 8 was
recovered.16 Now, protection of 9 as the TBDMS silyl ether
could be readily achieved in 81% unoptimized yield using
the Corey method15 with TBSCl and imidazole. On the
other hand, with TBSOTf as the silylating agent, a variety of
amine bases lead to dual elimination product 11: DIPEA,
2,6-lutidine or pyridine. Finally, the double bond of 14
could be smoothly cleaved to the desired ketoacid 4 in 67%
yield by the Sharpless method17 employing NaIO4 and
RuCl3 in CCl4/CH3CN/H2O (1:1:1.6) (Scheme 5). The keto-
acid thus obtained (4) had a negative sign of optical rotation
([a]2D5¼215.8 (c 4.7, CHCl3); while 4 prepared by a
literature method7,10 showed [a]D25¼215 (c 0.56, CHCl3).
Further, 4 had an identical 1H and 13C NMR spectra
compared to literature values.2e,7 This result confirmed that
the absolute configuration at the chiral center of 8 was 3S.
3.1. General
3.1.1. (2)-4S-4-Hydroxy-5,5-dimethyl-2,6-octanedione
(8). A mixture of D-proline (2.0 g, 0.35 mmol) in anhydrous
acetone (50 mL) and anhydrous DMSO (200 mL) was
stirred at room temperature for 15 min. At this time, the
aldehyde 5 was added and the mixture stirred at room
temperature for 24 h. Saturated aqueous ammonium chlor-
ide (250 mL) was added and the reaction mixture was
extracted with ethyl acetate (3£200 mL). The combined
organic phase was dried over anhydrous sodium sulfate,
filtered and the solvent was evaporated. The residue was
subjected to flash chromatography (silica gel, EtOAc–
hexanes 1:1) providing 8 (7.0 g, 75%) and 9 (160 mg, 1.9%)
as colorless oils; for 8. Rf¼0.53 (silica gel, 50% ethyl
acetate in hexane); [a]D25¼248.8 (c¼1.2, CHCl3); IR (thin
film) nmax 3493, 2975, 2940, 2857, 1704, 1701, 1469, 1366,
In summary, we have developed a new approach to ketoacid
4, a common C1–C6 fragment for total synthesis of
1
1099, 970 cm21; H NMR (400 MHz, CDCl3) d 4.02 (m,
Scheme 5. (a) 0.1 equiv. pyrrolidine, CH2Cl2, rt, 3 h, 76% yield; (b) TBSCl, imidazole, DMF, rt, 72 h, 81%; (c) 0.03 equiv. RuCl3, 5.5 equiv. NaIO4, CCl4–
CH3CN–H2O 1:1:1.6, 1 h, 67%.

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Y. Zheng, M. A. Avery / Tetrahedron 60 (2004) 2091–2095
1H, CHOH), 3.46 (s, 1H, OH), 2.35–2.28 (m, 4H,
CHCH2CO, CH3CH2CO), 1.95 (s, 3H, CH3CO), 0.90,
0.87 (2s, 6H, C(CH3)2), 0.76 (t, J¼6.8 Hz, 3H, CH2CH3);
13C NMR (100 MHz, CDCl3) d 215.9, 209.0, 71.7, 51.0,
45.1, 31.0, 30.4, 20.8, 19.5, 7.5; ESIþ HRMS m/z 209.1108,
MþNaþ calcd for C10H18O3Na 209.1154.
hexanes) to give 10 as a colorless oil (8.1 g, 90%). Rf¼0.79
(silica gel, 25% ethyl acetate in hexane); [a]2D5¼247.5 (c
1.67, CHCl3); IR (thin film) nmax 2956, 2934, 2886, 2857,
1
1716, 1471, 1362, 1254, 1091, 1024, 837, 777 cm21; H
NMR (400 MHz, CDCl3) d 4.32–4.45 (m, 1H, SiOCHCH2),
2.52–2.25 (m, 4H, SiOCHCH2, CH2CH3), 1.99 (s, 3H,
COCH3), 0.94, 0.95 (2s, 6H, C(CH3)2), 0.84 (t, 3H,
J¼7.2 Hz, CH2CH3), 0.70 (s, 9H, SiC(CH3)3), 20.05,
20.18 (2s, 6H, Si(CH3)2); 13C NMR (100 MHz, CDCl3) d
215.1, 206.2, 71.9, 52.4, 48.2, 31.8, 30.7, 25.9, 21.4, 20.4,
18.0, 7.6, 23.6, 24.4; ESIþ HRMS m/z 323.2017, MþNaþ
calcd for C16H32O3NaSi 323.2018.
