Total synthesis and determination of the absolute configuration of coscinosulfate. A new selective inhibitor of Cdc25 protein phosphatase

Article abstract of DOI:10.1021/jo010154c

The first total synthesis of coscinosulfate 1, a metabolite isolated from a sea sponge, starting from (+)-sclareolide 3 is described. The convergent synthesis strategy relies on the coupling of sulfone 21 with the bromide 26. The sulfone fragment 21 was obtained by successive asymmetric aldol reaction with aldehyde 2 to introduce the stereocenters at C-12 and C-13, followed by one-carbon homologation via Horner - Wadsworth - Emmons olefination. The selective sulfatation at C-12 was accomplished through the quinone intermediate 31 obtained by selective oxidation of hydroquinone 30 this, when followed by reduction, furnished the desired coscinosulfate 1. X-ray analysis of the intermediate aldehyde 18 confirmed the proposed stucture.

Full text of DOI:10.1021/jo010154c

J . Org. Chem. 2001, 66, 7263-7269
7263
Tota l Syn th esis a n d Deter m in a tion of th e Absolu te Con figu r a tion
of Coscin osu lfa te. A New Selective In h ibitor of Cd c25 P r otein
P h osp h a ta se§
Ste´phane Poigny,† Samia Nouri,† Ange`le Chiaroni,‡ Miche`le Guyot,† and
Mohammad Samadi*,†
Laboratoire de Chimie des Substances Naturelles, associe´ au CNRS, Muse´um National d'Histoire
Naturelle, 63, rue Buffon, F-75005 Paris, France, and Institut de Chimie des Substances Naturelles,
CNRS, 1 Avenue de la terrasse, 91198 Gif-sur-Yvette, France
samadi@mnhn.fr
Received February 7, 2001
The first total synthesis of coscinosulfate 1, a metabolite isolated from a sea sponge, starting from
(+)-sclareolide 3 is described. The convergent synthesis strategy relies on the coupling of sulfone
21 with the bromide 26. The sulfone fragment 21 was obtained by successive asymmetric aldol
reaction with aldehyde 2 to introduce the stereocenters at C-12 and C-13, followed by one-carbon
homologation via Horner-Wadsworth-Emmons olefination. The selective sulfatation at C-12 was
accomplished through the quinone intermediate 31 obtained by selective oxidation of hydroquinone
30; this, when followed by reduction, furnished the desired coscinosulfate 1. X-ray analysis of the
intermediate aldehyde 18 confirmed the proposed stucture.
Cdc25 is a dual specificity family of the protein tyrosine
phosphatase involved in the regulatory activation of
cyclin dependent kinases (CDKs) by dephosphorylations
of a threonine and a tyrosine of the subunit of the CDKs.
Human cells contain three Cdc25 genes named cdc25A,
cdc25B, and cdc25C. Cdc25A is thought to activate
CDK2/cyclin E and thereby trigger the G1/S transition
of the cell cycle. Cdc25B appears to play a role in both
G1 and G2 phases, while cdc25C specifically dephospho-
rylates CDK1/cyclin B, thereby triggering the G2/M
transition. Cdc25A and cdc25B are known to be oncogenic
and overexpressed in a number of tumor cell lines. Cdc25
phosphatases constitute attractive screening targets to
identify new antimitotic compounds of potential thera-
peutic interest, and several synthetic and natural com-
pounds were found to be inhibitors of these enzymes.1
Coscinosulfate 1, a sesterterpene sulfate, was recently
isolated in our group from the marine sponge Coscino-
derma mathewsi (New Caledonia).2 It exhibits a selective
inhibition of the cdc25A protein phosphatase,3 with an
IC50 of 3 µM.
