First asymmetric total synthesis of penarolide sulfate A1

Article abstract of DOI:10.1002/ejoc.200800680

Penarolide sulfate A₁, with three contiguous stereogenic centers on a macrocyclic skeleton, affords promise as an α-glucosidase inhibitor. Herein, we describe the first asymmetric total synthesis of this natural product. A stereoselective strat

Full text of DOI:10.1002/ejoc.200800680

FULL PAPER
DOI: 10.1002/ejoc.200800680
First Asymmetric Total Synthesis of Penarolide Sulfate A1
Debendra K. Mohapatra,*[a][‡] Debabrata Bhattasali,[a] Mukund K. Gurjar,[a]
M. Islam Khan,[b] and K. S. Shashidhara[b]
Keywords: Macrocycles / Asymmetric synthesis / C–C coupling / Dihydroxylation / Epoxidation / Total synthesis / Regio-
selectivity
Penarolide sulfate A1, with three contiguous stereogenic cen-
ters on a macrocyclic skeleton, affords promise as an α-gluco-
sidase inhibitor. Herein, we describe the first asymmetric to-
tal synthesis of this natural product. A stereoselective strat-
egy for rapid assembly of the complete framework of the 30-
membered macrocyclic core is delineated herein. Sequential
amidation and intramolecular Sonogashira cross-coupling re-
actions were pivotal to the success of our efforts.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
In 2000, Fusetani and coworkers reported the isolation,
structure elucidation, and biological activity of new α-glu-
cosidase inhibitors Penarolide sulfate A1 (1) and A2 (2)
(Figure 1) from the marine sponge Penares sp., with IC50
values of 1.2 and 1.5 µgmL–1, respectively.[1] The consti-
tution and relative stereochemistry of Penarolide sulfate A1
and A2 were elucidated by chemical degradation and exten-
sive 2D NMR spectroscopic studies; the absolute configura-
tion was established by application of Mosher’s method.
Penarolide sulfate A1 and A2 are 30- and 31-membered
macrolides encompassing a proline residue and three sulfate
groups.
The intriguing structural features, noteworthy biological
profiles, and limited availability make Penarolide sulfate A1
and A2 attractive targets for total synthesis. No report has
yet appeared on the total synthesis of any of these natural
products. We report, herein, a novel convergent strategy for
the total synthesis of Penarolide sulfate A1; efficient as-
sembly of its 30-membered macrolide core is realized
through sequential amidation[2] and macrocyclization by an
intramolecular Sonogashira cross-coupling reaction.[3]
Retrosynthesis of 1 into three segments 4, 5 and 8 pro-
vided the impetus for our work. The assembly of the 30-
membered macrocyclic core was envisioned to be a se-
Figure 1. Penarolide sulfate A1 (1) and A2 (2).
quence of amidation between the C1–C18 acid and amine
segments (8 and 4) followed by intramolecular Sonogashira
reaction of the amide thus formed. Key segment 4 would
be elaborated from chiral building block 6 by a simple ester-
ification[4] reaction with commercially available N-Boc--
proline. Our plan for the synthesis of the C1–C18 subunit
is founded upon the regioselective Sharpless asymmetric di-
hydroxylation[5] and Sharpless asymmetric epoxidation re-
actions[6] (Scheme 1).
[a] Division of Organic Chemistry, National Chemical Laboratory,
Dr. Homi Bhabha Road, Pune 411008, India
Fax: +91-40-27160512
Results and Discussion
E-mail: mohapatra@iict.res.in
The synthesis of C1–C18 segment 8 was initiated with
the introduction of the diene appendage at C14 of aldehyde
12 through a Horner–Wadsworth–Emmons reaction[7] (pro-
duced exclusive E,E diastereomer 9 in 83% yield). Asym-
metric dihydroxylation of 9 (E,E-dienoate) by using (DHQ)2-
PHAL (= hydroquinine 1,4-phthalazinediyl diether) as the
chiral ligand at 0 °C for 6 h gave exclusively the regioselec-
dkm_77@yahoo.com
[b] Division of Biochemical Sciences, National Chemical Labora-
tory,
Dr. Homi Bhabha Road, Pune 411008, India
[‡] Current Address: Division of Organic Chemistry, Indian Insti-
tute of Chemical Technology,
Tarnaka, Hyderabad 500007, India
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Scheme 1. Retrosynthetic analysis of penarolide sulfate A1 (1).
tive dihydroxy derivative 13 (ee = 98.4%)[8] in 70% yield.
We next turned our attention to the preparation of amine
Protection of the diol group present in compound 13 as an building block 4. Reaction of known aldehyde 21[12] under
isopropylidene derivative followed by reduction with DI- Corey–Chakovsky reaction[13] conditions produced racemic
BAL-H gave alcohol 15 (Scheme 2). Sharpless asymmetric terminal epoxide 22. Compound 22 was then subjected to
epoxidation of 15 produced 16 as a single diastereomer hydrolytic kinetic resolution (HKR)[14] by using (R,R)-
(confirmed from its 13C NMR spectra). Epoxy chloride 17 salen-CoIIIOAc (0.5 mol-%) and distilled water (0.55 equiv.)
was then prepared from 16 by treatment with Ph3P and at 0 °C to afford chiral epoxide 23 with 98.8% ee[15] along
CCl4 at reflux. Compound 17, upon treatment with an ex- with diol 24 with 93.3% ee.[16] Unrequired diol 24 was con-
cess amount of nBuLi (3 equiv.), afforded alkynol 18.[9] Pro- verted into required epoxide 23 following a known strat-
tection of the secondary alcohol as its TBS ether followed egy[17] (Scheme 4).
by oxidative removal of the PMB ether with DDQ[10]
Secondary alcohol 6 was derived by the regioselective
yielded the penultimate C18 alcohol 20. Oxidation of 20 to ring opening[18] of 23 with propylmagnesium bromide in the
the corresponding aldehyde with IBX followed by further presence of catalytic CuCN in dry THF. Esterification with
oxidation with NaClO2 in tBuOH at 0 °C gave the required commercially available N-Boc--proline under standard
C18 acid 8 in 88% yield[11] (Scheme 3).
EDC/DMAP {EDC = 1-ethyl-3-[3Ј-(dimethylamino)propyl]-
Scheme 2. Synthesis of allylic alcohol 15.
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First Asymmetric Total Synthesis of Penarolide Sulfate A1
Scheme 3. Synthesis of C18 acid 7.
Scheme 4. Synthesis of chiral epoxide 23.
carbodiimide} conditions afforded 25. In a sequence of
three simple chemical transformation, viz., hydro-
genolysis,[19] IBX oxidation, and Takai olefination,[20] 25
was transformed into 27. Deprotection of the tert-butoxy-
carbonyl protecting group under acidic conditions[21] gave
target amine building block 4 in 81% yield (Scheme 5).
Assembly of fragments 4 and 8 to target molecule 1 be-
came our next task. EDC/HOBt-mediated (HOBt = 1-hy-
droxybenzotriazole) coupling of amine 4 with carboxylic
Scheme 5. Synthesis of amine 4.
Finally, we tried persulfation[24] on compound 30 under
acid 8 was facile and afforded coupled product 3. Forma- various standard persulfation reaction conditions (men-
tion of the 30-membered macrocyclic ring following an in- tioned in Table 1), but we were dismayed to obtain complex,
tramolecular Sonogashira cross-coupling reaction was our intractable reaction mixtures in all cases. However, we were
next goal; several reaction conditions to tune the macrocy- delighted to see that modification of procedure 1 (Table 1)
clization under Sonogashira coupling conditions were at- for persulfation of 30 as depicted in Scheme 7 yielded trisul-
tempted. Finally, the reagent combination of tetrakis(tri- fated natural product 1 (Penarolide sulfate A1) in 84%
phenylphosphane)palladium(0) and CuI in anhydrous di- yield. The spectral and analytical data of synthetic 1 com-
ethylamine at 0 °C for 30 min gave the best result. Re- pletely matched that of the natural product isolated by Fu-
duction of both the double and triple bonds present in the setani et al.[1]
macrocycle by Raney Ni[22] in ethanol under a hydrogen
At this stage, we thought it would be pertinent to evalu-
atmosphere and complete deprotection by using TsOH[23] ate also the enzyme inhibition activity of 30, because then
in methanol led to the formation of triol 30. The spectral we would be able to rationalize the importance of the sul-
as well as analytical data of synthetic 30 was in good agree- fate groups toward biological activity for this class of mole-
ment with the assigned structure (Scheme 6).
cules.
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Scheme 6. Synthesis of desulfated penarolide sulfate A1 (30).
Table 1. Various persulfation reaction conditions.
Conditions for Persulfation of 30
Observation
1. (a) Py·SO3, DMF, r.t., 36 h; (b) NaHCO3, 0 °C
complex intractable reaction mixture
complex intractable reaction mixture
complex intractable reaction mixture
2. Py·SO3, Na2SO4, microwave, 10 min
3. (a) Py·SO3, DMF, r.t., 20 h; (b) acetone/methanol (9:1), H2O, 0 °C; (c) then 1  NaOH, 0 °C
inhibits β-glucosidase, β-mannosidase, and β-galactosidase,
but the extent of inhibition towards the corresponding α-
analogs is negligible at 1 m inhibitor concentration
(Table 2, Figure 2).
Table 2. Inhibition of various glycosides by desulfated penarolide
sulfate A1 (30) as the inhibitor.[a]
Glycosidases
Ki [µ]
α-Glucosidase
β-Glucosidase
α-Galactosidase
β-Galactosidase
α-Mannosidase
β-Mannosidase
160
21.0%[b]
7.5%[b]
30.0%[b]
2.4%[b]
35%[b]
[a] The enzyme inhibition study was carried out under similar con-
ditions to those reported in ref.[25] and the same is detailed in the
Experimental Section. [b] Percentage inhibition at 1 m inhibitor
concentration.
As compound 30 was found to be weakly active in com-
parison to compound 1, we attempted the preparation of
the partially sulfated derivatives of 30. For this endeavor,
controlled deprotection of compound 29 by using TBAF in
Scheme 7. Synthesis of penarolide sulfate A1.