3.1.2. (2)-5S-3-Ethyl-4,4-dimethyl-5-hydroxycyclohex-
2-enone (9). To the solution of 8 (2.90 g, 15.6 mmol) in
dichloromethane (10 mL) at room temperature was added
pyrrolidine (0.11 g, 1.56 mmol). The solution was stirred at
room temperature for 3 h and then concentrated on the
rotary evaporator at room temperature. The residue was
purified by flash chromatography (silica gel, 40% ethyl
acetate in hexanes) to give the product 9 as a colorless oil
(1.16 g, 76% based on converted 8) along with recovered 8
(1.20 g or 41%). Rf¼0.32 (silica gel, 50% ethyl acetate in
hexane); [a]2D5¼217.8 (c¼0.70, CHCl3); IR (thin film) nmax
3430, 2971, 2938, 2881, 1666, 1647, 1610, 1468, 1417,
1362, 1283, 1047, 863 cm21; 1H NMR (400 MHz, CDCl3) d
5.61 (s, 1H, CHyC), 4.16 (s, 1H, OH), 3.70–3.60 (m, 1H,
CHOH), 2.47–2.29 (m, 2H, HOCHCH2), 2.10 (q, 2H,
J¼6.8 Hz, CH2CH3), 1.01, 0.96 (2s, 6H, C(CH3)2), 0.89 (t,
J¼6.8 Hz, 3H, CH2CH3); 13C NMR (100 MHz, CDCl3) d
198.4, 173.5, 122.8, 73.7, 42.4, 41.1, 24.7, 23.9, 20.3, 11.3;
ESIþ HRMS m/z 151.1104, M2H2OþHþ calcd for
C10H15O 151.1123.
3.1.5. 3-Ethyl-4,4-dimethylcyclohex-2,5-dienone (11) and
(1)-3S,5S,6S-3-(tert-butyldimethylsilyl)oxy-5-hydroxy-
2,2,5,6-tetramethylcyclohexanone (13). To the solution of
10 (0.30 g, 1 mmol) in THF (1 mL) at room temperature
was added pyrrolidine (0.071 g, 1 mmol). The solution was
stirred at room temperature for 72 h. Saturated aqueous
ammonium chloride was added and extracted with ethyl
acetate. The organic phase was dried, filtered and evapo-
rated under reduced pressure. The residue was purified by
flash chromatography (silica gel, 20% ethyl acetate in
hexanes) to give 13 (0.084 g, 56%) as a white solid and 11
(0.065 g, 23%) as colorless oil; 11. Rf¼0.52 (silica gel, 25%
ethyl acetate in hexane); IR (thin film) nmax 2971, 2936,
1
2879, 1666, 1625, 1603, 1486, 1294, 1138, 891 cm21; H
NMR (400 MHz, CDCl3) d 6.85, 6.12 (2d, J¼8 Hz, 2H,
CHyCH), 6.08 (s, 1H, CHyC), 2.28 (q, J¼6.2 Hz, 2H,
CH2CH3), 1.18 (s, 6H, C(CH3)2), 1.15 (t, J¼6.2 Hz, 3H,
CH2CH3); 13C NMR (100 MHz, CDCl3) d 187.0, 170.5,
158.4, 126.5, 124.3, 40.6, 26.1, 24.2, 12.1; ESIþ HRMS m/z
151.1122, MþHþ calcd for C10H15O 151.1123. 13. Rf¼0.53
(silica gel, 25% ethyl acetate in hexane); mp 93.2 8C;