the small coupling constant J 12,13 < 1 Hz. In contrast,
coscinosulfate 1 presents a large coupling constant (J 12,13
) 11 Hz), and the relative configuration at C-12 and C-13
has been assigned as 12R,13R through Mosher ester
analysis of the free secondary alcohol.3
Given these conflicting data, and as a part of our
program directed toward the synthesis of bioactive
marine natural products, we undertook the synthesis of
1. Our strategy for the synthesis of 1 is presented in the
retrosynthetic plan shown in Scheme 1. Accordingly, the
sesterterpene sulfate 1 was dissected into two fragments
A and B, which could be joined by alkylation and
subsequent reductive desulfonylation, followed by selec-
tive sulfatation of the secondary alcohol at C-12. The
sulfone fragment A could be prepared by successive
stereocontrolled aldol reactions, to introduce the C-12 and
C-13 stereocenters, and one carbon homologation via
Horner-Wadsworth-Emmons (HWE) olefination. In
turn, aldehyde 2 could be derived from the (3aR)-(+)-
sclareolide 3 bearing the chiral centers at C-5, C-9, and
C-10 required for the drimane skeleton.
As outlined below, herein we report the concise syn-
thesis of this sesterterpene sulfate which enabled us to
confirm the absolute configuration of the naturally oc-
curring 1.
The same structure was proposed for halisulfate-1
isolated from the marine sponge Halicondriidea by Ker-
nan and Faulkner et al.,4 for which the optical rotation
([R]D -27) was of the opposite sign to that of coscinosul-
fate 1 ([R]D +5). The stereochemistry at C-13 and C-12
for halisulfate-1 was postulated as 12R*,13R* based on
The readily available 3 was converted to diol 4,5 which
was followed by selective protection of the primary
alcohol to give compound 5 in 99% yield over two steps
(Scheme 2). Dehydration of alcohol 6 afforded, in quan-
titative yield, an inseparable mixture of exo- and endo-
* To whom correspondence should be addressed. Tel: 33-1-40-79-
31-44. Fax: 33-1-40-79-31-35. E-mail: Samadi@mnhn.fr.
§ Presented at the Second Euroconference on Marine Natural
Products, Santiago de Compostela, Spain, Sept 12-16, 1999, abstract
PS-24.
olefins 6 (∆:8,22 ∆:7,8 8,9) in a 80:15:5 ratio (coscinosulfate
∆
numbering). Selective allylic oxidation6 produced an
alcohol (7) as the sole isomer in 62% yield over two steps.
In the described conditions only the exo-olefin undergoes
† Laboratoire de Chimie.
‡ Institut de Chimie des Substances Naturelles.
(1) Eckstein, J . W. Invest. New Drugs 2000, 18, 149-156.
(2) Loukaci, A.; Le Saout, I.; Samadi, M.; Leclerc, S.; Damiens, E.;
Meijer, L.; Debitus, C.; Guyot, M. Bioorg. Med. Chem., in press.
(3) Baratte B.; Meijer, L.; Galaktionov, K.; Beach D. Anticancer Res.
1992, 12, 873.
(5) Zahra, J . P.; Chauvet, F.; Coste-Manie`re, I.; Martres, P.; Perfetti,
P.; Waegell, B. Bull. Soc. Chim. Fr. 1997, 134, 1001.
(6) Umbreit, M. A.; Sharpless, K. B. J . Am. Chem. Soc. 1977, 99,
5527.
(4) Kernan, M. R.; Faulkner, D. J . J . Org. Chem. 1988, 53, 4574.
10.1021/jo010154c CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/03/2001

7264 J . Org. Chem., Vol. 66, No. 22, 2001
Poigny et al.
