The Meinwald reaction of alkyl propionates. Synthesis of the C1-C9 fragment of aurisides

Article abstract of DOI:10.1016/S0040-4020(03)01064-0

The C1-C9 northern fragment of aurisides 12a was prepared in eight steps and 41% overall yield starting from Grieco's bicyclic lactone (+)-4. The synthesis features a key stereoselective Meinwald reaction of the lithium enolate of alkyl propionate with the functionalized δ-lactone 3.

Full text of DOI:10.1016/S0040-4020(03)01064-0

Tetrahedron 59 (2003) 6531–6537
The Meinwald reaction of alkyl propionates. Synthesis of the
C1–C9 fragment of aurisides
*
´ ´ ´
Marıa-Yolanda Rıos, Francisco Velazquez and Horacio F. Olivo
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, IA 52242, USA
Received 27 May 2003; revised 30 June 2003; accepted 30 June 2003
Abstract—The C1–C9 northern fragment of aurisides 12a was prepared in eight steps and 41% overall yield starting from Grieco’s bicyclic
lactone (þ)-4. The synthesis features a key stereoselective Meinwald reaction of the lithium enolate of alkyl propionate with the
functionalized d-lactone 3.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
amounts isolated of these marine macrolides, their unique
structure, and their interesting biological activity, we are
engaged in a program toward their syntheses.4,5
Two marine natural products, aurisides A and B, were
isolated in minute amounts from the Japanese sea hare
Dolabella auricularia by Yamada and Kigoshi in 1996.1
These halogenated macrolides showed potent cytotoxicity
against HeLa S3 cell lines and large structural similarities to
the macrolides isolated from the marine sponge Callipelta
sp., callipeltosides A, B, and C.2 Both aurisides and
callipeltosides possess a rhamnose-derived glycoside
attached to C5 of a 14-membered macrolactone. The
macrocycle rings are bridged through a 6-membered
hemiketal and possess a halogenated and unsaturated side-
chain attached to C13. Yamada reported the first synthesis
of the auriside aglycone in 1998.3 Because of the small
In our synthetic strategy toward these marine macrolides,
we proposed a general and highly convergent approach with
main disconnections that provide two key intermediates as
illustrated in Figure 1. We envision coupling of the northern
fragment 1 with the southern fragment 2 via a chemo-
selective halogen–metal exchange of the vinylic iodide in 2
followed by condensation with the aldehyde moiety of
fragment 1. Further macrolactonization and allylic oxi-
dation of the newly formed hydroxyl group should provide
the auriside aglycone. We recently reported the stereo-
selective synthesis of the C10–C17 southern fragment 2
Figure 1. Retrosynthesis of the auriside aglycon.
Keywords: Meinwald reaction; alkyl propionates; aurisides.
*
Corresponding author. Tel.: þ1-319-335-8849; fax: þ1-319-335-8766; e-mail: horacio-olivo@uiowa.edu
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01064-0

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6532
featuring a highly diastereoselective aldol condensation
using a chiral N-acetyl 1,3-thiazolidine-2-thione.5 In this
article, we report the synthesis of the C1–C9 fragment of
aurisides.
We began the synthesis of d-lactone 3 starting from bicyclic
lactone (þ)-4, Fig. 2. Double methylation of bicyclic
lactone 4 was accomplished in one flask in excellent yield.
Stereoselective installation of the C5-hydroxyl group11 was
accomplished by oxymercuration–demercuration of lactone
5 delivering the endo-alcohol 6 in good yield. The
o-bromobenzoate derivative 7 was prepared to confirm the
structural assignments by X-ray single crystal analysis.12
Protection of the hydroxyl group in 6 as the corresponding
silylether followed by reduction with lithium aluminum
hydride delivered diol 9. Selective protection of the primary
alcohol as the TBS ether gave cyclopentanol 10. Cyclo-
pentanol 10 was oxidized to cyclopentanone 11 using Ley’s
protocol in excellent yield.13 Cyclopentanone 11 was
subjected to Baeyer–Villiger oxidation to afford d-lactone
3.
Having d-lactone 3 in hand, we investigated the Meinwald
reaction using lithium enolates derived from alkyl propio-
nates to form b-hemiketal esters, see Table 1. We observed
that when LHMDS was used to generate the lithium
enolates of alkyl propionates, only Claisen autocondensa-
tion products were isolated, and d-lactone 3 was recovered
unreacted.14 However, when LDA was used to generate the
corresponding enolates, and further addition to d-lactone 3,
the desired b-hemiketal esters were obtained in good yields.
Addition of the enolates occurred on the less hindered
alpha-face of the d-lactones giving initially the beta-
hydroxy products. These intermediates tautomerized to the
more stable anomeric hemiketals during the aqueous work-
up.15 The two epimeric products at C2 12 and 13 were
separated by column chromatography. We observed that the
ratio of epimers on C2 changed during silica gel
chromatography purification.16 NOE experiments of the
epimeric products to determine the configuration of C2 were
not conclusive because of the free rotation of the propionate
unit. Efforts to obtain crystals of compounds 12, 13 and
other derivatives were not successful. In contrast, a
2. Discussion and results
Grieco’s bicyclic lactone 4 is a valuable starting material for
constructing functionalized d-lactones.6 We utilized
bicyclic lactone 4 to efficiently construct the C1–C9
fragment of callipeltosides.4a Bicyclic lactone 4 can also
be easily functionalized to provide d-lactone 3 valuable for
the synthesis of the northern fragment of aurisides. The
Meinwald reaction, addition of the lithium enolate of ethyl
acetate to a d-lactone to give b-kemiketal esters,7 has been
employed in the synthesis of soraphen-A,8 aplasmomycin-
A,9 elfemycins,10 and by our group in the C1–C9 fragment
of callipeltosides.4a For the synthesis of the C1–C9
fragment of aurisides, we envisioned a Meinwald reaction
using a lithium enolate derived from an appropriate alkyl
propionate to achieve stereocontrol in the formation of the
C2 stereogenic center.
Figure 2. Preparation of d-lactone 3.

