Formal total synthesis of (-)-saliniketals

Article abstract of DOI:10.1021/jo901913h

(Chemical Equation Presented) A highly stereoselective formal total synthesis of the ornithine decarboxylase inhibitors (-)-saliniketals A and B is described. The salient features of the synthesis are the utilization of a desymmetrization technique to cre

Full text of DOI:10.1021/jo901913h

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amide. The structures were assigned mainly by 2D NMR
Formal Total Synthesis of (-)-Saliniketals
spectroscopic methods. The absolute stereochemistry was
assigned by modified Mosher’s method.4 The total synthesis
of 1 and 2 was considered of interest, as part of our ongoing
research activities in the total syntheses of complex biologi-
cally active natural and designed molecules,5 by a desymme-
trization strategy to create contiguous chiral centers from a
single bicyclic precursor. We report herein a highly stereo-
selective formal total synthesis of saliniketals A (1) and B (2).
To date only two total syntheses of these have been reported
by Paterson et al. and De Brabander et al.6
J. S. Yadav,* Sk. Samad Hossain, Madasu Madhu, and
Debendra K. Mohapatra
Organic Chemistry Division-I, Indian Institute of Chemical
Technology (CSIR), Hyderabad 500007, India
yadavpub@iict.res.in; mohapatra@iict.res.in
Received September 4, 2009
FIGURE 1. Structures of (-)-saliniketals A and B.
The details of our approach toward the synthesis of
saliniketals A and B are depicted in Scheme 1, which
illustrates that they could be constructed by Stille coupling7
through a common advanced intermediate 3, which in turn
could be obtained from 4. The aldehyde 4 could be prepared
from 5, which in turn could be accessed from 6. Compund 6
would be obtained by utilizing a desymmetrization technique
to create six contiguous centers.
A highly stereoselective formal total synthesis of the
ornithine decarboxylase inhibitors (-)-saliniketals A
and B is described. The salient features of the synthesis
are the utilization of a desymmetrization technique to
create six contiguous chiral centers from a single bicyclic
precursor as well as substrate-controlled Grignard reac-
tion, intramolecular Wacker-type oxidation, and antial-
dol reaction following Pirrung-Heathcock conditions.
SCHEME 1. Retrosynthetic Analysis of (-)-Saliniketals A and B
Saliniketals A (1) and B (2), unusual bicyclic polyketides,
constitute a novel class of bioactive marine natural products
that were isolated in 2007 by Fenical and co-workers from
actinomycete Salinispora arenicola (Figure 1).1 They inhibit
ornithine decarboxylase (ODC) induction, which is used as a
marker of tumorigenesis and is often seen in epithelial
tumors of the colon, skin, prostate, and stomach.2 Thus,
the inhibition of ODC activity decreases the cellular con-
centration of polyamines and this may provide an effective
strategy to prevent carcinogenesis.3
The exo-alkylated lactone 68 was obtained by the follow-
ing sequence, Zn-Cu couple mediated (-10 °C) [4þ3]
The saliniketals A and B possess a 1,4-dimethyl-2,8-
dioxabicyclo[3.2.1]octane ring featuring an elaborate side
chain at C11 that terminates in an unsaturated primary
(4) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
(5) Yadav, J. S.; Srinivas Rao, C.; Chandrasekhar, S.; Rama Rao, A. V.
Tetrahedron Lett. 1995, 36, 7717.
(6) (a) Paterson, I.; Razzak, M.; Anderson, E. A. Org. Lett. 2008, 10,
3295. (b) Liu, J.; De Brabander, J. K. J. Am. Chem. Soc. 2009, 131, 12562.
(7) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4442 and references cited therein.
*To whom correspondence should be addressed. Fax: þ91-40-27160512.
(1) Williams, P. G.; Asolkar, R. N.; Kondratyuk, T.; Pezzuto, J. M.;
Jensen, P. R.; Fenical, W. J. Nat. Prod. 2007, 70, 83.
(2) (a) Saunders, L. R.; Verdin, E. Mol. Cancer Ther. 2006, 5, 2777.
(b) Thomas, T.; Thomas, T. J. Cell Mol. Life Sci. 2001, 58, 244.