Sch em e 1
Sch em e 2
allylic oxidation to produce the corresponding allylic
alcohol, whereas the endo-olefins remain unreacted and
can be easily separated. Catalytic hydrogenation fur-
nished the saturated alcohol (8) (80%) as a mixture of
isomers, along with the endo-olefin (12) (17%). Oxidation
of 8 followed by treatment with NaOMe in MeOH gave
ketone 9 in 88% yield (over two steps). Ketone 9 was
transformed into the endo-olefin 12 as follows. Luche
reduction7 of ketone 9 gave alcohol 10, which after
mesylation furnished mesylate 11, and in situ bromina-
tion and debromination gave pure12 in 89% yield over
three steps. To us, the sequence of reactions described
above seemed to be the only alternative to obtain
pure 12 without contamination either with the exo- or
with the tetrasubstituted endo-olefins. Deprotection of
TBDPS’s ether afforded compound 138 (98%), and oxida-
tion of the resulting primary alcohol furnished 2 in 96%
yield.
At this stage, the desired 2 was submitted to asym-
metric aldol reaction to introduce the C-12 and C-13
stereocenters. Thus, stereoselective aldol coupling of the
Evans oxazolidinone 149 with 2 furnished the syn adduct
(15) in 87% yield (Scheme 3). Transamidation10 of 15 gave
16 (98%), which was followed by protection of the
secondary alcohol to afford 17 in 98% yield. Reduction of
the amide moiety11 gave aldehyde 18 in almost quantita-
tive yield. Single-crystal X-ray analysis of 18 confirmed
the structure of this advanced intermediate (Figure 1).
HWE olefination of 18 with (EtO)2OPCH2SO2Ph (19)12
gave the trans olefin 20 (70%), and subsequent selective
reduction13 of the activated double bond provided the
saturated sulfone 21 (fragment A) in 92% yield.
The remaining right side chain fragment B, the allyl
bromide, was prepared as follows: protection of 22 14 gave
23 (97%) (Scheme 4). Allylic oxidation of 23 gave alde-
hyde 24 and alcohol 25 in a ratio of 3:1, and reduction of
the crude mixture provided the alcohol 25 in 54% yield
over two steps. Bromination using CBr4 and PPh3 on
polymer support gave allyl bromide 26 in 99% yield.15
Coupling of sulfone 21 through its lithium anion in the
presence of bromide 26 gave the intermediate 27 as a
mixture of isomers (Scheme 5). Reductive desulfonyla-
tion16 of the phenyl sulfone moiety furnished the addition
(7) Luche, J .-L. J . Am. Chem. Soc. 1978, 100, 2226.
(8) The endo-olefin 13 has been previously prepared in 12 steps
starting from S-carvon in 15% overall yields. See: Verstegen-Haaksma,
A. A.; Swarts, H. J .; J ansen, J . M.; de Groot, A. Tetrahedron 1994, 50,
10095.
(12) (a) Blumenkopf, T. A. Synth. Commun. 1986, 16, 139. (b) Lee,
I. W.; Oh, D. Y. Synth. Commun. 1990, 20, 273.
(9) Evans, D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem. Soc. 1981,
103, 2127. Evans, D. A.; Nelson, J . V.; Vogel, E.; Taber, T. R. J . Am.
Chem. Soc. 1981, 103, 3099.
(10) Levin, J . I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982,
12, 989.
(11) Evans, D. A.; Miller, S. J .; Ennis, M. D.; Ornstein, P. L. J . Org.
Chem. 1992, 57, 1067.
(13) J acobi, P. A.; Craig, T. A.; Walker, D. G.; Arrick, B. A.;
Frechette, R. F. J . Am. Chem. Soc. 1984, 106, 5585.
(14) J urd, L.; Stevens, K.; Manners, G. Tetrahedron Lett. 1971, 25,
2275.
(15) Bromination of 25 using CBr4 and PPh3 and further purification
over silica gel gave 26 in 50% yield. For this reason, PPh3 was replaced
by PPh3 on polymer support to avoid the purification step.