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6533
Table 1. The Meinwald reaction of d-Lactones 3 and 14 with alkyl propionates
Entry
Lactone
R
Products
Diasterom. ratio
Yield (%)
1
2
3
4
5
3
3
3
14
14
Ethyl
12a:13a
12b:13b
12c:13c
15a:16a
15b:16b
4.4:1
3.3:1
1:2.3
5.4:1
4:1
85
82
99
65
90
Benzyl
t-butyl
Ethyl
Benzyl
product that would be amenable for X-ray crystallographic
analysis. Indeed, we were delighted to observe that a major
crystalline product (15a) with the desired 2S configuration
was formed as the major product in the addition of the ethyl
propionate enolate to d-lactone 14 (Fig. 3). Addition of the
enolate of ethyl propionate to d-lactone 3 gave hemiketal
12a as the major product. Interestingly, we observed that
addition of the enolate of tert-butyl propionate to d-lactone
3 gave the C2 epimeric product 13c preferentially.16
We noted that the H4 chemical shifts of the Meinwald
products were valuable to assign the configuration at C2
(see Table 2).17 The H4 equatorial hydrogen signal appeared
down field in hemiketals with the 2S configuration (products
12 and 15). Also, the difference in chemical shifts between
the two H4 proton signals was larger for the (S)-C2 epimer
(Dd,1.0 ppm) compared to the ones with the 2R configur-
ation (Dd,0.5 ppm). Configuration of C2’s were assigned
to Meinwald products based on these observations.
3. Conclusions
In summary, we have efficiently prepared the C1–C9
fragment of aurisides from bicyclic lactone 4 in eight
steps and more than 40% overall yield. Addition of the
lithium enolate of ethyl propionate to d-lactone 3 gave the
b-hemiketal ester product with the functionality and
stereochemistry required for the synthesis of aurisides.
Efforts to couple the C1–C9 fragment with the C10–C17
Figure 3. The X-ray crystal structure of 15a.
crystalline product was formed in the Meinwald reaction in
our synthesis of the C1–C9 fragment of callipeltosides.4a
Thus, we expected that a Meinwald reaction of d-lactone 14,
a key intermediate in our synthesis of callipeltosides, with
the enolate of an alkyl propionate would deliver a hemiketal
Table 2. Comparison of 1H NMR d at C4 of Meinwald products
Auriside-A
12a
13a
15a
16a
H-4a
H-4b
1.03 td (J¼11.7, 4.4)
2.33 dd (J¼11.7, 4.4)
1.23 ddd (J¼12.2, 11.0, 2.7)
2.33 ddd (J¼12.0, 4.7, 1.5)
1.47 ddd (J¼12.0, 10.7, 2.6)
1.88 ddd (J¼12.5, 4.7, 1.7)
1.16 m
2.40 dd (J¼12.3, 4.6)
1.57 m
2.17 dd (J¼12.0, 4.4)

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6534
fragment are currently undergoing in our laboratory and the
synthesis of the auriside aglycon will be reported in due
course.
was stirred at 08C for 1 h. A solution of NaOH (5 ml) was
added dropwise and the reaction mixture was stirred at rt for
30 min. The reaction mixture was cooled at 08C and then
NaBH4 was added in small portions (the temperature should
not above 08C). The reaction was stirred at 08C for 30 min.
1N HCl was added dropwise until pH 2 and then the reaction
was stirred at 08C for 30 min. The reaction mixture was
saturated with NaCl. The organic phase was separated and
the aqueous phase was extracted with AcOEt (3£30 ml).
The aqueous phase was concentrated in rotary evaporator
and extracted with AcOEt (3£15 ml). Combined organic
phases were dried over Na2SO4 and filtered. Solvent was
removed under vacuum to give an oil that was purified by
FCC: 2.18 g (85% yield). Colorless oil, TLC: Rf 0.3
(EtOAc–hexanes 7:3); [a]D¼þ61.1 (c 1.0, CHCl3); IR:
3447, 2971, 2935, 2863, 1752, 1455, 1383, 1342, 1198,
1081, 979 cm21; 1H NMR (CDCl3, 360 MHz): d 4.96 (1H,
ddd, J¼6.4, 5.2, 2.4 Hz), 4.37 (1H, q, J¼4.8 Hz), 2.55 (1H,
dt, J¼8.8, 6.4 Hz), 2.10 (2H, m), 1.87 (2H, m, H-6), 1.31
(3H, s), 1.25 (3H, s); 13C NMR (CDCl3, 90 MHz): d 182.6
(C), 81.6 (CH), 72.7 (CH), 49.5 (CH), 43.3 (C), 41.2 (CH2),
36.2 (CH2), 27.8 (CH3), 20.6 (CH3).
4. Experimental
4.1. General procedures
1H and 13C NMR spectra were recorded using Bruker
AVANCE-300, WM-360 or AMX-400 spectrometers.
Carbon multiplicities were determined using DEPT exper-
iments. IR spectra were recorded using a Nicolet 210
spectrometer. Melting points were obtained in a Thomas
Hoover melting point apparatus. Melting points reported
here are uncorrected. Analytical TLC was performed using
pre-coated silica gel 60 F254 Merck plates. Optical rotations
were obtained using a Jasco P-1020 polarimeter.
4.1.1. (1S,5R)-4,4-Dimethyl-2-oxabicyclo[3.3.0]oct-6-en-
3-one (5). LHMDS (1.0 M soln. in THF, 2.2 equiv.,
33.48 mmol, 33.5 ml) was added by syringe over a period
of 20 min to a well stirred solution of lactone 4
(15.22 mmol, 1.88 g) dissolved in dry THF and maintained
at 2788C. After the addition was completed the reaction
was stirred for further 90 min. Iodomethane (2.6 equiv.,
39.57 mmol, 2.6 ml) was added by syringe over a period of
5 min to the enolate solution held at 2608C. Reaction was
stirred at 2608C for 30 min and then at 08C for 30 min. The
reaction mixture was cooled to 2788C. LHMDS (soln.
1.0 M in THF, 1.1 equiv., 16.74 mmol, 16.75 ml) was
added. After the addition was completed reaction was
stirred for further 90 min. Methyliodide (1.3 equiv.,
19.8 mmol, 1.3 ml) was added by syringe over a period of
5 min to the enolate solution held at 2608C. Reaction was
stirred at 2608C for 30 min and then at 08C for 30 min. The
reaction mixture was diluted with diethyl ether (100 ml) and
treated with sat. soln. NH4Cl (60 ml). The organic phase
was separated and the aqueous layer was extracted with
diethyl ether (2£60 ml). Combined organic layers were
washed with brine (2£40 ml) and with water (2£40 ml) and
dried over Na2SO4. Solvent was removed under vacuum.