(3) (a) Basuroy, U. K.; Gerner, E. W. J. Biochem. 2006, 139, 27.
(b) Gerner, E. W., Jr. Nat. Rev. Cancer 2004, 4, 781.
(8) (a) Kindly see the Supporting Information. (b) Rama Rao, A. V.; Yadav,
J. S.; Vidyasagar, V. J. Chem. Soc., Chem. Commun. 1985, 55.
8822 J. Org. Chem. 2009, 74, 8822–8825
Published on Web 10/29/2009
DOI: 10.1021/jo901913h
r
2009 American Chemical Society

Yadav et al.
JOCNote
SCHEME 2. Initial Attempt To Synthesize the Fragment 4
SCHEME 3. Synthesis of the Fragment 5
SCHEME 4. Synthesis of the Advanced Intermediate 3
cycloaddition between 2,4-dibromopentan-3-one (7) and
furan to form 2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-ene-3-
ones,9 DIBAL-H reduction, benzyl protection, asymmetric
hydroboration, PCC mediated oxidation, Bayer-Villiger
reaction,10 and alkylation. Acid-catalyzed methanolysis11
of the bicyclic lactone 6 proceeded smoothly to furnish ester
14 in 85% yield. Lithium aluminum hydride mediated re-
duction of the ester afforded the primary alcohol in 90%
yield, which was subsequently oxidized to aldehyde 15 with
IBX12 in DMSO. Our initial approach for a substrate-
controlled Grignard reaction13 with protected bromoke-
tone14 in THF afforded the alcohol 16 with good stereo-
selectivity (86:14 by HPLC) in high yield (Scheme 2).
HPLC) in high yield. The absolute stereochemistry of the
newly introduced chiral center was confirmed at a later stage
of the synthesis. The hydroxyl group was protected as its
acetate derivative, and upon further treatment with aq acetic
acid (60%) at 60 °C afforded the lactol 19 in 86% yield.
Treatment of compound 19 with LiBH4 gave the triol 20. The
TBDPS ether derivative 5 was obtained in 94% yield by
treating 20 with TBDPSCl and imidazole (Scheme 3).
Compound 16 on treatment with BF3 Et2O in CH2Cl2 at
3
0 °C afforded a new product 17 instead of 4, which was
assigned based on 1H NMR spectroscopy and mass analysis.
Even treatment with aqueous acetic acid at 80 °C afforded
compound 17 as the sole product.
To avoid the protecting group manipulation, Grignard
reaction with 1-butenylmagnesium bromide15 in THF af-
forded the alcohol 18 with excellent stereoselectivity (96:4 by
At this stage, we utilized the intramolecular Wacker
oxidation reaction as followed by Paterson et al. for the total
synthesis of saliniketals A and B. An intramolecular Wacker-
type cyclization16 of the 1,3-diol 5 with a catalytic amount of
PdCl2 and CuCl2 in THF under oxygen at 0 °C afforded the
(9) Hoffmann, H. M. R. Angew Chem., Int. Ed. 1984, 23, 1.
(10) Corey, E. J.; Weinshenker, N. M.; Schoff, T. F.; Hubber, W. J. J. Am.
Chem. Soc. 1969, 91, 5675.
1
desired [3.2.1]-dioxabicycle 21 (Scheme 4). The H and 13C
(11) Yadav, J. S.; Venkatram Reddy, P.; Chandraiah, L. Tetrahedron
Lett. 2007, 48, 145.
(12) Frigeno, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019.
(16) (a) Ploysuk, C.; Kongkathip, B.; Kongkathip, N. Synth. Commun.
2007, 37, 1463. (b) Bulman Page, P. C.; Rayner, C. M.; Sutherland, I. O.
Tetrahedron Lett. 1986, 27, 3535. (c) Mori, K.; Seu, Y.-B. Tetrahedron 1985,
41, 3429. (d) Kongkathip, B.; Kongkathip, N. Tetrahedron Lett. 1984, 25,
2175.
€
(13) Francke, W.; Schroder, F.; Philipp, P.; Meyer, H.; Sinnwell, V.;
Gries, G. Bioorg. Med. Chem. 1996, 4, 363.