Synthesis and Configuration of Coscinosulfate
J . Org. Chem., Vol. 66, No. 22, 2001 7265
Sch em e 3
Sch em e 4
Finally, selective oxidation of the hydroquinone moiety
of 30 afforded the quinone 31 and in situ sulfatation of
the secondary alcohol followed by reduction of the quino-
ne intermediate 32 provided coscinosulfate 1 in 58% yield
over three steps. The synthetic material was found to be
1
identical to the natural coscinosulfate as judged by H
NMR, mass spectrometry (MS), and high-resolution mass
spectrometry (HRMS). Comparison of optical rotation
confirmed that the synthetic and natural compounds
possess the same absolute stereochemistry (synthetic [R]D
+4.8 (c 0.25, MeOH); natural [R]D +5 (c 1.4, MeOH)). The
synthesis of coscinosulfate 1 described above requires 24
steps from readily available sclareolide 3.
In conclusion, we have described the first total syn-
thesis of coscinosulfate 1, which allowed us to establish
its absolute stereochemistry. The present strategy could
be applied to the synthesis of other isomers, at C-12 and
C-13 through a stereocontrolled aldol reaction step using
an appropriate oxazolidinone auxiliary,17 for the deter-
mination of the absolute stereochemistry of other com-
pounds in the series, such as halisulfate-1.
Exp er im en ta l Section
All the reactions were carried out under an argon atmo-
1
sphere. H and 13C NMR spectra were recorded on a Bruker
AC 300 MHz spectrometer. Chemical shifts (δ) are expressed
in ppm from Me4Si as internal standard. Mass spectra were
recorded on a Kratos MS 50 instrument at 70 eV (EI) or a
Nermag 10-10 (CI, NH3). IR spectra were recorded on a
Nicholet (impact 400D) FT-IR. All reagents were obtained from
commercial suppliers and used without further purification.
THF was freshly distilled from sodium benzophenone. Meth-
ylene chloride and triethylamine were distilled from CaH2.
DMSO was dried and stored over 4 Å molecular sieves. Flash
chromatography was carried out using silica gel 60F254
(Merck) with mixtures of ethyl acetate and hexane as eluent
unless specified otherwise. TLC analyses were performed on
thin-layer analytical plates 60F254 (Merck).
F igu r e 1. Ortep drawing of 18. Displacement ellipsoids are
shown at the 30% probability level.
product 28 in 70% yield over two steps. Deprotection of
TBS ether gave 29 in 93% yield. Catalytic transfer
hydrogenolysis of 29 (Pd/C 10%) in the presence of
ammonium formate as hydrogen donor caused the re-
moval of the aromatic benzyl ethers and the reduction
of the double bond (∆17,18) on the side chain, whereas with
the use of cyclohexadiene as hydrogen donor only one
benzyl group was removed. We found that the freshly
prepared lithium naphthalenide selectively removed the
benzyl ethers of 29 to afford triol 30 in 83% yield.
(8a S,1R,2R)-1-(2-H yd r oxyet h yl)-2,5,5,8a -t et r a m et h yl-
p er h yd r o-2-n a p h th a len ol (4). To a solution of (3aR)-(+)-
scalareolide 3 (34.23 mmol, 8.57 g) in dry THF (100 mL) at 0
°C was added LiAlH4 (34.23 mmol, 1.3 g) in portions. The
(17) (a) See ref 13. (b) Evans, D. A.; Takacs, J . M.; McGee, L. R.;
Ennis, M. D.; Mathre, D. J .; Bartroli, J . Pure Appl. Chem. 1981, 53,
1109. (c) Evans, D. A.; Nelson, J . V.; Taber, T. R. Top. Stereochem.
1982, 13, 1-115. (d) Gage, J . R.; Evans, D. A. Org. Synth. 1989, 68,
83. (e) Ager, D. J .; Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997,
30, 3-12.
(16) Sum, F. W.; Weiler, I. J . Am. Chem. Soc. 1979, 101, 4401.

7266 J . Org. Chem., Vol. 66, No. 22, 2001
Poigny et al.