The residue was purified by FCC and product was obtained
as a yellow oil: 2.34 g (95% yield), TLC: Rf 0.3 (EtOAc–
hexanes 1:4); [a]D¼þ61.7 (c 1.0, CHCl3); IR: 2973, 2873,
1768, 1469, 1387, 1299, 1202, 1050, 1012 cm21; 1H NMR
(CDCl3, 360 MHz): d 5.81 (1H, dd, J¼5.6, 2.3 Hz), 5.63
(1H, ddd, J¼5.9, 4.2, 2.3 Hz), 5.06 (1H, ddd, J¼5.9, 5.6,
3.5 Hz), 3.18 (1H, ddd, J¼5.8, 3.7, 2.0 Hz), 2.68 (2H, bs),
1.36 (3H, s), 1.22 (3H, s); 13C NMR (CDCl3, 90 MHz): d
181.7 (C), 130.4 (CH), 128.6 (CH), 79.6 (CH), b (CH), 42.5
(C), 39.6 (CH2), 26.9 (CH3), 21.3 (CH3).
4.1.3. 4,4-Dimethyl-7-(20-bromobenzoyl)-2-oxabicyclo-
[3.3.0]octan-3-one (7). To a well stirred solution of the
alcohol 6 (0.2 mmol, 33.7 mg) in CH2Cl2 (5 ml) was added
DMAP (cat.), 2-bromobenzoyl chloride (1.5 equiv.,
0.3 mmol, 65 mg) and Et3N (3.0 equiv., 0.3 mmol,
0.1 ml). The reaction mixture was stirred at rt for 2.5 h.
Brine solution (5 ml) was added to the reaction mixture and
the organic phase was separated. The aqueous phase was
extracted with CH2Cl2 (3£10 ml). Combined organic layers
were dried over Na2SO4, filtered and concentrated. The
residue was purified by FCC: 63.7 mg (91% yield). White
1
crystals, TLC: Rf 0.33 (EtOAc–hexanes, 3:7); H NMR
(CDCl3, 360 MHz): d 7.78 (1H, dd, J¼7.5, 1.5 Hz), 7.65
(1H, d, J¼7.5 Hz), 7.41–7.20 (2H, m), 5.44 (1H, ddd,
J¼9.6, 5.5, 4.1 Hz), 5.02 (1H, dd, J¼5.5, 5.5 Hz), 2.66 (1H,
ddd, J¼9.3, 6.5, 6.2 Hz), 2.37 (2H, m), 2.22 (1H, m), 2.05
(1H, m), 1.34 (3H, s), 1.22 (3H, s); 13C NMR (CDCl3,
90 MHz): d 181.6 (C), 165.6 (C), 134.5 (CH), 133.0 (CH),
131.7 (CH), 127.5 (CH), 127.3 (C), 122.0 (C), 81.2 (CH),
76.7 (CH), 49.8 (CH), 43.4 (CH2), 38.8 (CH2), 33.6 (CH2),
27.7 (CH3), 20.8 (CH3). HRMS Calcd For C16H18BrO4:
353.0395. Found: 353.0388.
4.1.4. 4,4-Dimethyl-7-(triisopropylsilyloxy)-2-oxabi-
cyclo[3.3.0]octan-3-one (8). Anhydrous CH2Cl2 (60 ml)
was placed under N2 atmosphere and cooled to 2508C.
TIPSOTf (1.5 equiv., 35.3 mmol, 9.5 ml) and 2,6-lutidine
(1.5 equiv., 35.3 mmol, 4.2 ml) were added dropwise.
Alcohol 7 (1.0 equiv., 23.5 mmol, 3.0 g) in anhydrous
CH2Cl2 (20 ml) was added to the solution and the reaction
was stirred at 2508C for 1 h. The reaction was treated with
sat. NaHCO3 soln. (50 ml). Organic layer was separated and
the aqueous phase was extracted with CH2Cl2 (3£30 ml).
Combined organic layers were dried over Na2SO4, filtered
and concentrated. The residue was purified by FCC: 5.4 g
(94% yield). Colorless oil, TLC: Rf 0.3 (EtOAc–hexanes
15:85); [a]D¼þ35.2 (c 1.0, CHCl3); IR: 2935, 2863, 1767,
1460, 1383, 1116, 1081, 1009, 881 cm21; 1H NMR (CDCl3,
360 MHz): d 4.81 (1H, ddd, J¼6.8, 6.3, 2.0 Hz), 4.29 (1H,
q, J¼5.6 Hz), 2.40 (1H, dt, J¼8.2, 6.8 Hz), 2.14 (1H, dt,
4.1.2. 4,4-Dimethyl-7-hydroxy-2-oxabicyclo[3.3.0]octan-
3-one (6). To a well stirred solution of mercuric diacetate
(1.5 equiv., 22.7 mmol, 7.23 g) in THF/H2O (2.5:1, 105 ml)
cooled to 08C (the solution acquired a yellow color and
some perchloric acid was added dropwise until a colorless
solution was obtained) was added a solution of lactone 11
(15.13 mmol, 2.3 g) in THF (7 ml). The reaction mixture
was stirred at 08C for 1 h. A solution of mercuric diacetate
(0.5 equiv., 7.5 mmol, 2.4 g) in THF/H2O (2.5:1, 35 ml) and
perchloric acid were added dropwise. The reaction mixture

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6535
J¼14.5, 6.9 Hz), 1.96 (1H, m), 1.84 (1H, m), 1.67 (1H, dt,
J¼14.0, 7.3 Hz), 1.21 (3H, s), 1.16 (3H, s); 0.98 (18H, s),
0.94 (3H, m); 13C NMR (CDCl3, 90 MHz): d 181.7 (C), 80.9
(CH), 73.6 (CH), 49.4 (CH), 43.1 (C), 41.8 (CH2), 37.2
(CH2), 27.5 (CH3), 20.8 (CH3), 18.1 (6CH3), 12.2 (3CH).
HRMS Calcd for C18H35O3Si: 327.2355. Found: 327.2329.
40.86 mg) were added and the reaction mixture was stirred
at rt for 24 h. Reaction mixture was filtered through celite
and concentrated. The residue was purified by FCC:
508.2 mg (99% yield). Colorless oil, TLC: Rf 0.3
(EtOAc–hexanes 5:95); [a]D¼þ89.9 (c 1.0, CHCl3); IR:
2945, 2863, 1742, 1470, 1358, 1250, 1112, 840, 774,
1
687 cm21; H NMR (CDCl3, 300 MHz): d 4.31 (1H, m),
4.1.5. 2-(20-Hydroxy-10,10-dimethyl)-ethyl-4-triisopropyl-
silyloxy-cyclopentanol (9). To a well stirred solution of
lactone 8 (1.0 equiv., 7.41 mmol, 2.417 g) dissolved in
anhydrous THF (30 ml) and cooled to 2208C was added
LiAlH4 (1.0 equiv., 7.41 mmol, 281 mg) in small portions.
The reaction mixture was stirred at 2208C for 30 min.