Enzyme Inhibition Study of 30
Thus, desulfated penarolide sulfate also acts as an α-glu- THF resulted in the formation of compound 31 in 94%
cosidase inhibitor (IC50 = 166 µ); the extent of inhibition yield (Scheme 8). Following our earlier method of sulfation,
is much less than that of parent molecule 1. Compound 30 compound 31 afforded a number of products that we failed
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First Asymmetric Total Synthesis of Penarolide Sulfate A1
Figure 2. Binding of 30 to α-glucosidase and kinetics of inhibition. (A) The sigmoidal curve indicates the best fit for the percentage
inhibition data obtained, and the IC50 value was calculated from the graph. (B) Enzymatic activity of the α-glucosidase was estimated
by using the substrate p-nitrophenyl-α--glucopyaranoside 250 µ (᭿) and 500 µ (᭹) at different concentrations of 30. Ki was determined
by following the method of Dixon.[26]
Scheme 8. Selective deprotection and partial sulfation.
to characterize. Similarly, controlled deprotection of the protocol was intramolecular Sonogashira cross-coupling re-
isopropylidene group present in compound 29 in the pres- action for the construction of the key 30-membered macro-
ence of the TBS group was attempted to obtain dihydroxy cyclic ring. Regioselective Sharpless asymmetric dihydrox-
derivative 32. Various Lewis acid [Zn(NO3)2·6H2O,[27] ylation, Sharpless asymmetric epoxidation, and Jacobsen
CuCl2·2H2O in ethanol,[28] FeCl3·6H2O/SiO2[29]] mediated HKR were employed for the generation of the four asym-
reaction conditions at room temperature were found to be metric centers present in the molecule. A biological activity
futile, and we ended up with unreacted starting material. profile of the desulfated penarolide sulfate A1 (30) was also
However, employment of harsh reaction conditions (heating disclosed. The reported approach is convergent in nature
from 70 to 110 °C in the presence of earlier-mentioned and provides considerable flexibility for the synthesis of re-
Lewis acids) furnished completely deprotected triol 30. lated unnatural analogs.
TMSOTf[30] mediated opening of the isopropylidene group
also failed to furnish desired product 32. Because we were
Experimental Section
unable to prepare the partially sulfated derivatives of 30,
their bioevaluation was not possible and the role of the sul-
fate groups toward biological activity remained inconclus-
ive for this class of natural product.
General Remarks: Air- and/or moisture-sensitive reactions were
carried out with anhydrous solvents under an atmosphere of argon
in oven/flame-dried glassware. All anhydrous solvents were distilled
prior to use: THF, benzene, toluene, and diethyl ether from Na and
benzophenone; CH2Cl2 from CaH2; MeOH, EtOH from Mg cake.
Commercial reagents were used without purification. Column
chromatography was carried out by using silica gel (60–120 mesh)
Conclusions
In conclusion, the first total synthesis of penarolide sul-
fate A1 is documented. The cornerstone of our synthetic and (230–400 mesh). Specific optical rotations [α]D are given in
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D. K. Mohapatra et al.
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10–1°cm2 g–1. Infrared spectra were recorded in CHCl3/neat (as
mentioned) and reported in wave number (cm–1). 1H and 13C NMR
chemical shifts are reported in ppm downfield from tetramethylsil-
ane and coupling constants (J) are reported in Hertz [Hz]. The
following abbreviations are used to designate signal multiplicity: s
= singlet, d = doublet, t = triplet, q = quartet, quint. = quintet, m
= multiplet, br. = broad.
9.5 Hz, 1 H), 7.28 (d, J = 8.7 Hz, 2 H), 6.89 (d, J = 8.7 Hz, 2 H),
6.21–6.11 (m, 2 H), 5.81 (d, J = 15.4 Hz, 1 H), 4.45 (s, 2 H), 4.22
(q, J = 7.1 Hz, 2 H), 3.82 (s, 3 H), 3.45 (t, J = 6.7 Hz, 2 H), 2.18
(q, J = 6.9 Hz, 2 H), 1.62 (quint., J = 6.9 Hz, 2 H), 1.45–1.42 (m,
2 H), 1.38–1.32 (m, 4 H), 1.31–1.28 (m, 17 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 167.3, 159.0, 145.1, 144.7, 130.8, 129.2,
128.3, 119.1, 113.7, 72.4, 70.2, 60.1, 55.2, 33.0, 29.7, 29.6, 29.5 (2
C), 29.4 (2 C), 29.1, 28.7, 26.2, 14.3 ppm. C28H44O4 (444.65): calcd.
C 75.63, H 9.97; found C 75.89, H 10.11.
14-(4-Methoxybenzyloxy)tetradecan-1-ol (10): To a stirred solution
of tetradecane-1,14-diol (11; 26.8 g, 116.3 mmol) in THF/DMF
(7:3, 200 mL) at 0 °C was added NaH (4.67 g, 116.3 mmol) por-
tionwise followed by the addition of PMBBr (16.41 mL,
116.3 mmol). After 12 h, the reaction was quenched by the addition
of ice-cold water (130 mL), and the reaction mixture was concen-
trated under reduced pressure. The residue thus obtained was di-
luted with water and extracted with ethyl acetate (3ϫ100 mL). The
combined organic fraction was washed with water (150 mL), brine,
and dried with anhydrous Na2SO4, and the solvent was evaporated.
The residue was purified on silica gel (light petroleum/ethyl acetate,
4:1) to afford 10 (36.7 g, 90%) as a white solid. M.p. 63 °C. IR
(4S,5S,E)-Ethyl-4,5-dihydroxy-18-(4-methoxybenzyloxy)octadec-2-
enoate (13): To a vigorously stirred mixture of K3[Fe(CN)6]
(56.02 g, 170.2 mmol), K2CO3 (23.52 g, 170.2 mmol), (DHQ)2-
PHAL (442 mg, 0.57 mmol), MeSO2NH2 (5.4 g, 56.7 mmol), and
K2OsO4·2H2O (84 mg, 0.23 mmol) in tBuOH/H2O (1:1, 300 mL)
at 0 °C was added compound 9 (25.2 g, 56.7 mmol). After 6 h, the
reaction was quenched with sodium sulfite (50 g) and tBuOH was
evaporated under reduced pressure. The aqueous phase was ex-
tracted with ethyl acetate (3ϫ100 mL). The combined organic frac-
tion was washed with 2  KOH, water, and brine, dried with anhy-
drous Na2SO4, and concentrated. The residue was purified by silica
gel column chromatography (light petroleum/ethyl acetate, 4:1) to
afford 13 (19.0 g, 70%) as a white solid. M.p. 67 °C. [α]2D5 = –17.1
(liquid film, CHCl ): ν = 3421, 1612, 1248, 1036 cm–1. 1H NMR
˜
3
(200 MHz, CDCl3): δ = 7.25 (d, J = 8.7 Hz, 2 H), 6.86 (d, J =
8.7 Hz, 2 H), 4.42 (s, 2 H), 3.80 (s, 3 H), 3.62 (t, J = 6.6 Hz, 2 H),
3.42 (t, J = 6.6 Hz, 2 H), 1.62–1.52 (m, 4 H), 1.25 (m, 20 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 159.0, 130.6, 129.1, 113.7 (2 C),
72.4, 70.1, 62.8, 55.1, 32.7, 29.7, 29.6 (2 C), 29.4 (2 C), 26.2,
25.7 ppm. C22H38O3 (350.54): calcd. C 75.38, H 10.93; found C
75.16, H 11.21.
(c = 1.2, CHCl ). IR (liquid film, CHCl ): ν = 3308, 2927, 1713,
˜
3
3
1464, 1251 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.31 (d, J =
8.7 Hz, 2 H), 6.99 (dd, J = 15.6, 5.0 Hz, 1 H), 6.93 (d, J = 8.7 Hz,
2 H), 6.19 (d, J = 15.6 Hz, 1 H), 4.49 (s, 2 H), 4.27 (q, J = 7.2 Hz,
2 H), 4.16 (m, 1 H) 3.87 (s, 3 H), 3.59 (m, 1 H), 3.49 (t, J = 6.7 Hz,
2 H), 2.73 (br. s, 2 H), 1.66 (quint., J = 6.9 Hz, 2 H), 1.60–1.51 (m,
2 H), 1.39–1.33 (m, 23 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 166.3, 159.1, 147.1, 130.7, 129.2, 122.3, 113.7, 74.1, 74.0, 72.5,
70.2, 60.5, 55.2, 33.1, 29.7, 29.6, 29.5, 26.2, 25.6, 14.2 ppm.
C28H46O6 (478.66): calcd. C 70.26, H 9.69; found C 70.37, H 9.84.
14-(4-Methoxybenzyloxy)tetradecanal (12): Iodoxybenzoic acid
(IBX; 28.12 g, 100.4 mmol) in DMSO (100 mL) was stirred at room
temperature for 30 min, till it become a clear solution. Compound
10 (35.2 g, 100.4 mmol) in THF (100 mL) was added to the clear
solution, and the mixture was stirred at room temperature for 4 h.
The reaction mixture was then diluted with water (100 mL) and
filtered. THF was removed under reduced pressure, and the reac-
tion mixture was extracted with diethyl ether (3ϫ75 mL), washed
with NaHCO3, water, brine, dried with anhydrous Na2SO4, and
concentrated. The residue was purified by silica gel column
chromatography (light petroleum/ethyl acetate, 9:1) to afford 12
(E)-Ethyl-3-{(4S,5S)-5-[13-(4-methoxybenzyloxy)tridecyl]-2,2-dimeth-
yl-1,3-dioxolan-4-yl}acrylate (14): To a solution of 13 (16.6 g,
34.7 mmol) and 2,2-dimethoxypropane (5.11 mL, 41.6 mmol) in
CH2Cl2 (125 mL) was added TsOH (250 mg). The reaction mixture
was stirred at room temperature for 1 h. After completion of the
reaction (monitored by TLC), the reaction mixture was washed
with NaHCO3 (75 mL), water and brine, dried with anhydrous
Na2SO4, and concentrated. The residue was purified on silica gel
(light petroleum/ethyl acetate, 9.5:0.5) to afford acetonide deriva-
tive 14 (17.3 g, 96%) as a colorless oil. [α]2D5 = –8.1 (c = 1.7, CHCl3).
(33.2 g, 95%) as a yellow oil. IR (liquid film, CHCl ): ν = 2926,
˜
3
1726, 1613, 1247, 1099 cm–1. 1H NMR (200 MHz, CDCl3): δ =
9.75 (t, J = 1.9 Hz, 1 H), 7.24 (d, J = 8.7 Hz, 2 H), 6.86 (d, J =
8.7 Hz, 2 H), 4.42 (s, 2 H), 3.79 (s, 3 H), 3.42 (t, J = 6.6 Hz, 2 H),
2.41 (dt, J = 7.3, 1.9 Hz, 2 H), 1.65–1.52 (m, 4 H), 1.25 (m, 18 H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 202.4, 159.0, 130.7, 129.1,
113.6, 72.4, 70.1, 55.0, 43.8, 29.7, 29.5, 29.4 (2 C), 29.3, 29.1, 26.1,
22.0 ppm. C22H36O3 (348.52): calcd. C 75.82, H 10.41; found C
75.59, H 10.29.