(14) Stowell, J. C.; Keith, D. R.; King, B. T. Org. Synth. 1984, 62, 140.
(15) Walkup, R. D.; Kim, Y. S. Tetrahedron Lett. 1995, 36, 3091.
J. Org. Chem. Vol. 74, No. 22, 2009 8823

Yadav et al.
JOCNote
(2 ꢀ 50 mL). The combined organic layer was dried over
anhydrous Na2SO4, concentrated to dryness under reduced
pressure, and purified by silica gel chromatography, utilizing
ethyl acetate and hexane (1:7) as mobile phase, to afford 16 as a
colorless oil (1.24 g, 90%). [R]27D þ36.6 (c 1, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.40-7.22 (m, 5H), 4.56 (s, 1H), 4.51 (s,
2H), 3.97-3.82 (m, 3H), 3.57 (dd, J = 2.8, 11.5 Hz, 2H),
3.53-3.35 (m, 3H), 3.40 (s, 3H), 2.29-1.46 (m, 7H), 1.39 (s,
3H), 1.07 (d, J = 7.5 Hz, 3H), 1.04 (s, 3H), 0.98 (d, J = 7.1 Hz,
3H), 0.88 (d, J = 6.9 Hz, 3H), 0.82 (d, J = 6.9 Hz, 3H); ESIMS
for C27H44O6 m/z 487 [M þ Na]þ.
(1S,3R,4S,5R,6S,7R,8R)-4,6,7,8-Tetramethyl-3-(2-(2,5,5-tri-
methyl-1,3-dioxan-2-yl)ethyl)-2,9-dioxabicyclo[3.3.1]nonane (17).
Compound 16 (100 mg, 0.22 mmol) was taken in CH2Cl2 (4 mL)
under N2 atmosphere and cooled to 0 °C. To this solution was
FIGURE 2. ORTEP diagram of compound 24.
added BF3 Et2O (0.01 mL), then the mixture was stirred for 1 h at
3
the same temperature. After completion of the reaction, the
reaction mixture was quenched with a saturated solution of NH4Cl
and the organic layer was separated and extracted with ethyl
acetate (2 ꢀ 10 mL). The combined organic layer was dried over
anhydrous Na2SO4, concentrated to dryness in vacuo, and purified
by silica gel chromatography, using 3% ethyl acetate in hexane as
the mobile phase to obtain compound 17 as a colorless liquid (56
mg, 60%). 1H NMR (300 MHz, CDCl3) δ 7.38-7.22 (m, 5H), 4.59
(dd, J = 12.4, 13.2 Hz, 2H), 4.52 (d, J = 5.3 Hz, 1H), 4.18 (dd, J =
3.6, 5.8 Hz, 1H), 3.76 (m, 1H), 3.64-3.53 (m, 2H), 3.43-3.33 (m,
3H), 2.11-1.65 (m, 7H), 1.50 (s, 3H), 1.25 (s, 6H), 1.05 (d, J = 7.2
Hz, 3H), 0.93 (d, J= 7.0 Hz, 3H), 0.68 (d, J= 8.7 Hz, 3H); ESIMS
for C26H40O5 m/z 455 [M þ Na]þ.