MeOH (6 ml) was added to the reaction mixture and sat. sol.
of Na2SO4 (10 ml) was also added. Reaction mixture was
refluxed for 15 min and filtered through a bed of celite.
Organic phase was concentrated under vacuum to give an
oil that was purified by FCC: 2.08 g (86% yield). Colorless
oil, TLC: Rf 0.3 (EtOAc–hexanes, 15:85); [a]D¼26.1 (c
1.0, CHCl3); IR: 3273, 2945, 2868, 1465, 1362, 1112, 1009,
3.43 (1H, d, J¼9.8 Hz), 3.31 (1H, d, J¼9.8 Hz), 2.56 (1H,
dd, J¼17.6, 7.0 Hz), 2.29 (1H, m), 2.22 (1H, m), 2.17 (1H,
m), 1.76 (1H, m), 1.04 (18H, s), 1.03 (3H, s), 0.98 (3H, s),
0.86 (9H, s), 0.85 (3H, s), 0.00 (6H, s); 13C NMR (CDCl3,
75 MHz): d 216.8 (C), 70.7 (CH2), 68.0 (CH), 54.3 (CH2),
50.6 (CH), 37.7 (C), 36.1 (CH2), 26.1 (3CH3), 22.7 (CH3),
22.2 (CH3), 18.4 (6CH3), 18.1 (C), 12.3 (3CH), 25.4 (CH3),
25.4 (CH3). HRMS Calcd For C24H51O3Si2: 443.3377.
Found: 443.3377.
4.1.8. 6-[20-(tert-Butyldimethylsilanyloxy)-10,10-dimethyl-
ethyl]-4-triisopropylsilanyloxy-tetrahydropyran-2-one
(3). Ketone 11 was dissolved in freshly distilled CH2Cl2
(10 ml). mCPBA (2.0 equiv., 2.33 mmol, 272.5 mg) and
NaHCO3 (2.0 equiv., 2.33 mmol, 272.5 mg) were added in
small portions. The reaction was stirred at rt for 24 h. The
reaction mixture was treated with sat. sol. NaHCO3. The
organic phase was separated and the aqueous phase was
extracted with CH2Cl2 (3£20 ml). Combined organic layers
were dried over Na2SO4, filtered and concentrated. The
residue was purified by FCC: 395.8 mg (75% yield).
Colorless oil, TLC: Rf 0.3 (EtOAc–hexanes 5:95);
[a]D¼23.3 (c 1.0, CHCl3); IR: 2955, 2868, 1736, 1475,
1465, 1244, 1091, 835, 773 cm21 1H NMR (CDCl3,
;
36000MHz): d 4.19 (1H, dddd, J¼9.2, 8.3, 6.0, 5.5 Hz,
H-4 ), 4.11 (1H, dd, J¼12.1, 2.9 Hz, H-600), 3.44 (1H, d,
J¼9.8 Hz), 3.33 (1H, d, J¼9.8 Hz), 2.83 (1H, ddd, J¼17.1,
6.0, 1.5 Hz), 2.41 (1H, dd, J¼17.1, 8.1 Hz), 2.13 (1H, dddd,
J¼13.5, 5.5, 3.0, 1.5 Hz), 1.60 (1H, ddd, J¼13.5, 12.1,
9.2 Hz), 1.02 (18H, s), 1.02 (3H, s), 0.93 (3H, s), 0.85 (9H,
s), 0.84 (3H, s), 0.01 (6H, s); 13C NMR (CDCl3, 75 MHz): d
171.9 (C), 80.3 (CH), 68.8 (CH2), 65.0 (CH), 40.4 (CH2),
38.9 (CH2), 33.6 (C), 25.8 (3CH3), 19.9 (CH3), 18.1 (CH3),
17.9 (6CH3), 17.7 (C), 12.1 (3CH), 25.7 (2CH3). HRMS
Calcd for C24H51O4Si2: 459.3326. Found: 459.3323.
1
876 cm21; H NMR (CDCl3, 360 MHz): d 4.48 (1H, bt,
J¼5.8 Hz), 4.20 (1H, bd, J¼3.3 Hz), 3.63 (1H, d,
J¼11.6 Hz), 3.12 (1H, d, J¼11.6 Hz), 2.10 (1H, m), 1.89
(1H, m), 1.80 (1H, m), 1.73 (1H, m), 1.61 (1H, m), 1.21 (3H,
s), 1.10 (3H, s,), 1.07 (18H, s), 1.02 (3H, m); 13C NMR
(CDCl3, 75 MHz): d 74.0 (CH), 73.7 (CH), 68.0 (CH2), 54.5
(CH), 44.6 (CH2), 36.7 (C), 35.1 (CH2), 26.8 (CH3), 24.8
(CH3), 17.9 (6CH3), 11.8 (3CH). HRMS Calcd for
C18H39O3Si: 331.2668. Found: 331.2680.
4.1.6. 2-[20-(tert-Butyldimethylsilyloxy)-10,10-dimethyl-
ethyl]-4-triisopropylsilyloxy-cyclopentanol (10). To a
well stirred solution of diol 9 (1.0 equiv., 1.17 mmol,
386.2 mg) in anhydrous CH2Cl2 (6 ml) at rt was added
TBSCl (1.2 equiv., 1.4 mmol, 210 mg) and DMAP
(0.2 equiv., 0.233 mmol, 27.6 mg). The reaction mixture
was stirred and Et3N (3.0 equiv., 3.51 mmol, 0.26 ml) was
added dropwise. The reaction mixture was stirred at rt for
1 h. The reaction mixture was diluted with CH2Cl2 (20 ml)
and treated with sat. NaHCO3 soln. (10 ml). The organic
phase was separated and the aqueous phase was extracted
with CH2Cl2 (3£15 ml). Combined organic layers were
dried over Na2SO4, filtered and concentrated. The residue
was purified by FCC: 517 mg (99% yield). Colorless oil,
TLC: Rf 0.3 (EtOAc–hexanes 5:95); [a]D¼212.4 (c 1.0,
CHCl3); IR: 3518, 2950, 2868, 1465, 1357, 1091, 1004,
4.2. General procedure for the Meinwald addition of
lithium enolates of alkyl propionates to d-lactones
1
835 cm21; H NMR (CDCl3, 300 MHz): d 4.40 (1H, m),
n-BuLi (0.869 mmol sol. 1.19 M, 0.73 ml) was added to a
solution of diisopropylamine (0.910 mmol, 92.1 mg,
0.127 ml) in anhydrous THF (3 ml) at 08C. The mixture
was stirred at 08C for 20 min and then cooled to 2788C.