[a]2D5¼þ132 (c 0.41, CHCl3); IR (thin film) nmax 3499,
2933, 2887, 2857, 1703, 1463, 1378, 1255, 1093, 1061,
3.1.3. (2)-5S-3-Ethyl-4,4-dimethyl-5-(tert-butyldi-
methylsilyl)oxycyclohex-2-enone (14). To a solution of
tert-butyldimethylsilylchloride (0.247 g, 1.65 mmol) at 0 8C
was added a solution of 9 (0.180 g, 1.07 mmol) and
imidazole (0.146 g, 2.14 mmol) in DMF (0.8 mL). The ice
bath was removed and the solution was stirred at room
temperature for 72 h until all of the starting material had
disappeared by TLC. The mixture was directly subjected
to flash chromatography to give 14 as a colorless oil
(0.255 mg, 81%). Rf¼0.88 (silica gel, 50% ethyl acetate in
hexane); [a]2D5¼27.7 (c¼0.58, CHCl3); IR (thin film) nmax
2957, 2931, 2884, 2857, 1673, 1614, 1471, 1256, 110, 1079,
837, 776 cm21; 1H NMR (400 MHz, CDCl3) d 5.62 (s, 1H,
CHyC), 3.65 (dd, 1H, J¼9.6, 4.4 Hz, 1H, CHOH), 2.39 (dd,
J¼16.4, 4.4 Hz, 1H, HOCHCH2), 2.08 (dd, J¼16.4, 9.6 Hz,
1H, HOCHCH2), 2.10 (q, 2H, J¼6.0 Hz, CH2CH3), 0.98,
0.0.93 (2s, 6H, C(CH3)2), 0.89 (t, J¼6.0 Hz, 3H, CH2CH3),
1030, 982, 867, 837, 775 cm21 1H NMR (400 MHz,
;
CDCl3) d 3.84 (dd, J¼9.6, 6.4 Hz, 1H, SiOCHCH2),
2.68 (q, J¼6.4 Hz, 1H, CHCH3), 1.92–1.99 (m, 2H,
SiOCHCH2), 1.65 (s, 1H, OH), 1.31, 1.08, 1.06 (3s, 9H,
CCH3, C(CH3)2), 1.02 (d, J¼6.4 Hz, 3H, CHCH3), 0.90
(s, 9H, SiC(CH3)3), 0.070, 0.041 (2s, 6H, Si(CH3)2); 13C
NMR (100 MHz, CDCl3) d 214.0, 73.0, 72.5, 51.0, 48.2,
44.7, 28.9, 25.8, 21.8, 19.3, 18.0, 7.4, 24.1, 25.0; ESIþ
HRMS m/z 323.2020, MþNaþ calcd for C16H32O3NaSi
323.2018.
0.70 (s, 9H, SiC(CH3)3), 20.11, 20.12 (2s, Si(CH3)2); 13
C
NMR (100 MHz, CDCl3) d 197.2, 172.2, 123.2, 74.7, 43.2,
41.7, 25.5, 24.8, 23.7, 20.5, 17.7, 11.6, 23.7, 24.4; ESIþ
HRMS m/z, 283.2106, MþHþ calcd for C16H31O2Si
283.2093.
3.1.6. (1)-5S-2,3,6,6-Tetramethyl-5-(tert-butyldimethyl-
silyl)oxy-cyclohex-2-enone (12). To the solution of 4
(0.30 g, 1 mmol) in ethanol (20 mL) and H2O (18 mL)
NaOH (0.16 g, 4 mmol in 2 mL of water) was added at 0 8C.
The reaction mixture was stirred at above temperature for
2 h and extracted with ethyl acetate. The organic phase was
dried, filtered and evaporated in reduced pressure. The
residue was purified by flash chromatography to give 12
(0.141 mg, 50%) and 11 (0.038 g, 25%) as colorless oil.