Sch em e 5
mixture was stirred at this temperature for 1 h. The reaction
was quenched with EtOAc (5 mL), and the solvents were
evaporated under reduced pressure. The residue was dissolved
in CH2Cl2 (200 mL), washed with 1 N aqueous HCl (100 mL),
water, and brine (100 mL), and dried over MgSO4. The solvent
was evaporated under reduced pressure to give compound 4
(8.69 g, 100%) as a white solid: mp 128-129 °C, lit.8 130 °C;
To a cooled (-50 °C) solution of 5 (10.16 mmol, 5 g) and
4-DMAP (10.1 mmol, 1.23 g) in dry pyridine (60 mL) was added
SOCl2 (26.3 mmol, 1.84 mL) in a dropwise manner. The
reaction was stirred at this temperature for 1 h and then
warmed to 0 °C. The reaction was quenched with some ice,
and the pyridine was removed in vacuo. The residue was
dissolved in ether, washed successively with water, saturated
NaHCO3, and brine, and dried over MgSO4. Solvent was
evaporated under reduced pressure to give compound 6 (4.72
g, 98%) as a colorless oil, which was used without further
purification in the next step. To a suspension of SeO2 (0.2
mmol, 22 mg) and salicylic acid (1 mmol, 138 mg) in dry
CH2Cl2 (30 mL) was added tert-butylhydroperoxide (80%, 35.6
mmol, 4.5 mL), and then the mixture was stirred at room
temperature for 10 min. A solution of olefins 6 (4.72 g, 9.96
mmol) in CH2Cl2 (20 mL) was added dropwise, and the mixture
was stirred at room temperature for 48 h. Toluene (50 mL)
was added, and the solvents were evaporated in vacuo. The
residue was diluted with ether, washed with 10% aqueous
KOH, water, and brine, dried over MgSO4, and concentrated.
Purification over silica gel using hexanes/EtOAc (95:5) gave
alcohol 7 (3.09 g, 62% from 5) as a colorless oil: Rf 0.20
MS m/z (EI) 254 [M]+; IR (KBr) 3390, 2950, 2847, 1050 cm-1
;
1H NMR (CDCl3) δ 3.75 (m, 1H), 3.45 (m, 1H), 2.50 (s large,
2H), 1.85 (dt, 1H), 1.15 (s, 3H), 0.86 (s, 3H), 0.79 (s, 6H); 13C
NMR (CDCl3) δ 72.5, 63.6, 59.1, 55.9, 43.6, 41.7, 39.6, 39.3,
33.2, 33.1, 27.6, 24.2, 21.5, 20.3, 18.5, 15.0.
(4aS,8aS,1R,2R)-1-(2-(ter t-Bu tyldiph en ylsilyloxy)eth yl)-
2,5,5,8a -tetr a m eth ylp er h yd r o-2-n a p h th a len ol (5). To a
solution of diol 4 (13.4 mmol, 3.4 g) and imidazol (40 mmol,
2.73 g) in dry N,N-dimethylformamide (DMF) (30 mL) was
added TBDPSiCl (3.61 mL, 1.05 equiv). The mixture was
stirred at room temperature for 1 h. The DMF was removed
in vacuo. The residue was dissolved in ether, washed with
water and brine, dried over MgSO4, and concentrated. Flash
chromatography using hexanes/EtOAc (90:10) gave compound
5 (6.52 g, 99%) as a colorless oil: Rf 0.49 (hexanes/EtOAc, 90:
10); [R]20D +24 (c 2.05, CHCl3); MS m/z (CI) 510 (M + NH4)+;1H
NMR (CDCl3) δ 7.70 (m, 4H), 7.40 (m, 6H), 3.77 (m, 1H), 3.52
(td, J ) 9.9, 4.5 Hz, 1H), 3.19 (s, 1H, OH), 1.92 (dt, J ) 12.4,
3.0 Hz, 1H), 1.14 (s, 3H), 1.07 (s, 9H), 0.86 (s, 3H), 0.76 (s,
3H), 0.74 (s, 3H); 13C NMR (CDCl3) δ 135.7, 135.6, 133.1, 133.0,
129.7, 129.6, 127.6, 72.2, 65.7, 58.3, 55.9, 43.9, 41.8, 39.2, 38.7,
33.3, 33.1, 27.5, 26.8, 24.3, 21.4, 20.4, 19.0, 18.3, 15.2; HRMS
(CI) calcd for C32H52O2NSi [M + NH4]+ 510.3767, found
510.3793.