Alkyl propionate (2.0 equiv., 0.828 mmol) in THF (1 ml)
was added over a period of 15 min. (syringe pump). The
mixture was kept at 2788C and stirred for 30 min.
followed by addition of d-lactone (0.474 mmol) dissolved
in THF (2 ml) over a period of 10 min. (syringe pump).
The reaction mixture was stirred at 2788C for 1 h.
Reaction was quenched at 2788C by addition of sat.
NH4Cl soln. (7 ml). The mixture was diluted with water
(7 ml) and Et2O (30 ml). Layers were separated and the
aqueous layer was extracted with Et2O (3£20 ml).
Combined organic layers were dried over Na2SO4, filtered
and concentrated. The residue was purified by FCC on
silica gel.
4.16 (1H, m), 3.43 (1H, d, J¼9.6 Hz), 3.28 (1H, d,
J¼9.6 Hz), 1.95 (1H, m), 1.81 (1H, m), 1.75 (1H, m),
1.62 (1H, ddd, J¼11.0, 8.8, 3.8 Hz), 1.38 (1H, m), 1.04
(18H, s), 1.03 (3H, s, CH), 0.98 (3H, s), 0.94 (3H, s), 0.87
(9H, s), 0.02 (6H, s); 13C NMR (CDCl3, 75 MHz): d 74.7
(CH), 74.0 (CH), 71.6 (CH2), 51.4 (CH2), 44.8 (CH2), 37.0
(C), 35.3 (CH2), 26.1 (3CH3), 24.2 (CH3), 23.9 (CH3), 18.5
(C), 18.2 (6CH3), 12.1 (3CH), 25.4 (CH3), 24.2 (CH3).
HRMS Calcd for C24H53O3Si2: 445.3533. Found: 445.3539.
4.1.7. 2-[20-(tert-Butyldimethylsilanyloxy)-10,10-dimethyl-
ethyl]-4-triisopropylsilanyloxy-ciclopentanone
(11).
Alcohol 10 (1.0 equiv., 1.16 mmol, 517 mg) was dissolved
in anhydrous CH2Cl2 (6 ml). Molecular sieves were added
and the solution was stirred at rt. NMO (2.0 equiv.,
2.33 mmol, 272.5 mg) and TPAP (0.1 equiv., 0.116 mmol,

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M.-Y. Rıos et al. / Tetrahedron 59 (2003) 6531–6537
6536
4.2.1. 2S-Methyl-2-[60R-[(100,100-dimethyl-200-tert-butyl-
dimethylsilyloxy)-eth-10-yl]-40R-triisopropylsilyloxy-20S-
hydroxy-tetrahydropyran-20-yl]-propionic acid ethyl
ester (12a). Colorless oil, TLC: Rf 0.35 (EtOAc–hexanes
5:95); [a]D¼29.2 (c 1.0, CHCl3); IR: 3472, 2950, 2889,
(3CH3), 20.8 (C), 20.7 (C), 18.4 (6CH3), 18.3 (C), 13.0 (C),
12.5 (CH), 25.3 (CH3), 25.4 (CH3).
4.2.4. 2R-Methyl-2-[60R-[(100,100-dimethyl-200-tert-butyl-
dimethylsilyloxy)-eth-10-yl]-40R-triisopropylsilyloxy-20S-
hydroxy-tetrahydropyran-20-yl]-propionic acid ethyl
ester (13a). Colorless oil, TLC: Rf 0.38 (EtOAc-hexanes
5:95); [a]D¼221.6 (c 1.0, CHCl3); IR: 3534, 3447, 2945,
2894, 2863, 1736, 1705, 1465, 1388, 1255, 1091, 855, 830,
2858, 1711, 1465, 1378, 1250, 1091, 855, 830, 768 cm21
;
1H NMR (CDCl3, 400 MHz): d 4.24 (1H, d, J¼2.5 Hz), 4.12
(2H, q, J¼7.1 Hz), 4.12 (1H, m), 3.70 (1H, dd, J¼12.0,
1.7 Hz), 3.27 (1H, d, J¼9.4 Hz), 3.22 (1H, d, J¼9.4 Hz),
2.57 (1H, q, J¼7.3 Hz), 2.09 (1H, ddd, J¼12.0, 4.7, 1.5 Hz),
1.85 (1H, ddd, J¼12.0, 4.7, 2.3 Hz), 1.25 (3H, t, J¼7.0 Hz),
1.21 (1H, m), 1.18 (3H, d, J¼7.3 Hz), 1.07 (1H, m), 1.04
(18H, s), 1.03 (3H, m), 0.86 (9H, s), 0.79 (3H, s), 0.75 (3H,
s), 20.013 (3H, s), 20.021 (3H, s); 1H NMR (C6D6,
360 MHz): d 4.84 (1H, d, J¼2.6 Hz), 4.48 (1H, m), 4.15
(1H, dd, J¼12.0, 1.7 Hz), 4.11 (1H, dq, J¼10.6, 7.1 Hz),
3.95 (1H, dq, J¼10.6, 7.1 Hz), 3.48 (1H, d, J¼9.2 Hz), 3.44
(1H, d, J¼9.2 Hz), 2.65 (1H, q, J¼7.2 Hz), 2.38 (1H, ddd,
J¼12.1, 4.6, 1.4 Hz), 2.16 (1H, ddd, J¼12.1, 4.4, 1.6 Hz),
1.57 (1H, ddd, J¼12.1, 12.2, 11.0 Hz), 1.23 (1H, ddd,
J¼12.2, 11.0, 2.7 Hz), 1.19 (3H, m), 1.17 (18H, s), 1.15
(3H, d, J¼7.3 Hz), 1.04 (3H, s), 1.02 (9H, s), 1.00 (3H, t,
J¼7.2 Hz), 0.98 (3H, s), 0.13 (3H, s), 0.11 (3H, s); 13C
NMR (CDCl3, 100 MHz): d 176.8 (C), 98.5 (C), 72.4 (CH),
69.4 (CH2), 66.5 (CH), 60.7 (CH2), 48.7 (CH), 42.1 (CH2),
38.6 (C), 35.8 (CH2), 26.1 (3CH3), 20.7 (CH3), 20.5 (CH3),
18.4 (6CH3), 18.3 (C), 14.4 (CH3), 12.7 (CH3), 12.5 (3CH),
25.4 (CH3), 25.5 (CH3).