IR (liquid film, CHCl ): ν = 2854, 1724, 1513, 1247 cm–1. 1H NMR
˜
3
(500 MHz, CDCl3): δ = 7.32 (d, J = 8.7 Hz, 2 H), 6.93 (d, J =
8.7 Hz, 2 H), 6.92 (dd, J = 15.7, 5.6 Hz, 1 H), 6.18 (dd, J = 15.7,
1.5 Hz, 1 H), 4.49 (s, 2 H), 4.28 (q, J = 7.2 Hz, 2 H), 4.22–4.18 (m,
1 H), 3.87 (s, 3 H), 3.79 (dt, J = 8.3, 5.9 Hz, 1 H), 3.49 (t, J =
6.7 Hz, 2 H), 1.68–1.63 (m, 4 H), 1.58–1.53 (m, 2 H), 1.50 (s, 3 H),
1.48 (s, 3 H), 1.39–1.33 (m, 21 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 165.9, 159.1, 144.2, 130.8, 129.2, 122.6, 113.7, 109.3,
80.6, 80.3, 72.5, 70.2, 60.5, 55.2, 32.1, 29.8, 29.7, 29.6 (2 C), 29.5,
27.3, 26.7, 26.2, 26.0, 14.3 ppm. C31H50O6 (518.73): calcd. C 71.78,
H 9.72; found C 71.62, H 9.63.
(2E,4E)-Ethyl-18-(4-methoxybenzyloxy)octadeca-2,4-dienoate (9):
To a solution of ethyl 4-(dimethylphosphono)crotonate (29.45 g,
132.6 mmol) in anhydrous THF (250 mL) at –78 °C was added
LiHMDS (1.0  in THF, 132.55 mL). After 1 h, this solution was
transferred by cannula into a solution of 12 (30.8 g, 88.4 mmol)
in THF (70 mL) maintained at –78 °C. The reaction mixture was
warmed to room temperature, stirred for 1 h, quenched with satu-
rated aqueous NH4Cl solution (100 mL), and concentrated. The
aqueous layer was extracted with ethyl acetate (3ϫ100 mL). The
combined organic fraction was washed with water and brine and
dried with anhydrous Na2SO4, and the solvent was evaporated. The
residue was purified by silica gel column chromatography (light
petroleum/ethyl acetate, 9:1) to afford 9 (32.6 g, 83%) as a light-
(S)-1-{(4S,5S)-5-[13-(4-Methoxybenzyloxy)tridecyl]-2,2-dimethyl-
1,3-dioxolan-4-yl}prop-2-yn-1-ol (15): To a solution of 14 (15.9 g,
30.7 mmol) in CH2Cl2 (150 mL) at –78 °C was added DIBAL-H
(1.3  in toluene, 51.91 mL, 67.5 mmol). After 1 h, excess of DI-
BAL-H was quenched with a saturated solution of sodium potas-
sium tartrate. The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2. The organic layer was washed
yellow oil. IR (liquid film, CHCl ): ν = 2926, 1715, 1247, with water, dried with anhydrous Na2SO4, and concentrated under
˜
3
1036 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.29 (dd, J = 15.4,
reduced pressure. The residue was purified by silica gel column
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First Asymmetric Total Synthesis of Penarolide Sulfate A1
chromatography (light petroleum/ethyl acetate, 4:1) to give 15
(12.5 g, 85%) as a colorless oil. [α]2D5 = –3.6 (c = 1.2, CHCl3). IR
(S)-1-{(4S,5S)-5-[13-(4-Methoxybenzyloxy)tridecyl]-2,2-dimethyl-
1,3-dioxolan-4-yl}prop-2-yn-1-ol (18): n-Butyllithium (1.6  in hex-
ane, 22.78 mL, 36.5 mmol) was added dropwise to a solution of 17
(6.2 g, 12.2 mmol) in dry THF (70 mL) at –78 °C under a nitrogen
(liquid film, CHCl ): ν = 3436, 2854, 1464, 1217 cm–1. 1H NMR
˜
3
(500 MHz, CDCl3): δ = 7.17 (d, J = 8.7 Hz, 2 H), 6.79 (d, J =
8.7 Hz, 2 H), 5.88 (dt, J = 15.4, 5.1 Hz, 1 H), 5.62 (dd, J = 15.4, atmosphere. After stirring for 1 h at –78 °C, the reaction mixture
7.3 Hz, 1 H), 4.35 (s, 2 H), 4.09 (d, J = 5.1 Hz, 2 H), 3.93 (t, J = was gradually warmed to room temperature over a period of 1 h,
8.1 Hz, 1 H), 3.73 (s, 3 H), 3.59 (dt, J = 8.1, 5.9 Hz, 1 H), 3.35 (t,
J = 6.7 Hz, 2 H), 1.54–1.49 (m, 2 H), 1.47–1.44 (m, 2 H), 1.33 (s,
quenched with aqueous NH4Cl solution (50 mL), and concen-
trated. The residue was extracted with ethyl acetate (3ϫ50 mL),
3 H), 1.33 (s, 3 H), 1.28–1.18 (m, 20 H) ppm. 13C NMR (125 MHz, washed with water and brine, dried with anhydrous Na2SO4, and
CDCl3): δ = 159.1, 133.9, 130.8, 129.2, 128.2, 113.8, 108.4, 81.7,
80.8, 72.5, 70.2, 62.7, 55.2, 31.9, 29.8, 29.7, 29.6 (3 C), 29.5, 27.3,
27.0, 26.2, 26.1 ppm. C29H48O5 (476.69): calcd. C 73.07, H 10.15;
found C 73.26, H 10.29.
evaporated. The residue was purified by silica gel column
chromatography (light petroleum/ethyl acetate, 4:1) to afford 18
(5.2 g, 72%) as a colorless oil. [α]2D5 = –8.8 (c = 1.7, CHCl3). IR
(liquid film, CHCl ): ν = 3425, 2926, 1612, 1465, 1247 cm–1. 1H
˜
3
NMR (200 MHz, CDCl3): δ = 7.24 (d, J = 8.7 Hz, 2 H), 6.86 (d,
J = 8.7 Hz, 2 H), 4.47 (dd, J = 3.8, 2.2 Hz, 1 H), 4.42 (s, 2 H), 4.05
(ddd, J = 8.0, 7.8, 3.8 Hz, 1 H), 3.80 (s, 3 H), 3.75 (dd, J = 7.8,
3.8 Hz, 1 H), 3.42 (t, J = 6.6 Hz, 2 H), 2.51 (d, J = 2.2 Hz, 1 H),
1.69–1.48 (m, 4 H), 1.42 (s, 6 H), 1.25 (m, 20 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 159.1, 130.7, 129.2, 113.7, 109.0, 82.4, 81.1,
77.4, 75.0, 72.5, 70.1, 62.3, 55.1, 34.1, 29.8, 29.7, 29.6, 29.5, 27.6,
27.0, 26.2, 26.0 ppm. C29H46O5 (474.67): calcd. C 73.38, H 9.77;
found C 73.63, H 9.55.
[(2R,3S)-3-{(4R,5S)-5-[13-(4-Methoxybenzyloxy)tridecyl]-2,2-dimeth-
yl-1,3-dioxolan-4-yl}oxiran-2-yl]methanol (16): To a solution of tita-
nium tetrakis(isopropoxide) (7.30 mL, 24.8 mmol) and -(–)-DIPT
(= diisopropyl tartrate) (6.31 mL, 24.8 mmol) in CH2Cl2 (125 mL)
carrying activated molecular sieves (4 Å, 12.0 g) at –22 °C was
added t-butylhydroperoxide (3.3  in toluene, 15.01 mL,
49.5 mmol) dropwise. After 15 min a solution of allylic alcohol 15
(11.8 g, 24.8 mmol) in CH2Cl2 (75 mL) was added dropwise. The
reaction mixture was kept at that temperature for 16 h; aqueous
tartaric acid (10%) was added followed by stirring for 1 h. The
reaction mixture was filtered, and the organic layer was separated.
The aqueous layer was extracted with CH2Cl2 (3ϫ75 mL), and the
combined CH2Cl2 extract was concentrated under reduced pressure
and then taken up in diethyl ether (125 mL). This solution was then
treated with 1  NaOH solution (60 mL) and stirred for another
1 h and then extracted with diethyl ether (3ϫ50 mL). The com-
bined organic fraction was washed with water and brine, dried with
anhydrous Na2SO4, and concentrated. The residue was purified by
silica gel column chromatography (230–400 mesh; light petroleum/
ethyl acetate, 3:1) to afford epoxy alcohol 16 (8.2 g, 67%) as a col-
tert-Butyl[(S)-1-{(4R,5S)-5-[13-(4-methoxybenzyloxy)tridecyl]-2,2-
dimethyl-1,3-dioxolan-4-yl}prop-2-ynyloxy]dimethylsilane: (19). To a
solution of 18 (4.7 g, 9.9 mmol) and imidazole (877 mg, 12.9 mmol)
in CH2Cl2 (40 mL) was added TBSCl (1.79 g, 11.9 mmol) in por-
tions, and the resulting mixture was stirred at room temperature
for 2 h. After completion of the reaction (monitored by TLC), the
reaction mixture was poured on ice, diluted with water, and ex-
tracted with ethyl acetate (3ϫ50 mL). The combined organic layer
was washed with brine, dried with anhydrous Na2SO4, and concen-
trated. The residue was purified by silica gel column chromatog-
raphy (light petroleum/ethyl acetate, 9:1) to furnish 19 (5.52 g,
94%) as a colorless oil. [α]2D5 = +2.1 (c = 1.1, CHCl3). IR (liquid
orless oil. [α]2D5 = +2.3 (c = 1.1, CHCl3). IR (liquid film, CHCl3):
ν = 3447, 2926, 1513, 1248 cm–1. H NMR (400 MHz, CDCl ): δ
film, CHCl ): ν = 2855, 1614, 1513, 1249, 1097 cm–1. 1H NMR
1
˜
˜
3
3
= 7.24 (d, J = 8.7 Hz, 2 H), 6.85 (d, J = 8.7 Hz, 2 H), 4.41 (s, 2
H), 3.96–3.91 (m, 2 H), 3.79 (s, 3 H), 3.66 (dd, J = 12.8, 4.3 Hz, 1
H), 3.41 (t, J = 6.7 Hz, 2 H), 3.39 (dd, J = 7.8, 6.3 Hz, 1 H), 3.09
(quint., J = 2.3 Hz, 1 H), 3.01 (dd, J = 6.3, 2.3 Hz, 1 H), 2.02 (br.