Rf¼0.61 (silica gel, 25% ethyl acetate in hexane);
[a]2D5¼þ57.8 (c 0.64, CHCl3); IR (thin film) nmax 2955,
2930, 2892, 2857, 1667, 1641, 1471, 1379, 1255, 1102,
3.1.4. (2)-4S-4-(tert-Butyldimethylsilyl)oxy-5,5-di-
methyl-2,6-octanedione (10). To the solution of 8
(5.58 g, 30 mmol) and N,N-diisopropylethylamine (6.19 g,
48 mmol) in dichloromethane (200 mL) at 278 8C was
slowly added tert-butyldimethylsilyl trifluoromethanesulfo-
nate (11.9 g, 45 mmol). The solution was slowly warmed to
room temperature and stirred for about 2 h until the starting
material disappeared. The reaction was quenched with
aqueous ammonium chloride and extracted with ethyl
acetate. The organic solution was dried over anhydrous
sodium sulfate and evaporated. The residue was purified by
flash chromatography (silica gel, 10% ethyl acetate in
1
1069, 873, 837, 775 cm21; H NMR (400 MHz, CDCl3) d
3.70–3.60 (m, 1H, SiOCHCH2), 2.30–2.40 (m, 2H,
SiOCHCH2), 1.83, 1.67, 1.05, 1.03 (4s, 12H, CH3CyCCH3,
C(CH3)2), 0.82 (s, 9H, SiC(CH3)3), 0.0029–0.020 (m, 6H,

Y. Zheng, M. A. Avery / Tetrahedron 60 (2004) 2091–2095
2095
Si(CH3)2); 13C NMR (100 MHz, CDCl3) d 203.3, 148.8,
129.4, 73.8, 47.2, 39.2, 25.9, 22.1, 21.4, 18.4, 18.1, 11.5,
24.1, 24.8; ESIþ HRMS m/z 151.1122, M2TBSOHþHþ
calcd for C10H15O 151.1123.
Angew. Chem., Int. Ed. Engl. 1997, 36, 525–527. (c) Nicolaou,
K. C.; Winssinger, N.; Pastor, J.; Ninkovic, S.; Sarabia, F.; He,
Y.; Vourloumis, D.; Yang, Z.; Li, T. Nature 1997, 387,
268–272. (d) Nicolaou, K. C.; He, Y.; Vourloumis, D.;
Vallberg, H.; Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang,
Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997, 119, 7960–7973.
(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. (f) Nicolaou, K. C.; Vourloumis,
D.; Li, T.; Pastor, J.; Winssinger, N.; He, Y.; Ninkovic, S.;
Sarabia, F.; Vallberg, H.; Roschangar, F.; King, N. P.; Finlay,
M. R. V.; Giannakakou, P.; Verdier-Pinard, P.; Hamel, E.
Angew. Chem., Int. Engl. 1997, 36, 2097–2103. (g) Nicolaou,
K. C.; Vallberg, H.; King, N. P.; Roschangar, F.; He, Y.;
Vourloumis, D.; Nicolaou, C. G. Chem. Eur. J. 1997, 3,
1957–1970.
3.1.7. (2)-3S-3-(tert-Butyldimethylsilyl)oxy-4,4-di-
methyl-5-oxo-heptanoic acid (4). Sodium periodate
(1.18 g, 5.5 mmol) was added into the solution of enone
14 (282 mg, 1.0 mmol) in CCl4 (1.8 mL) and CH3CN
(1.8 mL). Under vigorous magnetic stirring, RuCl3 (2.9 mL,
9.28 mM in distilled H2O, 0.027 mmol) was added and
stirring was continued for about 1 h until the starting
material had disappeared by TLC. Water was gradually
added until the separated NaIO3 dissolved and the mixture
was then extracted with ethyl acetate (3£5 mL). The
combined organic phase was dried over anhydrous
Na2SO4, filtered, and the solvent was then rotary evapo-
rated. The residue was subjected to flash chromatography
(silica gel, 50% ethyl acetate in hexanes) to give 4 (0.202 g,
3. Kalesse, M.; Quitschalle, M.; Claus, E.; Gerlach, K.; Pahl, A.;
Meyer, H. Eur. J. Org. Chem. 1999, 2817–2823.
4. Borzilleri, R. M.; Zheng, X.; Schmidt, R. J.; Johnson, J. A.;
Kim, S.-H.; DiMarco, J. D.; Fairchild, C. R.; Gougoutas, J. Z.;
Lee, F. Y. F.; Long, B. H.; Vite, G. D. J. Am. Chem. Soc. 2000,
122, 8890–8897.
1
67%) as a colorless oil. [a]2D5¼215.8 (c 4.7, CHCl3); H
NMR (400 MHz, CDCl3) d 10.51 (s, 1H, COOH), 4.45
(dd, 1H, J¼6.8, 3.6 Hz, SiOCH), 2.62–2.42 (m, 3H,
CH2CH23, CH2COOH), 2.34, 2.30 (dd, J¼6.8, 16 Hz,
SiOCHCH2), 1.12, 1.06 (2s, 6H, 2CH3), 0.98 (t, 3H,
J¼7.2 Hz, CH2CH23), 0.83 (s, 9H, SiC(CH3)3), 0.036,
0.017 (s, 6H, Si(CH3)2); 13C NMR (100 MHz, CDCl3) d
215.4, 178.5, 73.7, 52.7, 39.5, 31.9, 26.1, 21.1, 20.7, 18.3,
7.9, 24.2, 24.7.