1
773 cm21; H NMR (CDCl3, 400 MHz): d 4.26 (1H, d,
J¼2.6 Hz), 4.19 (H, m), 4.14 (2H, q, J¼7.0 Hz), 3.71 (1H,
dd, J¼12.0, 1.7 Hz), 3.30 (1H, d, J¼9.4 Hz), 3.25 (1H, d,
J¼9.4 Hz), 2.60 (1H, q, J¼7.3 Hz), 1.88 (1H, ddd, J¼12.5,
4.7, 1.7 Hz), 1.84 (1H, ddd, J¼12.5, 4.3, 1.7 Hz), 1.47 (1H,
ddd, J¼12.0, 10.7, 2.6 Hz), 1.25 (3H, t, J¼7.0 Hz), 1.20
(3H, d, J¼7.3 Hz), 1.19 (1H, m), 1.04 (18H, s), 1.03 (3H,
m), 0.86 (9H, s), 0.80 (3H, s), 0.75 (3H, s), 20.014 (3H, s),
1
20.017 (3H, s); HNMR (C6D6, 360 MHz): d 4.80 (1H, d,
J¼2.4 Hz), 4.58 (H, m), 4.10 (1H, dd, J¼12.3, 1.7 Hz), 3.95
(1H, dq, J¼10.3, 7.0 Hz), 3.94 (1H, dq, J¼10.3, 7.0 Hz), 3.44
(4H, s), 2.51 (1H, q, J¼7.2 Hz), 2.17 (1H, ddd, J¼12.2, 4.6,
1.4 Hz), 2.13 (1H, ddd, J¼11.0, 4.0, 1.6 Hz), 1.73 (1H, ddd,
J¼12.2, 11.0, 2.4 Hz), 1.51 (1H, ddd, J¼12.0, 12.0, 11.0 Hz),
1.20 (3H, m), 1.18 (18H, s), 1.16 (3H, d, J¼7.3 Hz), 1.02 (3H,
s), 1.09 (9H, s), 0.96 (3H, t, J¼7.2 Hz), 0.10 (3H, s), 0.04 (3H,
s); 13C NMR (CDCl3, 100 MHz): d 174.4 (C), 98.3 (C), 72.5
(CH), 69.4 (CH2), 66.5 (CH), 61.0 (CH2), 49.5 (CH), 41.6
(CH2), 38.8 (C), 35.6 (CH2), 26.1 (3CH3), 20.6 (CH3), 20.5
(CH3), 18.4 (6CH3), 18.3 (C), 14.4 (CH3), 12.5 (3CH), 11.9
(CH3), 25.4 (CH3), 25.4 (CH3).
4.2.2. 2S-Methyl-2-[60R-[(100,100-dimethyl-200-tert-butyl-
dimethylsilyloxy)-eth-10-yl]-40R-triisopropylsilyloxy-20S-
hydroxy-tetrahydropyran-20-yl]-propionic acid benzyl
4.2.5. 2R-Methyl-2-[60R-[(100,100-dimethyl-200-tert-butyl-
dimethylsilyloxy)-eth-10-yl]-40R-triisopropylsilyloxy-20S-
hydroxy-tetrahydropyran-20-yl]-propionic acid tert-
butyl ester (13c). Colorless oil, TLC: Rf 0.38 (EtOAc–
hexanes 5:95); [a]D¼221.6 (c 1.0, CHCl3); IR: 3426, 2950,
2888, 2863, 1731, 1705, 1460, 1388, 1362, 1250, 1163, 1091,
845, 773 cm21; 1H NMR (CDCl3, 360 MHz): d 4.41 (1H, d,
J¼2.2 Hz), 4.16 (1H, m), 3.72 (1H, dd, J¼12.0, 1.9 Hz), 3.34
(1H, d, J¼9.3 Hz), 3.27 (1H, d, J¼9.3 Hz), 2.51 (1H, q,
J¼7.2 Hz), 1.84 (1H, dd, J¼12.2, 4.8 Hz), 1.82 (1H, m), 1.44
(9H, s), 1.23 (1H, m), 1.21 (1H, m), 1.16 (3H, d, J¼7.3 Hz),
1.04 (18H, s), 1.03 (3H, m), 0.86 (9H, s), 0.83 (3H, s), 0.77
(3H, s), 20.014 (6H, s); 13C NMR (CDCl3, 90 MHz): d 173.6
(C), 98.2 (C), 81.6 (C), 72.6 (CH), 69.5 (CH), 66.5 (CH2), 50.0
(CH), 42.3 (CH2), 38.9 (C), 35.7 (CH2), 28.3 (3CH3), 26.1
(3CH3), 20.8 (CH3), 20.7 (CH3), 18.5 (C), 18.3 (6CH3), 12.5
(3CH), 12.1 (C), 25.3 (CH3), 25.4 (CH3).
1
ester (12b). H NMR (CDCl3, 400 MHz): d 7.37 (5H, m),
5.16 (1H, d, J¼12.3 Hz), 5.13 (1H, d, J¼12.2 Hz), 4.20 (1H,
d, J¼2.7 Hz), 4.17 (1H, m), 3.77 (1H, dd, J¼12.0, 1.8 Hz),
3.30 (1H, d, J¼9.5 Hz), 3.25 (1H, d, J¼9.5 Hz), 2.70 (1H, q,
J¼7.3 Hz), 2.15 (1H, ddd, J¼12.2, 4.7, 1.5 Hz), 1.89 (1H,
ddt, J¼12.2, 4.6, 1.7 Hz), 1.28 (1H, m), 1.24 (3H, d,
J¼7.2 Hz), 1.10 (1H, m), 1.08 (18H), 1.07 (3H, s), 0.90 (9H,
s), 0.81 (3H, s), 0.77 (3H, s), 0.03 (3H, s), 0.02 (3H, s); 13C
NMR (CDCl3, 100 MHz): d 176.6 (C), 135.7 (C), 128.8
(2CH), 128.5 (CH), 128.3 (2CH), 98.6 (C), 72.4 (CH), 69.3
(CH2), 66.6 (CH2), 66.5 (CH), 48.8 (CH), 42.0 (CH2), 38.5
(C), 35.8 (CH2), 26.1 (3CH3), 20.7 (CH3), 20.6 (CH3), 18.4
(C), 18.3 (6CH3), 12.8 (CH3), 12.5 (3CH), 25.4 (CH3),
25.4 (CH3).