(200 MHz, CDCl3): δ = 7.25 (d, J = 8.7 Hz, 2 H), 6.86 (d, J =
8.7 Hz, 2 H), 4.42 (s, 2 H), 4.39 (dd, J = 5.7, 2.2 Hz, 1 H), 4.01
(ddd, J = 8.0, 7.2, 3.3 Hz, 1 H), 3.80 (s, 3 H), 3.70 (dd, J = 7.2,
5.7 Hz, 1 H), 3.42 (t, J = 6.6 Hz, 2 H), 2.45 (d, J = 2.2 Hz, 1 H),
s, 1 H), 1.62–1.55 (m, 4 H), 1.40 (s, 3 H), 1.39 (s, 3 H), 1.33–1.26 1.62–1.54 (m, 4 H), 1.41 (s, 3 H), 1.39 (s, 3 H), 1.38–1.25 (m, 20
(m, 20 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.1, 130.8, H), 0.91 (m, 9 H), 0.17 (s, 3 H), 0.13 (s, 3 H) ppm. 13C NMR
129.2, 113.7, 109.2, 80.4, 79.8, 72.5, 70.2, 61.0, 56.7, 55.2, 55.0,
33.2, 29.8, 29.7, 29.6, 29.5, 27.3, 26.7, 26.2, 25.9 ppm. C29H48O6
(492.69): calcd. C 70.70, H 9.82; found C 70.53, H 9.96.
(50 MHz, CDCl3): δ = 159.0, 130.8, 129.2, 113.7, 108.9, 83.0 (2 C),
78.5, 73.9, 72.5, 70.2, 63.9, 55.2, 34.5, 29.8, 29.7, 29.6 (2 C), 29.5
(2 C), 27.6, 27.1, 26.2, 25.7, 18.2, –4.7, –5.0 ppm. C35H60O5Si
(588.93): calcd. C 71.38, H 10.27; found C 71.47, H 10.08.
(4R,5S)-4-[(2R,3S)-3-(Chloromethyl)oxiran-2-yl]-5-[13-(4-ethoxy-
benzyloxy)tridecyl]-2,2-dimethyl-1,3-dioxolane (17): Sodium hydro-
gen carbonate (3.5 g) was added to a solution of 16 (7.5 g,
13-{(4S,5R)-5-[(S)-1-(tert-Butyldimethylsilyloxy)prop-2-ynyl]-2,2-di-
methyl-1,3-dioxolan-4-yl}tridecan-1-ol (20): To a stirred solution of
15.2 mmol) and triphenylphosphane (7.98 g, 30.5 mmol) in CCl4 19 (3.47 g, 5.9 mmol) in CH2Cl2/buffer (pH = 7) (18:1, 30 mL) was
(100 mL), and the reaction mixture was heated at reflux for 2 h.
Removal of solvent under reduced pressure and residue purification
by silica gel column chromatography (light petroleum/ethyl acetate,
9.5:0.5) gave 17 (7.0 g, 90%) as a colorless oil. [α]2D5 = +1.3 (c =
added DDQ (1.61 g, 7.1 mmol) at 0 °C. After 3 h, the reaction was
quenched by the addition of saturated NaHCO3 solution (50 mL)
and extracted with CH2Cl2 (3ϫ75 mL). The combined organic
fraction was washed with water and brine, dried with anhydrous
Na2SO4, and evaporated. The residue was purified by silica gel col-
1.5, CHCl ). IR (liquid film, CHCl ): ν = 2928, 1612, 1465,
˜
3
1
3
1216 cm–1. H NMR (200 MHz, CDCl3): δ = 7.26 (d, J = 8.7 Hz, umn chromatography (light petroleum/ethyl acetate, 3:1) to furnish
2 H), 6.87 (d, J = 8.7 Hz, 2 H), 4.43 (s, 2 H), 4.00–3.90 (m, 1 H),
3.80 (s, 3 H), 3.67 (dd, J = 11.9, 4.7 Hz, 1 H), 3.55 (dd, J = 11.9,
6.2 Hz, 1 H), 3.43 (t, J = 6.7 Hz, 2 H), 3.42–3.39 (m, 1 H), 3.23
(ddd, J = 6.2, 4.7, 1.9 Hz, 1 H), 2.97 (dd, J = 5.8, 1.9 Hz, 1 H),
1.63–1.52 (m, 4 H), 1.40 (s, 6 H), 1.26 (m, 20 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 159.0, 130.8, 129.1, 113.7, 109.3, 79.8, 79.7,
72.4, 70.1, 57.9, 55.4, 55.1, 43.9, 33.1, 29.7, 29.6, 29.4, 27.2, 26.6,
20 (2.1 g, 76%) as a light-yellow oil. [α]2D5 = +2.4 (c = 1.0, CHCl3).
IR (liquid film, CHCl ): ν = 3311, 2856, 2117, 1464, 1253,
˜
3
1167 cm–1. 1H NMR (200 MHz, CDCl3): δ = 4.40 (dd, J = 5.7,
2.2 Hz, 1 H), 4.02 (ddd, J = 8.0, 7.2, 3.3 Hz, 1 H), 3.72 (dd, J =
7.2, 5.7 Hz, 1 H), 3.64 (t, J = 6.5 Hz, 2 H), 2.46 (d, J = 2.2 Hz, 1
H), 1.63–1.50 (m, 4 H), 1.42 (s, 3 H), 1.39 (s, 3 H), 1.27 (m, 20 H),
0.92 (m, 9 H), 0.18 (s, 3 H), 0.14 (s, 3 H) ppm. 13C NMR (50 MHz,
26.2, 25.8 ppm. C29H47ClO5 (511.13): calcd. C 68.14, H 9.27; found CDCl3): δ = 108.9, 83.1, 83.0, 78.4, 74.0, 63.9, 63.0, 34.5, 32.8,
C 68.27, H 9.47.
29.7 (2 C), 29.6, 29.5, 27.6, 27.1, 26.2, 25.8, 18.2, –4.6, –4.9 ppm.
Eur. J. Org. Chem. 2008, 6213–6224
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6219

D. K. Mohapatra et al.
FULL PAPER
C27H52O4Si (468.78): calcd. C 69.18, H 11.18; found C 69.24, H
11.33.
7-(Benzyloxy)heptanal (21): To a stirred solution of 7-benzyloxy-
heptan-1-ol (7a; 21.13 g, 95.0 mmol) in CH2Cl2 (250 mL) was
added PCC (40.97 g, 190.1 mmol), and the resulting mixture was
stirred at room temperature for 2 h. After completion of the reac-
tion (monitored by TLC), the reaction mixture was diluted with
diethyl ether (200 mL) and filtered. The filtrate was concentrated
under reduced pressure, and the residue thus obtained was purified
by silica gel column chromatography (light petroleum/ethyl acetate,
4:1) to give 21 (18.22 g, 87%) as a colorless oil. IR (liquid film,
13-{(4S,5R)-5-[(S)-1-(tert-Butyldimethylsilyloxy)prop-2-ynyl]-2,2-di-
methyl-1,3-dioxolan-4-yl}tridecanoic Acid (8): Iodoxybenzoic acid
(IBX; 1.17 g, 4.2 mmol) in DMSO (15 mL) was stirred at room
temperature for 30 min till it become a clear solution. Compound
20 (1.96 g, 4.2 mmol) in THF (10 mL) was added to the clear solu-
tion, and the mixture was stirred for 4 h at room temperature. The
reaction mixture was then diluted with water (40 mL) and filtered.
The filtrate was extracted with diethyl ether (3ϫ50 mL), washed
with NaHCO3, water, and brine, dried with anhydrous Na2SO4,
and concentrated. The residue was purified by silica gel column
chromatography (light petroleum/ethyl acetate, 9:1) to afford 20ald
(1.9 g, 95%) as a yellow oil. [α]2D5 = +3.6 (c = 1.4, CHCl3). IR
CHCl ): ν = 2926, 1725, 1614, 1462, 1301 cm–1 1H NMR
.
˜
3
(200 MHz, CDCl3): δ = 9.74 (t, J = 1.7 Hz, 1 H), 7.34–7.25 (m, 5
H), 4.49 (s, 2 H), 3.45 (t, J = 6.6 Hz, 2 H), 2.41 (dt, J = 7.2, 1.7 Hz,
2 H), 1.70–1.55 (m, 4 H), 1.46–1.26 (m, 4 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 202.3, 138.5, 128.2, 127.5, 127.4, 72.7, 70.0,
43.7, 29.4, 28.9, 25.9, 21.9 ppm. C14H20O2 (220.31): calcd. C 76.33,
H 9.15; found C 76.19, H 9.33.
(liquid film, CHCl ): ν = 2855, 2117, 1711, 1463, 1252, 1132 cm–1.
˜
3
1H NMR (200 MHz, CDCl3): δ = 9.77 (t, J = 1.9 Hz, 1 H), 4.40
(dd, J = 5.7, 2.2 Hz, 1 H), 4.02 (ddd, J = 8.3, 7.2, 3.3 Hz, 1 H),
3.72 (dd, J = 7.2, 5.7 Hz, 1 H), 2.47 (d, J = 2.2 Hz, 1 H), 2.42 (dt,
J = 7.3, 1.9 Hz, 2 H) 1.77–1.46 (m, 6 H), 1.46 (s, 3 H), 1.42 (s, 3
H), 1.39–1.26 (m, 16 H), 0.92 (m, 9 H), 0.17 (s, 3 H), 0.13 (s, 3 H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 202.9, 108.9, 83.1, 83.0,
78.5, 73.9, 63.9, 43.9, 34.5, 29.7, 29.6, 29.4 (2 C), 29.2, 27.6, 27.1,
26.2, 25.8, 22.1, 18.2, –4.6, –5.0 ppm. C27H50O4Si (466.77): calcd.
C 69.48, H 10.80; found C 69.32, H 10.98.