NMR data for the bicyclic acetal 21 were in good agreement
with the corresponding region of saliniketals A and B.17
Deprotection of the TBDPS group with a 1 M solution of
TBAF in THF at room temperature afforded the primary
alcohol, which was oxidized with IBX to obtain the aldehyde
intermediate 4 in 91% yield. The resulting aldehyde 4 on
antialdol reaction following Pirung-Heathcock18 protocol
(lithium enolate of 2,6-dimethylphenyl propionate) gave the
required compound 22 in 96:4 ratio (by HPLC). Catalytic
hydrogenation of compound 22 followed by acetonide pro-
tection afforded compound 24, whose nOe correlation pro-
vided the information about its anti-geometry. The value at
100.6 ppm in 13C NMR also supported the anti-geometry
between C7 and C9.19 In addition, the single crystal X-ray
crystallographic analysis unambiguously confirmed its rela-
tive and absolute stereochemistry (Figure 2). The absolute
configuration of the molecule was further confirmed by
converting the ester 24 to an advanced common intermediate
3. The spectral and analytical data of 3 {[R]25D þ6.1 (c 1.24,
(2R0,3S0)-2-((2R,3R,4S,5S)-4-(Benzyloxy)-6-methoxy-3,5-di-
methyltetrahydro-2H-pyran-2-yl)hept-6-en-3-ol (18). To a stirred
solution of aldehyde 15 (3.8 g, 12.45 mmol) in dry THF
(50 mL) under nitrogen atmosphere was added butenyl magne-
sium bromide in THF [prepared from magnesium (0.76 g, 31.37
mmol) and butenyl bromide (2.54 mL, 25.09 mmol) in THF
(25 mL)] at -78 °C, then stirring was continued for 2 h. The
reaction mixture was quenched with saturated ammonium chlor-
ide solution at -78 °C and allowed to warm to room temperature.
The organic layer was separated and the aqueous layer was
extracted with ethyl acetate (3 ꢀ 50 mL). The combined organic
layers were dried over anhydrous Na2SO4, concentrated under
reduced pressure, and purified by silica gel column chromatogra-
phy with ethyl acetate and hexane (1:9) as eluent to afford alcohol
18 (4.06 g, 90%) as a colorless liquid. [R]27D þ31.2 (c 1.4, CHCl3);
IR (neat) ν 3492, 3068, 3030, 2974, 2916, 1639 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.30 (d, J = 4.5 Hz, 4H), 7.24 (m, 1H), 5.80
(ddt, J = 16.6, 9.8, 6.8 Hz, 1H), 5.03 (dd, J = 16.6, 1.5 Hz, 1H),
4.95 (dd, J = 9.8, 1.5 Hz, 1H), 4.51 (s, 1H), 4.49 (s, 2H), 3.91 (m,
1H), 3.81 (m, 1H), 3.35 (s, 3H), 2.36-1.99 (m, 4H), 1.96-1.77 (m,
2H), 1.67-1.39 (m, 3H), 1.06 (d, J = 7.6 Hz, 3H), 0.97 (d, J = 6.8
Hz, 3H), 0.79 (d, J = 7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
138.8, 138.6, 128.2, 127.2, 127.1, 114.5, 104.7, 75.2, 71.8, 71.0,
69.3, 55.4, 38.5, 36.4, 33.4, 33.1, 30.8, 13.2, 9.7, 7.6; HRMS calcd
for C22H34O4 [M þ Na]þ 385.2354, found 385.2344.
CHCl3); lit.6a [R]25 þ6.2 (c 0.81, CHCl3)} were in good
D
agreement with the reported values by Paterson et al.
In conclusion, we have achieved the formal total synthesis
of saliniketals A and B following our own protocol of
desymmetrization approach to create six contiguous asym-
metric centers from a bicyclic lactone and following a 19-step
synthetic sequence with 18% overall yield starting from a
known intermediate 11.
Experimental Section
(3S,4R)-4-((2R,3R,4S,5S,6S)-4-Benzyloxy)-6-methoxy-3,5-di-
methyltetrahydro-2H-pyran-2yl)-1-(2,5,5-trimethyl-1,3-dioxan-
2-yl)pentan-3-ol (16). To a mixture of magnesium (1.083 g, 44.56
mmol) in 1,2-dibromoethane (0.01 mL) in THF (20 mL) was
added a solution of 2,5,5-trimethyl-2-(bromoethyl)-1,3-dioxan
(7.014 g, 29.72 mmol) in THF (30 mL) under argon at a rate to
maintain the internal temperature of the reaction below 25 °C.