4.2.3. 2S-Methyl-2-[60R-[(100,100-dimethyl-200-tert-butyl-
dimethylsilyloxy)-eth-10-yl]-40R-triisopropylsilyloxy-20S-
hydroxy-tetrahydropyran-20-yl]-propionic acid tert-
butyl ester (12c). Colorless oil, TLC: Rf 0.35 (EtOAc–
hexanes 5:95); [a]D¼212.0 (c 1.0, CHCl3); IR: 3452, 2960,
2893, 2868, 1710, 1465, 1368, 1255, 1214, 1142, 1091, 845,
4.2.6. 2S-Methyl-2-[(20S,40S,50R,60S)-60-[(100R-methyl)-
prop-200-en-100-yl)-50-methyl-40-(4-methoxybenzyloxy)-20-
hydroxy-tetrahydropyran-20-yl]-propionic acid ethyl
ester (15a). TLC: Rf 0.47 (EtOAc–hexanes 1:4); 1H
NMR (CDCl3, 300 MHz): d 7.29 (1H, d, J¼7.9 Hz), 6.89
(1H, d, J¼8.7 Hz), 5.78 (1H, ddd, J¼17.4, 10.4, 7.1 Hz),
4.94 (1H, m), 4.93 (1H, m), 4.59 (1H, d, J¼10.8 Hz), 4.42
(1H, d, J¼2.6 Hz), 4.38 (1H, d, J¼10.8 Hz), 4.16 (2H, m),
3.81 (3H, s), 3.63 (1H, dd, J¼10.5, 2.2 Hz), 3.50 (1H, ddd,
J¼10.7, 10.4, 4.7 Hz), 2.64 (1H, q, J¼7.5 Hz), 2.40 (1H, dd,
J¼12.3, 4.6 Hz), 1.57 (1H, m), 1.29 (3H, t, J¼7.0 Hz), 1.24
(3H, d, J¼7.3 Hz), 1.16 (1H, m), 0.97 (3H, d, J¼6.5 Hz),
0.93 (3H, d, J¼7.0 Hz); 13C NMR (CDCl3, 75 MHz): d
178.8 (C), 159.3 (C), 143.2 (CH), 131.0 (C), 129.5 (2CH),
1
773 cm21; H NMR (CDCl3, 300 MHz): d 4.53 (1H, d,
J¼2.6 Hz), 4.12 (H, m), 3.72 (1H, dd, J¼12.0, 1.8 Hz), 3.31
(1H, d, J¼9.3 Hz), 3.25 (1H, d, J¼9.3 Hz), 2.44 (1H, q,
J¼7.2 Hz, H-2), 2.07 (1H, ddd, J¼12.2, 4.8, 1.5 Hz), 1.85
(1H, m), 1.44 (9H, s), 1.21 (1H, dt, J¼12.1, 11.0 Hz), 1.16
(3H, d, J¼7.3 Hz), 1.04 (18H, s), 1.03 (3H, m), 1.01 (1H,
m), 0.86 (9H, s), 0.82 (3H, s), 0.76 (3H, s), 20.010 (3H, s),
20.020 (3H, s); 13C NMR (CDCl3, 75 MHz): d 176.3 (C),
98.7 (C), 81.2 (C), 72.4 (CH), 69.3 (CH), 66.5 (CH2), 49.2
(CH), 42.2 (CH2), 38.6 (C), 35.9 (CH2), 28.3 (3CH3), 26.1

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M.-Y. Rıos et al. / Tetrahedron 59 (2003) 6531–6537
6537
114.0 (2CH), 113.0 (CH2), 98.3 (C), 77.6 (CH), 76.3 (CH),
Acknowledgements
71.1 (CH2), 60.9 (CH2), 55.5 (CH3), 48.6 (CH), 39.0 (CH),
37.9 (CH), 37.7 (CH2), 14.3 (CH3), 12.7 (CH3), 12.6 (CH3),
12.0 (CH3).
Financial support of this work by the National Science
Foundation (CHE-0111292) is gratefully acknowledged.
F. V. and M. Y. R. thank CONACyT for a predoctoral and a
postdoctoral fellowship, respectively. We thank Dr Dale
Swenson (Chemistry Department) for obtaining the X-ray
crystal structures of compounds 7 and 15a.
4.2.7. 2S-Methyl-2-[(20S,40S,50R,60S)-60-[(100R-methyl)-
prop-200-en-100-yl)-50-methyl-40-(4-methoxybenzyloxy)-20-
hydroxy-tetrahydropyran-20-yl]-propionic acid benzyl
ester (15b). TLC: Rf 0.49 (EtOAc–hexanes 1:4); 1H
NMR (CDCl3, 400 MHz): d 7.36 (5H, m), 7.27 (2H, d,
J¼8.5 Hz), 6.87 (2H, d, J¼8.5 Hz), 5.70 (1H, ddd, J¼17.4,
10.3, 7.1 Hz), 5.14 (1H, m), 5.12 (1H, d, J¼5.7 Hz), 4.96–
4.86 (2H, m), 4.57 (1H, d, J¼10.9 Hz), 4.36 (1H, d,
J¼10.9 Hz), 4.32 (1H, d, J¼2.5 Hz), 3.79 (3H, s), 3.61 (1H,
dd, J¼10.7, 2.3 Hz), 3.48 (1H, dd, J¼10.7, 10.4, 4.8 Hz),
2.71 (1H, q, J¼7.3 Hz), 2.39 (1H, m), 2.37 (1H, m), 1.54
(1H, m), 1.24 (3H, d, J¼7.3 Hz), 1.14 (1H, ddd, J¼12.1,
11.0, 2.8 Hz), 0.94 (3H, d, J¼6.7 Hz), 0.89 (3H, d,
J¼7.1 Hz); 13C NMR (CDCl3, 75 MHz): d 176.5 (C),
159.3 (C), 143.2 (CH), 135.6 (C), 130.9 (C), 129.6 (2CH),
128.8 (CH), 128.5 (2CH), 114.0 (2CH), 113.1 (C), 98.3 (C),
76.4 (CH), 71.1 (CH2), 66.8 (CH2), 55.5 (CH3), 48.7 (CH),
39.0 (CH), 37.9 (CH), 37.7 (CH2), 12.8 (CH3), 12.5 (CH3),
12.1 (CH3).
References
1. Sone, H.; Kigoshi, H.; Yamada, K. J. Org. Chem. 1996, 61,
8956–8960.
2. (a) Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C.;
Roussakis, C. J. Am. Chem. Soc. 1996, 118, 11085–11088.
(b) Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C.
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3. (a) Sone, H.; Suenaga, K.; Bessho, Y.; Kondo, T.; Kigoshi, H.;
Yamada, K. Chem. Lett. 1998, 85–86. For other efforts in the
synthesis of aurisides: (b) Vakalopoulos, A.; Smits, R.;
Hoffmann, H. M. R. Eur. J. Org. Chem. 2002, 1538–1545.