2-[6-(Benzyloxy)hexyl]oxirane (22): To a suspension of NaH (60%
dispersion in oil, 4.33 g, 108.3 mmol) and trimethylsulfoxonium io-
dide (23.84 g, 108.3 mmol) in DMSO (150 mL) under an atmo-
sphere of argon at 10 °C was added 21 (15.9 g, 72.2 mmol) in
DMSO (100 mL) over a period of 30 min. After 3 h, the reaction
was quenched with ice-cold water and extracted with ethyl acetate
(3ϫ125 mL). The combined organic layer was washed with water
and brine, dried with anhydrous Na2SO4, and concentrated. The
residue was purified by silica gel column chromatography (light
To a solution of the above aldehyde (1.43 g, 3.1 mmol),
NaH2PO4·2H2O (1.45 g, 9.3 mmol), and 2-methyl-2-butene (2 mL)
in tBuOH (20 mL) was added a solution of NaClO2 (840 mg,
9.3 mmol) in water (10 mL) dropwise. After 2 h, the reaction mix-
ture was diluted with water (30 mL) and extracted with ethyl ace-
tate (3ϫ25 mL). The combined organic layer was washed with
brine, dried with anhydrous Na2SO4, and concentrated. The residue
was purified by silica gel column chromatography (light petroleum/
ethyl acetate, 4:1) to give 8 (1.3 g, 88%) as a light yellow oil. [α]D
petroleum/ethyl acetate, 9:1) to afford 22 (14.22 g, 84%) as a yellow
1
oil. IR (liquid film, CHCl ): ν = 2929, 1603, 1454, 1258 cm–1. H
˜
3
NMR (200 MHz, CDCl3): δ = 7.33–7.28 (m, 5 H), 4.49 (s, 2 H),
3.46 (t, J = 6.6 Hz, 2 H), 2.90–2.84 (m, 1 H), 2.73 (dd, J = 5.1,
4.0 Hz, 1 H), 2.44 (dd, J = 5.1, 2.7 Hz, 1 H), 1.63–1.30 (m, 10 H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 138.5, 128.2, 127.5, 127.3,
72.7, 70.2, 52.1, 46.8, 32.3, 29.6 (2 C), 29.2, 26.1, 25.9 ppm.
C15H22O2 (234.33): calcd. C 76.88, H 9.46; found C 76.71, H 9.31.
= +4.3 (c = 1.0, CHCl ). IR (liquid film, CHCl ): ν = 3310, 2928,
˜
3
3
(R)-2-[6-(Benzyloxy)hexyl]oxirane (23) and (S)-8-(Benzyloxy)oc-
tane-1,2-diol (24): (R,R)-Salen-CoIIIOAc (172 mg, 0.26 mmol) was
added to (R/S)-epoxide 22 (12.18 g, 52.0 mmol), followed by the
dropwise addition of water (0.51 mL, 28.6 mmol) over 1 h at 0 °C.
The reaction mixture was allowed to come to room temperature
and then stirred for 36 h. The reaction mixture was filtered, and
the filtrate was concentrated. The residue was purified by column
chromatography (light petroleum/ethyl acetate, 9:1) to afford 23
(5.7 g, 47%) as a light-yellow oil. [α]2D5 = +5.6 (c = 2.0, CHCl3). IR
1712, 1463, 1217 cm–1. 1H NMR (400 MHz, CDCl3): δ = 4.40 (dd,
J = 5.5, 2.3 Hz, 1 H), 4.02 (ddd, J = 8.3, 7.3, 3.3 Hz, 1 H), 3.73
(dd, J = 7.3, 5.5 Hz, 1 H), 2.45 (d, J = 2.3 Hz, 1 H), 2.34 (t, J =
7.3 Hz, 2 H) 1.77–1.51 (m, 6 H), 1.42 (s, 3 H), 1.39 (s, 3 H), 1.26
(m, 16 H), 0.91 (m, 9 H), 0.17 (s, 3 H), 0.13 (s, 3 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 179.8, 108.9, 83.1, 83.0, 78.5, 73.9,
63.9, 34.5, 34.0, 29.7, 29.6, 29.5 (2 C), 29.4, 29.2, 29.0, 27.6, 27.1,
26.1, 25.7, 24.7, 18.2, –4.7, –5.0 ppm. C27H50O5Si (482.77): calcd.
C 67.17, H 10.44; found C 67.08, H 10.30.
(liquid film, CHCl ): ν = 2933, 1603, 1454, 1216 cm–1. 1H NMR
˜
3
7-(Benzyloxy)heptan-1-ol (7a): To a solution of heptane-1,7-diol (7;
21.23 g, 160.6 mmol) in THF/DMF (7:3, 200 mL) at 0 °C was
slowly added sodium hydride (60 % in dispersion oil, 6.42 g,
160.6 mmol). The reaction mixture was stirred at 0 °C for 30 min.
Benzyl bromide (19.06 mL, 160.6 mmol) in THF was added drop-
wise. After being stirred for 30 min at that temperature, the reaction
mixture was allowed to warm to room temperature. The reaction
mixture was stirred overnight at room temperature and quenched
with water. After removal of THF under reduced pressure, the resi-
due was partitioned between ether (250 mL) and water (300 mL).
The organic layer was dried with anhydrous Na2SO4 and concen-
trated, and the residue was purified by silica gel column chromatog-
raphy (light petroleum/ethyl acetate, 7:3) to give 7a (30.7 g, 86%)
(200 MHz, CDCl3): δ = 7.33–7.28 (m, 5 H), 4.49 (s, 2 H), 3.46 (t,
J = 6.6 Hz, 2 H), 2.90–2.84 (m, 1 H), 2.73 (dd, J = 5.1, 4.0 Hz, 1
H), 2.44 (dd, J = 5.1, 2.7 Hz, 1 H), 1.63–1.30 (m, 10 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 138.5, 128.2, 127.5, 127.3, 72.7, 70.2,
52.2, 46.9, 32.4, 29.6 (2 C), 29.2, 26.1, 25.9 ppm. C15H22O2
(234.33): calcd. C 76.88, H 9.46; found C 76.97, H 9.29.
Further elution (petroleum ether/ethyl acetate, 1:1) gave diol 24
(5.5 g, 42%) as a yellow oil. [α]2D5 = +2.9 (c = 1.0, CHCl3). IR
(liquid film, CHCl ): ν = 3392, 2932, 1454, 1216, 1028 cm–1. 1H
˜
3
NMR (400 MHz, CDCl3): δ = 7.32–7.26 (m, 5 H), 4.49 (s, 2 H),
3.67 (m, 2 H), 3.46 (t, J = 6.6 Hz, 2 H), 3.41–3.39 (m, 1 H), 2.53
(br. s, 2 H), 1.64–1.58 (m, 2 H), 1.42–1.33 (m, 8 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 138.4, 128.3, 127.5, 127.4, 72.8, 72.1, 70.3,
66.5, 33.0, 29.6, 29.4, 26.0, 25.5 ppm. C15H24O3 (252.35): calcd. C
71.39, H 9.59; found C 71.68, H 9.37.
as a colorless oil. IR (liquid film, CHCl ): ν = 3433, 2853, 1613,
˜
3
1586, 1464, 1247 cm–1. 1H NMR (200 MHz, CDCl3): δ = 7.34–7.25
(m, 5 H), 4.49 (s, 2 H), 3.59 (t, J = 6.7 Hz, 2 H), 3.45 (t, J = 6.6 Hz,
2 H), 1.85 (br. s, 1 H), 1.68–1.48 (m, 4 H), 1.33 (m, 6 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 138.4, 128.2, 127.5, 127.4, 72.7, 70.2,
62.5, 32.5, 29.5, 29.1, 26.1, 25.6 ppm. C14H22O2 (222.32): calcd. C
75.63, H 9.97; found C 75.76, H 10.08.
(S)-8-(Benzyloxy)-1-(tert-butyldiphenylsilyloxy)octan-2-ol (24a): To
a solution of 24 (5.32 g, 21.1 mmol), imidazole (1.87 g, 27.4 mmol),
and DMAP (103 mg, 0.8 mmol) in CH2Cl2 (75 mL) was added
TBDPSCl (6.95 g, 25.3 mmol) in portions. The resulting mixture
6220
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 6213–6224

First Asymmetric Total Synthesis of Penarolide Sulfate A1
was stirred at room temperature for 3 h. After completion of the
reaction (monitored by TLC), the reaction mixture was poured on
ice, diluted with water, and extracted with diethyl ether (3ϫ75 mL).
The combined organic layer was washed with brine, dried with an-
hydrous Na2SO4, and concentrated. The residue was purified on
silica gel by (light petroleum/ethyl acetate, 9:1) to produce 24a
(9.21 g, 89%) as a colorless oil. [α]2D5 = +0.9 (c = 1.3, CHCl3). IR
drous Na2SO4, and concentrated. The residue was purified by silica
gel column chromatography (light petroleum/ethyl acetate, 4:1) to
afford 25 (7.0 g, 95%) as a light-yellow oil. [α]2D5 = –34.5 (c = 1.2,
CHCl ). IR (liquid film, CHCl ): ν = 2932, 1736, 1692, 1406,
˜
3
3
1163 cm–1. H NMR (200 MHz, CDCl3): δ = 7.33–7.25 (m, 5 H),
4.92–4.80 (m, 1 H), 4.49 (s, 2 H), 4.34–4.20 (m, 2 H), 3.61–3.47 (m,
1 H), 3.44 (t, J = 6.6 Hz, 2 H), 2.21–1.87 (m, 4 H), 1.62–1.48 (m,
4 H), 1.45 and 1.42 (rotamers, s, s, 9 H), 1.30–1.22 (m, 12 H), 0.89
1
(liquid film, CHCl ): ν = 3467, 2857, 1589, 1427, 1362 cm–1. 1H
˜
3
NMR (200 MHz, CDCl3): δ = 7.68–7.24 (m, 15 H), 4.48 (s, 2 H), (t, J = 6.5 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 172.5
3.74–3.60 (m, 2 H), 3.50–3.41 (m, 1 H), 3.43 (t, J = 6.7 Hz, 2 H),
2.27 (br. s, 1 H), 1.62–1.52 (m, 2 H), 1.37–1.26 (m, 8 H), 1.06 (m,
9 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 138.6, 135.5, 133.1 (2
C), 129.8, 128.3, 127.7, 127.5, 127.4, 72.8, 71.8, 70.3, 68.0, 32.7,
29.7, 29.4, 26.9, 26.1, 25.4, 19.2 ppm. C31H42O3Si (490.75): calcd.
C 75.87, H 8.63; found C 75.93, H 8.41.
and 172.4 (rotamers), 153.9 and 153.6 (rotamers), 138.5, 132.6,
129.3, 128.1, 127.3, 127.2, 79.5 and 79.2 (rotamers), 74.7 and 74.5
(rotamers), 72.6, 70.1 and 70.1 (rotamers), 58.9, 46.3 and 46.1 (rot-
amers), 33.8 and 33.7 (rotamers), 33.6, 30.9, 29.6 and 29.5 (rota-
mers), 29.1 and 29.0 (rotamers), 28.5 and 28.2 (rotamers), 27.3 and
27.2 (rotamers), 25.9 and 25.8 (rotamers), 25.1 and 24.9 (rotamers),
24.1, 23.1, 22.4, 13.8 and 13.7 (rotamers) ppm. C28H45NO5
(475.66): calcd. C 70.70, H 9.54, N 2.94; found C 70.88, H 9.41, N
2.79.