(hexanes/EtOAc, 95:5); [R]20 -12.9 (c 1.11, CHCl3); MS m/z
D
1
(CI) 508 (M + NH4)+; H NMR (CDCl3) δ 7.67 (m, 4H), 7.36
(m, 6H), 4.83 (s, 1H), 4.42 (s, 1H), 4.22 (bs, 1H), 3.71 (m, 1H),
3.55 (dt, J ) 9.9 Hz, 7.6 Hz, 1H), 2.14 (m, 1H), 1.05 (s, 9H),
1.04 (s, 3H), 0.85 (s, 3H), 0.76 (s, 3H), 0.60 (s, 3H); 13CNMR
(CDCl3) δ 149.6, 135.6, 134.8, 134.0, 133.9, 129.5, 127.5, 109.5,
73.9, 63.2, 47.4, 46.6, 42.0, 39.4, 38.6, 33.2, 33.0, 30.6, 26.9,
26.6, 21.5, 19.3, 19.1, 13.4; HRMS (CI) calcd for C32H50O2NSi
[M + NH4]+ 508.3600, found 508.3611.
(4aS,8aS,2R,4R)-4-(2-[ter t-Bu tyldiph en ylsilyloxy]eth yl)-
4a,8,8,tr im eth yl-3-m eth ylen eper h ydr o-2-n aph th alen ol (7).
(3S,4S,8aS,4aR)-4-(2-(ter t-Bu tyldiph en ylsilyloxy)eth yl)-
3,4a ,8,8-tetr a m eth ylp er h yd r o-2-n a p h th a len on e (9). A so-

Synthesis and Configuration of Coscinosulfate
J . Org. Chem., Vol. 66, No. 22, 2001 7267
lution of alcohol 7 (3.47 mmol, 1.7 g) and 10% Pd/C (170 mg)
in EtOH (30 mL) was stirred at room temperature under 1
atm of hydrogen for 12 h. The reaction was filtered through
Celite, and the filtrate was concentrated in vacuo. Purification
over silica gel using hexanes gave olefin 12 (279 mg, 17%).
Further elution using hexanes/EtOAc (95:5) gave alcohol 8
(1.37 g, 80%) as a colorless oil, which was dissolved in dry
CH2Cl2 (15 mL) followed by addition of PCC (5.48 mmol, 1.18
g) at 0 °C. The reaction mixture was stirred at room temper-
ature for 12 h. CH2Cl2 was evaporated in vacuo, and the
residue was triturated with ether, filtered, and solvent evapo-
rated under reduced pressure. The mixture of ketones thus
obtained was dissolved in anhydrous MeOH (20 mL), sodium
methylate (2.74 mmol, 148 mg) was added, and the reaction
was stirred overnight at room temperature. Methanol was
evaporated under reduced pressure, and the residue was
dissolved in ether, washed with brine, dried over MgSO4, and
concentrated. Flash chromatography using hexanes/EtOAc (95:
5) gave ketone 9 (1.196 g, 88%) as a white solid: Rf 0.17
39.2, 36.4, 33.1, 32.9, 30.4, 23.8, 22.0, 21.8, 18.7, 13.5; HRMS
(CI) calcd for C16H29O [M + H]+ 237.2218, found 237.2215.