The solution was stirred for an additional 2 h at room tempera-
ture before being cooled to -40 °C. A solution of aldehyde
15 (0.9 g, 2.97 mmol) in THF (15 mL) was added to the reac-
tion mixture, which was stirred for another 1 h at the same
temperature. After completion of reaction, the reaction mixture
was quenched with saturated NH4Cl solution. The organic layer
was separated and the aqueous layer extracted with ethyl acetate
(2R,3R,4R)-3-(Benzyloxy)-4-((1S,3R,4R,5S)-1,4-Dimethyl-2,
8-dioxabicyclo[3.2.1]octan-3-yl)-2-(methylpentyloxy)(tert-butyl)-
diphenylsilane (21). To a stirred solution of diol compound 5
(500 mg, 0.85 mmol) in dry THF (10 mL) at 0 °C was added
CuCl2 (22.8 mg, 0.17 mmol) and PdCl2 (30 mg, 0.17 mmol). The
reaction mixture was flushed with O2 twice at 0 °C and stirring
was continued for 12 h at the same temperature under O2
atmosphere. The reaction mixture was quenched with Et2O
(10 mL) and filtered through a pad of a 1:1 mixture of
MgSO4:SiO2 and washed with Et2O. The combined organic
layer was concentrated to dryness under reduced pressure and
the resulting oil was purified by silica gel chromatography with
ethyl acetate and hexane (1:19) as the mobile phase to obtain
compound 21 (448 mg, 90%) as a colorless oil. [R]27D -22.3 (c
(17) Kindly see the Supporting Information.
(18) Pirrung, M. C.; Heathcock, C. H. J. Org. Chem. 1980, 45, 1727.
(19) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58,
3511.
8824 J. Org. Chem. Vol. 74, No. 22, 2009

Yadav et al.
JOCNote
3.05, CHCl3); IR (neat) ν 3451, 3067, 2958, 2932, 2859, 1725,
(R)-2,6-Dimethyl-2-((4R,5S,6S)-6-((R)-1-((1S,3R,4R,5S)-1,4-
dimethyl-2,8-dioxabicyclo[3.2.1]octan-3-yl)ethyl)-2,2,5-trimethyl-
1,3-dioxan-4-yl)propanoate (24). To a stirred solution of
compound 23 (150 mg, 0.35 mmol) in dry dichloromethne
(4 mL) was added 2,2-dimethoxypropane (0.4 mL, 3.4 mmol)
followed by a catalytic amount of p-TSA at °C. The reac-
tion mixture was stirred for 4 h at room temperature and
quenched with H2O (2 mL). The aqueous layer was extracted
with dichloromethane (2 ꢀ 10 mL). The combined organic
layer was dried over anhydrous Na2SO4, concentrated to dry-
ness under reduced pressure, and purified by silica gel chro-
matography to afford compound 24 (157 mg, 96%) as a crystal-
1
1631, 1463, 1428 cm-1; H NMR (300 MHz, CDCl3) δ 7.61
(m, 4H), 7.40-7.21 (m, 11H), 4.58 (dd, J = 18.1, 11.3 Hz, 2H),
4.11 (m, 1H), 3.81 (dd, J = 9.8, 6.0 Hz, 1H), 3.70 (dd, J = 10.5,
1.5 Hz, 1H), 3.51 (dd, J = 10.5, 7.5 Hz, 1H), 3.34 (dd, J = 9.8,
1.5 Hz, 1H), 1.94-1.76 (m, 2H), 1.75-1.61 (m, 3H), 1.41 (s, 3H),
1.42-1.34 (m, 2H), 1.08-1.01 (m, 12H), 0.78 (d, J = 7.5 Hz,
3H), 0.56 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
139.4, 135.6, 133.9, 133.8, 129.5, 128.2, 127.5, 127.1, 126.9,
104.7, 83.2, 80.1, 74.9, 73.0, 64.9, 38.2, 36.4, 34.2, 33.8, 29.7,
26.8, 24.2, 23.9, 19.2, 16.2, 12.7, 10.0; HRMS calcd for
C37H50O4NaSi [M þ Na]þ 609.3376, found 609.3367.