(S)-8-(Benzyloxy)-1-(tert-butyldiphenylsilyloxy)octan-2-yl-methane-
sulfonate (24b): To a solution of alcohol 24a (8.94 g, 18.2 mmol)
and triethylamine (3.81 mL, 27.3 mmol) at 0 °C in CH2Cl2 (75 mL)
was added methanesulfonyl chloride (2.5 g, 21.9 mmol) in CH2Cl2
(20 mL) dropwise. The reaction mixture was stirred for 2 h. After
completion of the reaction (monitored by TLC), the reaction mix-
ture was washed successively with aqueous sodium hydrogen car-
bonate and water, dried with anhydrous Na2SO4, and concentrated.
The residue thus obtained was purified by silica gel column
chromatography (light petroleum/ethyl acetate, 4:1) to afford 24b
(9.43 g, 91%) as a colorless oil. [α]2D5 = –5.7 (c = 0.5, CHCl3). IR
(S)-1-tert-Butyl-2-[(S)-11-hydroxyundecan-5-yl]pyrrolidine-1,2-di-
carboxylate (26): A solution of 25 (6.71 g, 14.1 mmol) in ethyl ace-
tate (60 mL) was stirred in the presence of 10 % Pd/C (750 mg,
5 mol-%) under a hydrogen atmosphere. After 6 h, the reaction
mixture was filtered through a pad of Celite and concentrated. The
residue was purified by silica gel column chromatography (light
petroleum/ethyl acetate, 3:2) to provide 26 (4.7 g, 87%) as a light-
yellow oil. [α]2D5 = –43.8 (c = 1.6, CHCl3). IR (liquid film, CHCl3):
(liquid film, CHCl ): ν = 2858, 1962, 1589, 1458, 1428, 1242 cm–1.
ν = 3455, 2934, 1736, 1690, 1406, 1215 cm–1. H NMR (200 MHz,
˜
1
3
˜
1H NMR (200 MHz, CDCl3): δ = 7.68–7.25 (m, 15 H), 4.75–4.64
(m, 1 H), 4.48 (s, 2 H), 3.83–3.68 (m, 2 H), 3.44 (t, J = 6.7 Hz, 2
H), 2.97 (s, 3 H), 1.68–1.52 (m, 4 H), 1.39–1.16 (m, 6 H), 1.06 (m,
9 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 138.6, 135.5, 135.4,
132.8, 132.6, 130.0, 129.9, 128.3, 127.8, 127.6, 127.4, 83.8, 72.8,
70.2, 65.3, 38.5, 31.4, 29.6, 29.1, 26.8, 25.9, 24.8, 19.2 ppm.
C32H44O5SSi (568.84): calcd. C 67.57, H 7.80; found C 67.73, H
7.74.
CDCl3): δ = 4.92–4.79 (m, 1 H), 4.32–4.20 (m, 1 H), 3.62 (t, J =
6.5 Hz, 2 H), 3.56–3.35 (m, 2 H), 2.25–1.86 (m, 4 H), 1.81–1.68 (m,
2 H), 1.55–1.49 (m, 4 H), 1.46 and 1.42 (rotamers, s, s, 9 H), 1.32–
1.26 (m, 10 H), 0.89 (t, J = 6.5 Hz, 3 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 172.7 and 172.6 (rotamers), 154.1 and 153.8 (rota-
mers), 79.7 and 79.4 (rotamers), 74.9 and 74.6 (rotamers), 62.5,
59.1, 46.4 and 46.2 (rotamers), 33.8 and 33.7 (rotamers), 32.5, 30.9,
30.0, 29.1 and 29.0 (rotamers), 28.4, 28.3, 27.4 and 27.3 (rotamers),
25.5, 25.1 and 25.0 (rotamers), 24.2, 23.3, 22.5, 13.9 and 13.8 (rota-
mers) ppm. C21H39NO5 (385.54): calcd. C 65.42, H 10.20, N 3.63;
found C 65.67, H 10.01, N 3.45.
(S)-11-(Benzyloxy)undecan-5-ol (6): To a suspension of magnesium
(1.5 g, 61.8 mmol) in dry THF (100 mL) at 0 °C was added a solu-
tion of n-propyl bromide (5.62 mL, 61.8 mmol) in THF (30 mL).
After 30 min, CuCN (2.22 g, 24.7 mmol) and 23 (4.83 g,
20.6 mmol) were added, and the mixture was stirred for 1 h at 0 °C.
The reaction mixture was quenched with saturated NH4Cl solution,
and the organic layer was separated. The aqueous layer was ex-
tracted with ethyl acetate (2ϫ50 mL). The organic layer was dried
with anhydrous Na2SO4 and concentrated. The residue was puri-
fied by silica gel column chromatography (light petroleum/ethyl
acetate, 4:1) to afford 6 (4.5 g, 78%) as a colorless oil. [α]2D5 = +1.5
(S)-1-tert-Butyl-2-[(S,E)-12-iodododec-11-en-5-yl]pyrrolidine-1,2-di-
carboxylate (27): Iodoxybenzoic acid (IBX; 3.56 g, 12.7 mmol) in
DMSO (50 mL) was stirred at room temperature for 30 min till it
become a clear solution. Compound 26 (4.08 g, 10.6 mmol) in THF
(30 mL) was added to the clear solution, and the mixture was
stirred for 4 h at room temperature. The reaction mixture was then
diluted with water (70 mL) and filtered. THF was removed under
reduced pressure, and the reaction mixture was extracted with di-
ethyl ether (3ϫ50 mL), washed with NaHCO3, water, and brine,
dried with anhydrous Na2SO4, and concentrated. The residue was
purified on silica gel (light petroleum/ethyl acetate, 9:1) to afford
26ald (3.7 g, 90%) as a yellow oil. [α]2D5 = –39.1 (c = 2.0, CHCl3).
(c = 1.3, CHCl ). IR (liquid film, CHCl ): ν = 3437, 2933, 1454,
˜
3
3
1
1278, 1216 cm–1. H NMR (500 MHz, CDCl3): δ = 7.33–7.25 (m,
5 H), 4.49 (s, 2 H), 3.57–3.54 (m, 1 H), 3.45 (t, J = 6.5 Hz, 2 H),
1.64–1.58 (m, 2 H), 1.45–1.30 (m, 14 H), 0.91 (t, J = 6.6 Hz, 3 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 138.7, 128.3, 127.6, 127.5,
72.9, 71.9, 70.4, 37.5, 37.2, 29.7, 29.6, 27.9, 26.2, 25.6, 22.8,
14.1 ppm. C18H30O2 (278.43): calcd. C 77.65, H 10.86; found C
77.46, H 10.69.
IR (liquid film, CHCl ): ν = 2934, 1733, 1694, 1405, 1215,
˜
3
1163 cm–1. H NMR (200 MHz, CDCl3): δ = 9.74 (m, 1 H), 4.90–
1
4.81 (m, 1 H), 4.29–4.21 (m, 1 H), 3.56–3.35 (m, 2 H), 2.43–2.39
(m, 2 H), 2.32–1.86 (m, 4 H), 1.65–1.50 (m, 6 H), 1.44 and 1.41
(rotamers, s, s, 9 H), 1.31–1.24 (m, 8 H), 0.87 (t, J = 6.6 Hz, 3 H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 202.2 and 202.0 (rotamers),
172.7 and 172.6 (rotamers), 154.2 and 153.8 (rotamers), 79.7 and
79.5 (rotamers), 74.8 and 74.5 (rotamers), 59.2, 46.5 and 46.3 (rota-
(S)-2-[(S)-11-(Benzyloxy)undecan-5-yl]-1-tert-butylpyrrolidine-1,2-
dicarboxylate (25): To a solution of N-Boc--proline (4.0 g,
18.6 mmol), EDCI (3.86 g, 20.1 mmol), and DMAP (946 mg,
7.7 mmol) in CH2Cl2 (60 mL), was added 6 (4.31 g, 15.5 mmol) at
0 °C. After 12 h at room temperature, the reaction mixture was mers), 43.7, 33.9 and 33.9 (rotamers), 33.9 and 33.8 (rotamers),
quenched with water, and the organic layer was separated. The
aqueous layer was extracted with ethyl acetate (3ϫ50 mL). The
combined organic layer was washed with brine, dried with anhy-
31.0 and 30.1 (rotamers), 29.7 and 29.0 (rotamers), 28.4 (2 C), 27.5
and 27.3 (rotamers), 25.1 and 24.9 (rotamers), 24.5 and 24.3 (rota-
mers), 23.4, 22.5, 21.9, 14.0 and 13.9 (rotamers) ppm. C21H37NO5
Eur. J. Org. Chem. 2008, 6213–6224
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6221

D. K. Mohapatra et al.
FULL PAPER
(383.52): calcd. C 65.77, H 9.72, N 3.65; found C 65.65, H 9.84, N
3.73.
H), 2.45 (d, J = 2.2 Hz, 1 H), 2.29 (dt, J = 7.3, 1.6 Hz, 2 H), 2.14–
2.00 (m, 6 H), 1.77–1.46 (m, 10 H), 1.41 (s, 3 H), 1.39 (s, 3 H),
1.36–1.26 (m, 26 H), 0.92 (m, 9 H), 0.91 (t, J = 6.7 Hz, 3 H), 0.17
(s, 3 H), 0.13 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.2
and 172.2 (rotamers), 171.7, 146.5 and 146.3 (rotamers), 108.9, 83.1
and 83.1 (rotamers), 78.4, 74.8 and 74.6 (rotamers), 74.5 and 74.4
(rotamers), 73.9, 63.9, 59.7 and 58.9 (rotamers), 47.0 and 46.3 (rot-
amers), 36.0 and 35.9 (rotamers), 34.1 and 33.9 (rotamers), 34.0
and 33.8 (rotamers), 32.0, 31.7, 29.7, 29.6, 29.5, 29.4, 28.8 and 28.7
(rotamers), 28.4 and 28.3 (rotamers), 27.9 and 27.7 (rotamers),
27.3, 27.2, 26.2, 25.8, 25.0, 24.8 (2 C), 22.6 and 22.5 (rotamers),
18.2, 14.1 and 14.0 (rotamers), –4.6, –4.9 ppm. C44H78INO6Si
(872.08): calcd. C 60.60, H 9.02, N 1.61; found C 60.39, H 9.22, N
1.47.