5. (a) Hindupur, R. M.; Panicker, B.; Valluri, M.; Avery, M. A.
Tetrahedron Lett. 2001, 42, 7341–7344. (b) Valluri, M.;
Hindupur, R. M.; Bijoy, P.; Labadie, G.; Jung, J.-C.; Avery,
M. A. Org. Lett. 2001, 3, 3607–3609.
6. Liu, Z.-Y.; Chen, Z.-C.; Yu, C.-Z.; Wang, R.-F.; Zhang, R.-Z.;
Huang, C.-S.; Yan, Z.; Cao, D.-R.; Sun, J.-B.; Li, G. Chem.
Eur. J. 2002, 8, 3747–3756.
3.2. Synthesis of Mosher ester
7. Altmann, K.-H.; Bold, G.; Caravatti, G.; Denni, D.;
Florsheimer, A.; Schmidt, A.; Rihs, G.; Wartmann, M. Helv.
Chim. Acta 2002, 85, 4086–4110.
Into a flask 8 (37.2 mmg, 0.2 mmol), R-(þ)-a-methoxy-a-
trifluromethylphenylacetic acid (MPTA, 56.2 mg,
0.24 mmol), DCC (53.6 mg, 0.26 mmol), DMAP (6.1 mg,
0.05 mmol) and dichloromethane (5 mL) were added in
order. The mixture was stirred at room temperature for 24 h
and directly subjected to flash chromatography (silica gel,
40% ethyl acetate in hexanes) to give the Mosher ester
(22 mg, 30% for 8 and 45 mg, 56% for racemic 8).
8. Gabriel, T.; Wessjohann, L. Tetrahedron Lett. 1997, 38,
1363–1366.
9. Panicker, B.; Karle, J. M.; Avery, M. A. Tetrahedron 2000, 56,
7859–7868.
10. De Brabander, J.; Rosset, S.; Bernardinelli, G. Synlett 1997,
824–826.
11. Avery, M. A. WO 02/030356 A2, Synthesis of Epothilones
and Related Analogs, 18 April 2002.
12. Shioji, K.; Kawaoka, H.; Miura, A.; Okuma, K. Synth.
Commun. 2001, 31, 3569–3575.
Acknowledgements
13. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc.
2000, 122, 2395–2396.
We wish to thank NaPro Biotherapeutics, Inc. for financial
support of this research.
14. Inukai, T.; Yoshizawa, R. J. Org. Chem. 1967, 32, 404–407.
15. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94,
6190–6191.
References and notes
16. See Section 3.1.2: ‘…was purified by flash chromatography
(silica gel, 40% ethyl acetate in hexanes) to give the product 9
as a colorless oil (1.16 g, 76% based on converted 8) along
with recovered 8 (1.20 g or 41%)’.
¨
1. (a) Hofle, G.; Bedorf, N.; Gerth, K.; Reichenbach, H. (GBF)
DE-4138042, 1993; Chem. Abstr. 1993, 120, 52841. (b) Gerth,
¨
K.; Bedorf, N.; Hofle, G.; Irschik, K.; Reichenbach, H.
17. (a) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J. Org. Chem. 1981, 46, 3936–3938. (b) Webster, F. X.;
Rivas-Enterrios, J.; Silverstein, R. M. J. Org. Chem. 1987, 52,
689–691.
¨
J. Antibiot. 1996, 49, 560–563. (c) Hofle, G.; Bedorf, N.;
Steinmetz, H.; Schomburg, D.; Gerth, K.; Reichenbach, H.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1567–1569.
2. (a) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou,
K. C. Angew. Chem., Int. Ed. Engl. 1997, 36, 166–168.
(b) Nicolaou, K. C.; Sarabia, F.; Ninkovic, S.; Yang, Z.
18. Perrin, D. D.; Armarego, L. F.; Perrin, D. R. Purification of
laboratory chemicals; 2nd ed. Pergamon: New York, 1980.