(2R,3R,4R,5R,6R)-2,6-Dimethylphenyl-5-(benzyloxy)-6-((1S,
3R,4R,5S)-1,4-dimethyl-2,8-dioxabicyclo[3.2.1]octan-3-yl)-3-hy-
droxy-2,4-dimethylheptanoate (22). n-Butyl lithium (3.6 mL,
1.6 M in hexane, 5.88 mmol) was added dropwise to an ice-
cooled solution of diisopropylamine (0.82 mL, 5.88 mmol) in
dry THF (10 mL) and the mixture was stirred for 20 min. The
reaction mixture was then cooled to -78 °C and propionate
ester (671 mg, 6.53 mmol) in dry THF (10 mL) was added slowly
to the in situ generated LDA solution with stirring for an
additional 45 min. Aldehyde 4 (452 mg, 1.31 mmol) in dry
THF (10 mL) was added to the reaction mixture, which was
stirred another 1 h at -78 °C. The reaction mixture was
quenched with aqueous ammonium chloride solution and ex-
tracted with ethyl acetate (3 ꢀ 30 mL). The combined organic
layer was dried over anhydrous Na2SO4, concentrated under
reduced pressure, and purified by silica gel chromatography,
using ethyl acetate and hexane (1:9) as the mobile phase, to
line solid. Mp 145 °C; [R]27 -1.5 (c 1.2, CHCl3); IR (neat) ν
D
2927, 2855, 1757, 1656 cm-1 1H NMR (300 MHz, CDCl3)
;
δ 7.04 (s, 3H), 4.21 (m, 1H), 4.07 (dd, J = 10.9, 3.7 Hz, 1H),
3.75 (dd, J = 10.5, 1.8 Hz 1H), 3.34 (dd, J = 9.1, 6.4 Hz, 1H),
2.90 (qd, J = 10.9, 6.9 Hz, 1H), 2.17 (s, 6H), 2.03-1.66 (m, 7H),
1.44 (s, 3H), 1.28 (d, J = 3.7 Hz, 6H), 1.25 (d, J = 6.9 Hz, 3H),
0.98 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 7.1 Hz, 3H), 0.69 (d, J =
6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.7, 148.1, 130.2,
128.4, 125.6, 104.8, 100.6, 80.2, 74.4, 72.7, 70.9, 40.6, 38.8,
35.2, 34.1, 33.7, 25.5, 24.1, 23.9, 23.4, 16.3, 13.7, 12.7, 12.4,
7.9; HRMS calcd for C28H42O6 [MþNa]þ 497.2874, found
497.2872.
(S)-2-((4S,5R,6R)-6-((R)-1-((1S,3R,4R,5S)-1,4-dimethyl-2,8-
dioxabicyclo[3.2.1]octan-3-yl)ethyl)-2,2,5-trimethyl-1,3-dioxan-
4-yl)propan-1-ol (3). To an ice-cooled suspension of LAH (16
mg, 0.42 mmol) in dry THF (4 mL) was added a solution of
compound 24 (100 mg, 0.21 mmol) in dry THF (3 mL) under N2
atmosphere with stirring for 4 h at room temperature. After
completion of the reaction (monitored by TLC), the reaction
mixture was quenched with aqueous ammonium chloride solu-
tion and the formed precipitate was filtered on a small pad of
Celite and washed with ethyl acetate (2 ꢀ 10 mL). The combined
organic layers were dried over anhydrous Na2SO4, concentrated
under reduced pressure, and purified by silica gel chromatogra-
phy, using ethyl acetate and hexane (1:5) as the mobile phase, to
obtain alcohol 3 (70 mg, 94%) as a colorless liquid. [R]27D þ6.1
afford aldol adduct 22 (555 mg, 81%) as a colorless oil. [R]27
D
-37.0 (c 2.1, CHCl3); IR (neat) ν 3486, 2971, 2882, 1755, 1636,
1461 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.40-7.26 (m, 5H),
7.02 (s, 3H), 4.72 (dd, J = 38.1, 11.3 Hz, 2H), 4.31 (d, J = 10.0
Hz, 1H), 4.23 (dd, J = 6.4, 3.5 Hz, 1H), 3.91 (s, 1H), 3.82 (dd,
J = 10.5, 1.3 Hz, 1H), 3.65 (dd, J = 10.1, 1.7 Hz, 1H), 2.88 (qd,
J = 10.0, 6.9 Hz, 1H), 2.17 (s, 6H), 2.11-1.95 (m, 3H),
1.92-1.64 (m, 4H), 1.48 (s, 3H), 1.25 (d, J = 7.1 Hz, 3H),
1.21 (d, J = 6.9 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H), 0.72 (d, J =
6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.5, 148.1, 138.0,
130.4, 128.7, 128.5, 128.3, 127.7, 126.9, 125.5, 104.8, 86.8, 80.0,
76.1, 72.9, 72.1, 44.0, 36.3, 34.3, 33.8, 33.7, 24.1, 23.8, 16.3, 16.2,
13.9, 12.8, 11.5, 9.9; HRMS calcd for C32H44O6 [M þ Na]þ
547.3030, found 547.3042.