Anhydrous CrCl2 (4.93 g, 40.1 mmol) was suspended in THF
(80 mL) under an argon atmosphere. A solution of the above alde-
hyde (2.56 g, 6.7 mmol) and iodoform (5.28 g, 13.4 mmol) in THF
(50 mL) was added dropwise to the suspension at 0 °C. After stir-
ring at 0 °C for 3 h, the reaction mixture was poured into water
(150 mL) and extracted with diethyl ether (3ϫ75 mL). The com-
bined extract was washed with brine, dried with anhydrous
Na2SO4, and concentrated. The residue was purified on silica gel
(light petroleum/ethyl acetate, 9:1) to provide 27 (3.1 g, 90%) as a
light-yellow oil. [α]2D5 = –35.4 (c = 1.2, CHCl3). IR (liquid film,
CHCl ): ν = 2400, 1737, 1690, 1405, 1162 cm–1 1H NMR
.
˜
3
(200 MHz, CDCl3): δ = 6.48 (dt, J = 14.3, 7.2 Hz, 1 H), 5.98 (d, J
= 14.3 Hz, 1 H), 4.91–4.82 (m, 1 H), 4.32–4.21 (m, 1 H), 3.58–3.35
(m, 2 H), 2.22–1.92 (m, 6 H), 1.61–1.49 (m, 4 H), 1.46 and 1.43
(rotamers, s, s, 9 H), 1.29 (m, 10 H), 0.89 (t, J = 6.5 Hz, 3 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 172.7 and 172.6 (rotamers), 154.1
and 153.8 (rotamers), 146.4 and 146.3 (rotamers), 79.7 and 79.4
(rotamers), 74.8 and 74.6 (rotamers), 74.5 and 74.4 (rotamers), 60.3
and 59.1 (rotamers), 46.4 and 46.2 (rotamers), 35.9, 33.9, 33.7, 31.0
and 30.0 (rotamers), 28.9 and 28.7 (rotamers), 28.4 (2 C), 28.2 and
27.8 (rotamers), 27.4 and 27.3 (rotamers), 25.0 and 24.9 (rotamers),
24.3, 23.4, 22.6, 14.0 and 13.9 (rotamers) ppm. C22H38INO4
(507.45): calcd. C 52.07, H 7.55, N 2.76; found C 52.25, H 7.43, N
3.03.
28: Tetrakis(triphenylphosphane)palladium(0) (253 mg, 0. 2 mmol)
and CuI (83 mg, 0.4 mmol) were added successively to a stirred
solution of 3 (1.91 g, 2.2 mmol) in anhydrous Et2NH (10 mL) at
room temperature, and the reaction mixture was degassed (4ϫ)
gently with argon under fringe throng process. After 30 min, the
reaction was quenched by the addition of water and extracted with
diethyl ether (3 ϫ 50 mL). The combined organic fraction was
washed with brine, dried with anhydrous Na2SO4, and concen-
trated. The residue was purified on silica gel (230–400 mesh; light
petroleum/ethyl acetate, 7:3) to afford 28 (572 mg, 35%) as a yellow
oil. [α]2D5 = +1.9 (c = 1.7, CHCl ). IR (liquid film, CHCl ): ν =
˜
3
3
2927, 1733, 1646, 1463, 1252, 1161, 1069 cm–1
.
1H NMR
(400 MHz, CDCl3): δ = 6.09 (dt, J = 15.8, 7.2 Hz, 1 H), 5.45 (d, J
= 15.8 Hz, 1 H), 4.92–4.85 (m, 1 H), 4.72–4.71 (m, 1 H), 4.51 (dd,
J = 9.1, 3.5 Hz, 1 H), 4.23 (dt, J = 7.8, 3.1 Hz, 1 H), 3.71 (dd, J =
8.0, 2.8 Hz, 1 H), 3.67–3.49 (m, 2 H), 2.35–2.18 (m, 4 H), 2.11 (t,
J = 6.6 Hz, 2 H), 2.02–1.87 (m, 4 H), 1.58–1.46 (m, 10 H) 1.40 (s,
3 H), 1.39 (s, 3 H), 1.27 (m, 24 H), 0.94 (m, 9 H), 0.90 (t, J =
6.7 Hz, 3 H), 0.16 (s, 3 H), 0.13 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 172.0 and 171.9 (rotamers), 171.8, 145.2 and 144.7
(rotamers), 109.1 and 108.9 (rotamers), 108.2, 86.3 and 86.1 (rota-
mers), 85.1 and 85.0 (rotamers), 83.1 and 83.0 (rotamers), 76.0 and
75.5 (rotamers), 74.7, 62.2, 60.2 and 59.4 (rotamers), 47.0 and 46.3
(rotamers), 34.6 and 34.5 (rotamers), 34.0, 33.9 and 33.9 (rota-
mers), 33.7 and 33.6 (rotamers), 33.2 and 33.0 (rotamers), 32.0 and
31.7 (rotamers), 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 29.1, 29.0, 28.9,
28.7, 28.6, 27.9 and 27.7 (rotamers), 27.5, 27.1 and 27.0 (rotamers),
25.9, 25.5, 25.3 and 25.2 (rotamers), 24.9, 24.8, 24.7 and 24.7 (rota-
mers), 22.7 and 22.7 (rotamers), 22.6 and 22.5 (rotamers), 18.4,
14.2 and 14.1 (rotamers), –4.8 ppm. C44H77NO6Si (744.17): calcd.
C 71.01, H 10.43, N 1.88; found C 71.23, H 10.62, N 1.67.
(S)-[(S,E)-12-Iodododec-11-en-5-yl]-1-(13-{(4S,5R)-5-[(S)-1-(tert-bu-
tyldimethylsilyloxy)prop-2-ynyl]-2,2-dimethyl-1,3-dioxolan-4-yl}tri-
decanoyl)pyrrolidine-2-carboxylate (3): A suspension of compound
27 (2.45 g, 4.8 mmol) and HCl (4  in ethyl acetate, 25 mL) was
stirred for 3 h at room temperature. After completion of the reac-
tion (monitored by TLC), the reaction mixture was diluted with
ethyl acetate and neutralized with saturated sodium hydrogen car-
bonate solution (55 mL). The aqueous phase was extracted with
ethyl acetate (3ϫ75 mL). The combined organic layer was washed
with brine, dried with anhydrous Na2SO4, and concentrated. The
residue was purified on neutral alumina (ethyl acetate) to provide
free amine 4 (1.59 g, 81%) as a yellow oil. [α]2D5 = –10.4 (c = 3.5,
CHCl ). IR (liquid film, CHCl ): ν = 3343, 2930, 1730, 1605, 1459,
˜
3
3
1377, 1215 cm–1. 1H NMR (200 MHz, CDCl3): δ = 6.49 (dt, J =
14.3, 7.2 Hz, 1 H), 5.98 (d, J = 14.3 Hz, 1 H), 4.95–4.83 (m, 1 H),
3.84–3.72 (m, 1 H), 3.20–3.08 (m, 1 H), 3.00–2.92 (m, 2 H), 2.27–
1.99 (m, 4 H), 1.90–1.70 (m, 4 H), 1.58–1.49 (m, 4 H), 1.33–1.25 (m,
8 H), 0.89 (t, J = 6.6 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 174.2, 146.3, 75.2, 74.6, 59.7, 46.7, 35.9, 33.8, 30.4, 29.7, 28.7,
28.2, 27.4, 25.2, 25.0, 22.5, 14.0 ppm. C17H30INO2 (407.33): calcd.
C 50.13, H 7.42, N 3.44; found C 50.29, H 7.21, N 3.32.
(3aR,4S,14S,16aS,33aS)-14-Butyl-4-(tert-butyldimethylsilyloxy)-
2,2-dimethylhexacosahydro-3aH-[1,3]dioxolo[4,5-r]pyrrolo[2,1-c][1,4]-
oxaazacyclotriacontine-16,21(4H,22H)-dione (29): A suspension of
28 (450 mg, 0.6 mmol) and Raney Ni (75 mg) in ethanol (5 mL)
was stirred under a hydrogen atmosphere at normal pressure and
temperature. After 12 h, the reaction mixture was filtered through
a pad of Celite and concentrated. The residue was purified by silica
gel column chromatography (light petroleum/ethyl acetate, 7:3) to
provide 29 (420 mg, 92%) as a colorless oil. [α]2D5 = –19.8 (c = 0.9,
To a solution of acid 8 (1.17 g, 2.4 mmol), HOBt (320 mg,
2.4 mmol), and EDC (600 mg, 3.1 mmol) in CH2Cl2 (15 mL) was
added free amine 4 (1.19 g, 2.9 mmol) at 0 °C. After 12 h at room
temperature, the reaction mixture was quenched with water, and
the organic layer was separated. The aqueous layer was extracted
with ethyl acetate (3ϫ50 mL). The combined organic layer was
washed with water and brine, dried with anhydrous Na2SO4, and
concentrated. The residue was purified by silica gel column
chromatography (light petroleum/ethyl acetate, 4:1) to afford 3
(2.0 g, 96%) as a yellow oil. [α]2D5 = –19.4 (c = 1.3, CHCl3). IR
CHCl ). IR (liquid film, CHCl ): ν = 2929, 1730, 1638, 1463, 1380,
˜
3
3
1
1215 cm–1. H NMR (400 MHz, CDCl3): δ = 4.92–4.86 (m, 1 H),
4.51 (dd, J = 9.1, 3.5 Hz, 1 H), 4.00–3.96 (m, 1 H), 3.84–3.79 (m,
1 H), 3.74–3.65 (m, 1 H), 3.62–3.47 (m, 2 H), 2.29–2.12 (m, 4 H),
2.05–1.86 (m, 4 H), 1.66–1.58 (m, 4 H), 1.54–1.49 (m, 8 H), 1.37
(s, 6 H), 1.25 (m, 32 H), 0.90 (m, 9 H), 0.89 (t, J = 6.7 Hz, 3 H),
(liquid film, CHCl ): ν = 2930, 2206, 2104, 1734, 1659, 1501, 1431,
˜
3
1215, 1081 cm–1. 1H NMR (200 MHz, CDCl3): δ = 6.49 (dt, J =
14.3, 7.1 Hz, 1 H), 5.98 (d, J = 14.3 Hz, 1 H), 4.94–4.81 (m, 1 H), 0.07 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.0 and
4.56–4.44 (m, 1 H), 4.40 (dd, J = 5.6, 2.2 Hz, 1 H), 4.02 (dt, J = 171.9 (rotamers), 171.8, 107.8, 81.8 and 81.7 (rotamers), 76.1, 75.0
7.6, 3.1 Hz, 1 H), 3.71 (dd, J = 7.2, 5.6 Hz, 1 H), 3.65–3.44 (m, 2
and 74.8 (rotamers), 72.0 and 71.8 (rotamers), 60.1 and 59.3 (rota-
6222
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 6213–6224

First Asymmetric Total Synthesis of Penarolide Sulfate A1
mers), 47.0 and 46.2 (rotamers), 34.9 and 34.5 (rotamers), 34.1 and
33.9 (rotamers), 33.7, 33.6, 33.5, 33.4, 31.9 and 31.8 (rotamers),
31.6 and 31.6 (rotamers), 30.0, 29.6 (2 C), 29.5, 29.3, 29.2, 29.0 and
28.9 (rotamers), 28.6, 27.4 and 27.3 (rotamers), 27.2, 25.9, 25.6 and
silica gel column chromatography (light petroleum/ethyl acetate,
3:2) to furnish 31 (75 mg, 94%) as a light-yellow oil. [α]2D5 = –25.5
(c = 0.3, CHCl ). IR (liquid film, CHCl ): ν = 3205, 2854, 1735,
˜
3
3
1638, 1404, 1246 cm–1. 1H NMR (400 MHz, CDCl3): δ = 4.91–4.85
25.3 (rotamers), 25.0 (2 C), 24.8 and 24.7 (rotamers), 24.6, 24.4, (m, 1 H), 4.50 (dd, J = 8.7, 3.3 Hz, 1 H), 4.03–4.00 (m, 2 H), 3.82
22.6 and 22.6 (rotamers), 22.5 and 22.4 (rotamers), 18.1, 14.1 and
13.9 (rotamers), –4.3, –4.5 ppm. C44H83NO6Si (750.22): calcd. C
70.44, H 11.15, N 1.87; found C 70.23, H 11.27, N 1.77.