(1S,4a S,8a S)-1,4,4a ,5,6,7,8,8a -Oct a h yd r o-2,5,5,8a -t et -
r a m eth yl-1-n a p h th a len eth a n a l (2). To a solution of alcohol
13 (3.2 mmol, 755 mg) in anhydrous DMSO (15 mL) was added
Et3N (20.8 mmol, 2.9 mL) followed by SO3‚pyridine (12.8 mmol,
2.04 g). The reaction was stirred at room temperature for 1 h
and then cooled in an ice bath. A 15 mL portion of 10% aqueous
KHSO4 was added dropwise, and the solution was stirred
vigorously for 15 min. The mixture was extracted with ether,
washed with water and brine, dried over MgSO4, and concen-
trated. The residue was purified over silica gel using hexanes/
EtOAc (98:2, then 95:5) to give aldehyde 3 (719 mg, 96%) as a
colorless oil: Rf 0.49 (hexanes/EtOAc, 95:5); [R]20 -33.6 (c
D
1.11, CHCl3); MS m/z (CI) 235 (M + H)+; IR (neat) 2922, 2842,
2714, 1726, 1650, 1447, 1386, 1146, 1093 cm-1 1H NMR
;
(CDCl3) δ 9.81 (t, J ) 1,5 Hz, 1H), 5.43 (dd, J ) 1.9, 1.6 Hz,
1H), 2.49 (m, 1H), 2.37 (m, 2H), 1.48 (t, J ) 1.4 Hz, 3H), 0.85
(s, 3H), 0.84 (s, 3H), 0.73 (s, 3H); 13C NMR (CDCl3) δ 203.4,
132.8, 123.3, 49.8, 48.5, 42.3, 42.0, 39.5, 35.9, 33.1, 32.9, 23.6,
22.5, 21.8, 18.7, 14.1; HRMS (CI) calcd for C16H27O [M + H]+
235.2062, found 235.2056.
(hexanes/EtOAc, 96:4); mp 64 °C; [R]20 -3.8 (c 1.04, CHCl3);
D
MS m/z (CI) 491 (M + H)+; H NMR (CDCl3) δ 7.66 (m, 4H),
1
7.39 (m, 6H), 3.65-3.47 (m, 2H), 2.39-2.10 (m, 3H), 1.84 (m,
1H), 1.05 (s, 9H), 0.95 (s, 3H), 0.90 (d, J ) 6.5 Hz, 3H), 0.82
(s, 3H), 0.81 (s, 3H); 13C NMR (CDCl3) δ 208.4, 135.6, 133.7,
129.6, 127.6, 64.6, 54.0, 53.6, 47.7, 41.7, 38.9, 38.4, 37.9, 33.5,
32.7, 32.5, 26.9, 21.1, 19.1, 18.3, 13.4, 12.6; HRMS (CI) calcd
for C32H47O2Si [M + H]+ 491.3333, found 491.3345.
(2S,3R)-1-[(4S)-4-Ben zyl-2-oxo-1,3-oxa zola n -3-yl]-3-h y-
d r oxy-2-m et h yl-4-[(1S,4a S,8a S)-1,4,4a ,5,6,7,8,8a -oct a h y-
dr o-2,5,5,8a-tetr am eth yl-1-n aph th alen yl]bu tan -1-on e (15).
To a cooled (0 °C) solution of oxazolidinone 14 (8.18 mmol,
1.906 g) in dry CH2Cl2 (15 mL) was added Bu2BOTf (8.9 mmol,
8.9 mL, 1 M in CH2Cl2) dropwise, followed by Et3N (11.14
mmol, 1.55 mL). After being stirred at 0 °C for 15 min, the
solution was cooled to -78 °C, and aldehyde 2 (1.74 g, 7.43
mmol) in dry CH2Cl2 (15 mL) was added. The reaction was
stirred at -78 °C for 1 h, warmed to 0 °C over 1 h, and stirred
at 0 °C for 2 h. The reaction was quenched by the addition of
phosphate buffer ( pH ) 7, 20 mL) followed by MeOH (20 mL).