(c) Sneddon, H. F.; Gaunt, M. J.; Ley, S. V. Org. Lett. 2003, 5,
1147–1150.
4.2.8. 2R-Methyl-2-[(20S,40S,50R,60S)-60-[(100R-methyl)-
prop-200-en-100-yl)-50-methyl-40-(4-methoxybenzyloxy)-20-
hydroxy-tetrahydropyran-20-yl]-propionic acid ethyl
ester (16a). TLC: Rf 0.35 (EtOAc–hexanes, 1:4); 1H
NMR (CDCl3, 300 MHz): d 7.29 (1H, d, J¼7.9 Hz), 6.89
(1H, d, J¼8.7 Hz), 5.83 (1H, ddd, J¼17.4, 10.4, 7.1 Hz),
4.98 (1H, dt, J¼17.3, 1.4 Hz), 4.92 (1H, d, J¼10.1 Hz), 4.58
(1H, d, J¼10.1 Hz), 4.39 (1H, d, J¼11.0 Hz), 4.19 (2H, q,
J¼7.1 Hz), 3.80 (3H, s), 3.62 (1H, dd, J¼10.5, 2.2 Hz), 3.56
(1H, ddd, J¼10.9, 10.5, 4.6 Hz), 2.66 (1H, q, J¼6.9 Hz),
2.41 (1H, m), 2.17 (1H, dd, J¼12.0, 4.4 Hz), 1.57 (1H, m),
1.53 (1H, m), 1.30 (3H, t, J¼6.9 Hz), 1.24 (3H, d,
J¼7.2 Hz), 0.97 (3H, d, J¼6.5 Hz), 0.94 (3H, d,
J¼6.9 Hz); 13C NMR (CDCl3, 75 MHz): d 174.4 (C),
159.3 (C), 143.3 (CH), 131.0 (C), 129.6 (2CH), 113.0
(CH2), 98.1 (C), 77.6 (CH), 76.6 (CH), 71.0 (CH2), 61.2
(CH2), 55.5 (CH3), 49.4 (CH2), 38.7 (CH), 38.1 (CH), 37.3
(CH2), 14.3 (CH3), 12.6 (CH3), 12.1 (CH3), 11.8 (CH3).
4. For our efforts in the synthesis of callipeltosides, see:
´
(a) Velazquez, F.; Olivo, H. F. Org. Lett. 2000, 2,
´
1931–1933. (b) Olivo, H. F.; Velazquez, F.; Trevisan, H. C.
Org. Lett. 2000, 2, 4055–4058.
5. Romero-Ortega, M.; Colby, D. A.; Olivo, H. F. Tetrahedron
Lett. 2002, 43, 6439–6441.
6. (a) Grieco, P. A. J. Org. Chem. 1972, 37, 2363–2364.
(b) Clissold, C.; Kelly, C. L.; Lawrie, K. W. M.; Willis, C. L.
Tetrahedron Lett. 1997, 38, 8105–8108.
7. Duggan, A. J.; Adams, M. A.; Brynes, P. J.; Meinwald, J.
Tetrahedron Lett. 1978, 45, 4323–4326.
8. (a) Loubinoux, B.; Sinnes, J.-L.; O’Sullivan, A. C. J. Chem.
Soc. Perkin Trans. 1 1995, 521–525. (b) Loubinoux, B.;
Sinnes, J.-L.; O’Sullivan, A. C.; Winkler, T. J. Org. Chem.
1995, 60, 953–959.
9. Nakata, T.; Saito, K.; Oishi, T. Tetrahedron Lett. 1986, 27,
6345–6348.
10. Dolle, R. E.; Nicolaou, K. C. J. Am. Chem. Soc. 1985, 107,
1691–1694.
4.2.9. C2R-Methyl-2-[(20S,40S,50R,60S)-60-[(100R-methyl)-
prop-200-en-100-yl)-50-methyl-40-(4-methoxybenzyloxy)-20-
hydroxy-tetrahydropyran-20-yl]-propionic acid benzyl
ester (16b). TLC: Rf 0.27 (EtOAc–hexanes, 1:4); 1H
NMR (CDCl3, 300 MHz): d 7.37 (5H, bs), 7.27 (2H, d,
J¼8.8 Hz), 6.88 (2H, d, J¼8.7 Hz), 5.79 (1H, ddd, J¼17.4,
10.2, 7.1 Hz), 5.14 (1H, m), 5.15 (1H, d, J¼2.3 Hz), 4.92
(2H, m), 4.55 (1H, d, J¼10.7 Hz), 4.36 (1H, d, J¼10.7 Hz),
4.34 (1H, m), 3.81 (3H, s), 3.61 (1H, dd, J¼10.6, 2.1 Hz),
3.54 (1H, ddd, J¼10.7, 10.7, 4.5 Hz), 2.73 (1H, q,
J¼7.1 Hz), 2.40 (1H, m), 2.15 (1H, dd, J¼12.1, 4.5 Hz),
1.59 (1H, m), 1.53 (1H, m), 1.27 (3H, d, J¼7.1 Hz), 0.96
(3H, d, J¼6.4 Hz), 0.92 (3H, d, J¼7.0 Hz); 13C NMR
(CDCl3, 75 MHz): d 174.2 (C), 159.4 (C), 143.2 (CH),
135.7 (C), 131.0 (C), 129.6 (2CH), 128.8 (2CH), 128.5
(CH), 128.3 (2CH), 114.0 (2CH), 113.2 (C), 98.1 (C), 77.5
(CH), 71.0 (CH2), 67.0 (CH2), 55.5 (CH3), 49.6 (CH), 38.7
(CH), 38.2 (CH), 37.3 (CH2), 12.6 (CH3), 12.1 (CH3), 11.9
(CH3).
11. Auriside numbering.
12. The X-ray data of 7 and 15a have been deposited as CCDC
numbers 205943 and 205944, respectively.
13. Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D.
J. Soc., Chem. Commun. Chem. 1987, 1625–1627.
14. Claisen autocondensation of alkyl propionates was also
observed by Sinnes, Ref. 8a.
15. Tautomerization was observed on TLC before and after
reaction work-up.
16. We speculate that the nature of the alkyl group of the
propionate ester determines the ratio of Meinwald
diastereomeric products. The C2 carbon epimerizes to
equilibrium during column chromatography.
17. 1H NMR Coupling constants were assigned according to
the method described by Hoye: (a) Hoye, T. R.; Hanson,
P. R.; Vyvyan, J. R. J. Org. Chem. 1994, 59, 4096–4103.
(b) Hoye, T. R.; Zhao, H. Y. J. Org. Chem. 2002, 67,
4014–4016.