(m, 1 H), 3.73–3.67 (m, 1 H), 3.64–3.50 (m, 2 H), 2.32–2.13 (m, 4
H), 2.06–1.91 (m, 4 H), 1.67–1.61 (m, 4 H), 1.52–1.43 (m, 8 H),
1.40 (s, 3 H), 1.39 (s, 3 H), 1.26 (m, 32 H), 0.89 (t, J = 6.7 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.0 and 171.9 (rota-
mers), 171.7, 108.0, 82.9 and 82.8 (rotamers), 76.0 and 75.4 (rota-
mers), 75.2 and 74.8 (rotamers), 70.2 and 70.0 (rotamers), 60.2 and
59.3 (rotamers), 47.0 and 46.3 (rotamers), 34.6 and 34.5 (rotamers),
34.0, 33.8 and 33.7 (rotamers), 33.6, 32.1, 32.0, 31.7, 29.7, 29.5,
29.4, 29.3 (2 C), 29.1 and 29.0 (rotamers), 28.8 and 28.7 (rotamers),
28.6, 27.5 (2 C), 27.4 (2 C), 27.1, 25.9 and 25.8 (rotamers), 25.4,
25.3, 25.2, 24.9 and 24.8 (rotamers), 22.7 and 22.6 (rotamers), 22.6
and 22.5 (rotamers), 14.2 and 14.1 (rotamers) ppm. C38H69NO6
(635.96): calcd. C 71.77, H 10.94, N 2.20; found C 71.64, H 11.03,
N 2.37.
(3S,13S,15S,32aS)-3-Butyl-13,14,15-trihydroxyoctacosahydro-1H-
pyrrolo[2,1-c][1,4]oxaazacyclotriacontine-1,28(3H)-dione (30): A
solution of 29 (336 mg, 0.45 mmol) and pTSA (50 mg) in methanol
(5 mL) was stirred at room temperature for 4 h. The reaction mix-
ture was neutralized (pH 6) by the addition of Et3N (0.5 mL) and
concentrated. The residue was purified by silica gel column
chromatography (light petroleum/ethyl acetate, 2:3) to afford 30
(217 mg, 82%) as a light-yellow oil. [α]2D5 = –19.4 (c = 1.0, CHCl3).
IR (liquid film, CHCl ): ν = 3413, 2924, 1737, 1631, 1463, 1277,
˜
3
1193 cm–1. H NMR (400 MHz, CDCl3): δ = 4.92–4.84 (m, 1 H),
1
4.50 (dd, J = 9.1, 3.5 Hz, 1 H), 3.92–3.80 (m, 2 H), 3.63–3.57 (m,
2 H), 3.52–3.44 (m, 1 H), 2.31–2.09 (m, 8 H), 2.03–1.89 (m, 4 H),
1.66–1.49 (m, 10 H), 1.27 (m, 30 H), 0.89 (t, J = 6.7 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 172.3 and 172.1 (rotamers),
172.0, 76.2, 75.0 and 74.9 (rotamers), 70.3, 60.2 and 59.3 (rota-
mers), 47.0 and 46.3 (rotamers), 34.6, 34.5, 34.0 and 33.8 (rota-
mers), 33.6 and 33.5 (rotamers), 32.7 and 32.7 (rotamers), 32.6 and
32.6 (rotamers), 31.9 and 31.6 (rotamers), 29.7, 29.6 (2 C), 29.5,
29.4, 29.3, 29.2, 28.8 and 28.8 (rotamers), 28.4 and 28.3 (rotamers),
27.4 and 27.4 (rotamers), 25.5 and 25.5 (rotamers), 24.8 and 24.7
(rotamers), 22.7 and 22.7 (rotamers), 22.5 and 22.4 (rotamers), 14.1
and 14.0 (rotamers) ppm. C35H65NO6 (595.89): calcd. C 70.55, H
10.99, N 2.35; found C 70.41, H 11.17, N 2.18.
General Procedure for Enzyme Inhibition Assay: Inhibition assay for
the inhibitory potencies of the desulfated penarolide sulfate A1 (30)
was determined by measuring the residual hydrolytic activities of
the glycosidases of the corresponding p-nitrophenyl glycosides in
the presence of desulfated penarolide sulfate A1 (30) spectrophoto-
metrically.
In the case of α-glucosidase (yeast), the assay was performed in a
citrate phosphate buffer (50 m, pH 6.8) with p-nitrophenyl α--
glucopyranoside as the substrate. The enzyme was incubated with
the inhibitor at various concentrations for 30 min, and the sub-
strate was then added. The reaction was carried out at 37 °C for
30 min and then quenched with a Na2CO3 solution.
In the case of β-glucosidase (almond), the assay was performed in
a citrate phosphate buffer (50 m, pH 5.5) with p-nitrophenyl β--
glucopyranoside as the substrate. The reaction was carried out at
37 °C for 30 min and then quenched with a Na2CO3 solution.
Penarolide Sulfate A1 (1): Sulfur trioxide/pyridine complex
(296 mg, 1.86 mmol) was added to a solution of triol 30 (37 mg,
0.06 mmol) in dry DMF (3 mL) under a nitrogen atmosphere, and
the mixture was stirred at room temperature for 36 h. Water (4 mL)
was added at 0 °C, and the reaction mixture was stirred for 30 min
and then basified (pH 9) at 0 °C by adding saturated NaHCO3
solution (6 mL). After stirring for 30 min, the resulting solution
was concentrated in vacuo. The residue was triturated with ethyl
acetate and filtered. The residue was purified by silica gel column
chromatography (methanol/ethyl acetate, 3:7) to afford penarolide
sulfate A1 (1; 47 mg, 84%) as an amorphous solid. [α]2D5 = –24.6 (c
In the case of α-galactosidase (green coffee beans), the assay was
performed in a citrate phosphate buffer (50 m, pH 6.5) with p-
nitrophenyl α--galactopyranoside as the substrate. The reaction
was carried out at 25 °C for 20 min and then quenched with a
Na2CO3 solution.
In the case of β-galactosidase, each assay was performed in citrate
buffer (50 m, pH 4.5) with p-nitrophenyl β--galactosidase as the
substrate. The reaction was carried out at 25 °C for 20 min and
then quenched with a Na2CO3 solution.
= 0.5, CH OH). IR (nujol): ν = 2927, 1734, 1636, 1248, 1184 cm–1.
˜
3
1H NMR (400 MHz, CD3OD): δ = 5.04 (d, J = 5.8 Hz, 1 H), 4.66
(d, J = 9.4 Hz, 1 H), 4.63–4.61 (m, 1 H), 4.40 (dd, J = 8.7, 4.6 Hz,
1 H), 3.63 (t, J = 7.5 Hz, 2 H), 2.43 (dt, J = 15.1, 7.5 Hz, 2 H),
2.30–2.23 (m, 2 H), 2.14–1.92 (m, 4 H), 1.85–1.77 (m, 2 H), 1.58–
1.45 (m, 14 H), 1.30 (m, 28 H), 0.90 (t, J = 6.7 Hz, 3 H) ppm. 13C
NMR (100 MHz, CD3OD): δ = 174.2, 173.8, 80.7, 79.4, 78.9, 76.2,
61.0, 48.8, 35.2, 34.7, 31.7, 31.3, 30.9, 30.8, 30.6, 30.4, 28.5, 26.4,
26.0, 25.8, 23.5, 14.3 ppm. MS (ESI): m/z = 924.69 [M + Na]+.
In the case of α-mannosidase (jack bean), the assay was performed
in an acetate buffer (50 m, pH 4.5) with p-nitrophenyl α--man-
nopyranoside as the substrate. The reaction was carried out at
25 °C for 20 min and then quenched with a Na2CO3 solution.
In the case of β-mannosidase (snail acetone), the assay was per-
formed in an acetate buffer (50 m, pH 4.0) with p-nitrophenyl β-
-mannopyranoside as the substrate. The reaction was carried out
at 25 °C for 20 min and then quenched with a Na2CO3 solution.
(3aS,4S,14S,16aS,33aS)-14-Butyl-4-hydroxy-2,2-dimethylhexacosa-
hydro-3aH-[1,3]dioxolo[4,5-γ]pyrrolo[2,1-c][1,4]oxaazacyclotriacon-
tine-16,21(4H,22H)-dione (31): To a stirred solution of compound
29 (94 mg, 0.13 mmol) in THF (3 mL) was added TBAF (1.0  in
THF, 0.19 mL) dropwise. The reaction mixture was then stirred for
1 h, by which time the reaction was complete (as monitored by
TLC). The reaction was then quenched by the addition of water,
Supporting Information (see footnote on the first page of this arti-
cle): Representative 1H and 13C NMR spectra of all compounds
outlined in the Experimental Section.
and the reaction mixture was concentrated under reduced pressure. Acknowledgments
The crude mass was taken up in water and extracted with ethyl
acetate (3ϫ10 mL), washed with brine, dried with anhydrous
Na2SO4, and concentrated. The crude residue was then purified by
D. B. and K. S. S. thank the Council of Scientific and Industrial
Research (CSIR), New Delhi, for financial assistance in the form
Eur. J. Org. Chem. 2008, 6213–6224
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6223

D. K. Mohapatra et al.
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Received: July 9, 2008
Published Online: November 14, 2008
6224
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Eur. J. Org. Chem. 2008, 6213–6224