(c 1.24, CHCl3); IR (neat) ν 3457, 2922, 1640, 1462, 1380 cm-1
;
1H NMR (400 MHz, CDCl3) δ 4.21 (dd, J = 6.1, 3.9 Hz, 1H),
3.72 (dd, J = 10.3, 3.9 Hz, 1H), 3.67 (dd, J = 10.3, 3.9 Hz, 1H),
3.63-3.49 (m, 2H), 3.34 (m, 2H), 2.03-1.60 (m, 8H), 1.43 (s,
3H), 1.38 (s, 3H), 1.31 (s, 3H), 0.93 (d, J = 6.8 Hz, 3H), 0.89 (d,
J = 7.1 Hz, 3H), 0.76 (d, J = 7.1 Hz, 3H), 0.68 (d, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 104.8, 100.5, 80.2, 76.3,
74.5, 72.7, 69.4, 38.8, 36.4, 34.7, 34.2, 33.7, 25.9, 24.2, 23.9,
23.4, 12.9, 12.6, 12.5, 7.8; HRMS calc for C20H36O5 [Mþ1]þ
357.2636, found 357.2635.
(2R,3R,4S,5R,6R)-2,6-Dimethylphenyl-6-((1S,3S,4R,5S)-1,4-
dimethyl-2,8-dioxa-bicyclo[3.2.1]octan-3-yl)-3,5-dihydroxy-2,4-
dimethylheptanoate (23). To a solution of compound 22 (200 mg,
0.38 mmol) in ethyl acetate (6 mL) was added a catalytic amount
Pd-C (10%) under H2 balloon pressure with stirring at room
temperature for 12 h. The reaction mixture was filtered on a
small pad of Celite, concentrated to dryness under reduced
pressure, and purified by silica gel chromatography, using ethyl
acetate and hexane (1:6), to obtain compound 23 (155 mg, 94%)
as a colorless liquid. [R]27D -9.6 (c 2.5, CHCl3); IR (neat) ν 3449,
2968, 1752, 1463 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.05 (s,
3H), 4.38 (dt, J = 9.8, 2.4 Hz, 1H), 4.24 (m, 1H), 3.86 (dd, J =
10.3, 1.8 Hz, 1H), 3.61 (dd, J = 12.8, 6.6 Hz, 1H), 3.36 (m, 2H),
2.96 (qd, J = 10.0, 7.1 Hz, 1H), 2.18 (s, 6H), 2.09 (m, 1H),
2.01-1.77 (m, 6H), 1.46 (s, 3H), 1.31 (d, J = 7.1 Hz, 3H), 1.04
(d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.73 (d, J = 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 173.9, 148.0, 130.2, 128.5,
125.7, 105.0, 80.0, 77.7, 77.2, 74.8, 72.3, 43.9, 35.5, 35.0, 34.4,
33.7, 23.9, 16.4, 14.1, 12.6, 11.1, 10.4; HRMS calcd for
C25H38O6 [M þ 1]þ 435.2741, found 435.2740.
Acknowledgment. S.H. and M.M. thank Council of Scien-
tific & Industrial Research (CSIR), New Delhi, India for the
financial assistance in the form of research fellowships.
D.K.M. thanks Council of Scientific & Industrial Research
(CSIR), New Delhi, India for a research grant (INSA Young
Scientist Award). We are thankful to Dr. B. Sridhar for his
help with X-ray crystallographic analysis.
Supporting Information Available: Experimental proce-
dures and spectroscopic data, copies of 1H and 13C NMR
spectra for new compounds, NOE spectrum of 18, 24, and a
CIF file of 24. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 22, 2009 8825