After 5 min, a solution of 20 mL of 30% aqueous H2O2/MeOH
(1:3) was added in a dropwise manner. The reaction mixture
was stirred vigorously at 0 °C for 1 h. Solvents were removed
under reduced pressure, and product was extracted with ether.
The residue was purified on silica gel to give 15 (3.02 g, 87%)
(1S,4a S,8a S)-1,4,4a ,5,6,7,8,8a -Oct a h yd r o-2,5,5,8a -t et -
r a m et h yl-1-[2′-ter t-b u t yld ip h en ylsilyloxy)et h yl]-n a p h -
th a len e (10). To a solution of ketone 9 (2.08 mmol, 1.02 g) in
MeOH (20 mL) was added CeCl3‚7H2O (2.28 mmol, 850 mg).
The suspension was stirred at room temperature for 10 min
and cooled to -50 °C. NaBH4 (6.24 mmol, 237 mg) was added
in small portions. The reaction was stirred at -20 °C for 1 h.
The reaction was quenched with saturated aqueous NH4Cl and
concentrated. The residue was dissolved in ether, washed
successively with saturated NH4Cl, water, and brine, and dried
over MgSO4. The solvent was evaporated under reduced
pressure to give alcohol 10 as a colorless oil, which was
dissolved in dry CH2Cl2 (20 mL). To this were successively
added 4-DMAP (0.2 mmol, 25 mg), Et3N (12.48 mmol, 1.73
mL), and MsCl (6.24 mmol, 0.482 mL). The reaction was
stirred at room temperature for 12 h. The CH2Cl2 was
evaporated under reduced pressure, and the residue was
extracted with ether, washed successively with water and
brine, dried over MgSO4, and concentrated. The crude mesylate
11 was dissolved in anhydrous DMF (10 mL) followed by the
addition of lithium bromide (10.4 mmol, 894 mg) and lithium
carbonate (10.4 mmol, 769 mg). The reaction was heated at
150 °C for 1 h and cooled to room temperature. Water was
added, and the mixture was extracted with ether. The organic
layer was washed with brine, dried over MgSO4, and concen-
trated. Purification over silica gel using hexane and then
hexanes/EtOAc (98:2) gave 12 (878 mg, 89%) as a colorless
oil: Rf 0.71 (hexanes/EtOAc, 98:2); [R]20D -12.1 (c 1.55, CHCl3);
as a colorless oil: Rf 0.38 (hexanes/EtOAc, 8:2); [R]20 +41.5
D
(c 0.39, CHCl3); MS m/z (CI) 468 (MH+); H NMR (CDCl3) δ
1
7.36-7.19 (m, 5H), 5.40 (bd s, 1H), 4.71 (m, 1H), 4.26-4.04
(m, 2H), 3.78 (m, 1H), 3.24 (dd, J ) 13.4, 3.3 Hz, 1H), 2.8 (dd,
J ) 13, 0.4, 9.4 Hz, 1H), 1.67 (s, 3H), 0.88 (s, 3H), 0.85 (s, 3H),
0.75 (s, 3H); 13C NMR (CDCl3) δ 177.1, 152.9, 134.9, 129.4,
128.9, 127.3, 122.5, 71.6, 66.0, 60.3, 54.9, 49.9, 49.8, 43.3, 42.1,
39.0, 37.6, 36.3, 33.1, 32.9, 31.9, 23.8, 22.4, 21.8, 18.7, 13.5,
11.1; HRMS (CI) calcd for C29H42O4N [M + H]+ 468.3114, found
468.3109.
(2S ,3R )-3-H y d r o x y -2-m e t h y l-4-[(1S ,4a S ,8a S )-1,4,-
4a ,5,6,7,8,8a -octa h yd r o-2,5,5,8a -tetr a m eth yl-1-n a p h th a -
len yl]bu ta n -1-[-N-m eth yl-N′-m eth oxy-a m id e] (16). A so-
lution of AlMe3 (2.0 M in toluene, 6.1 mmol, 6.1 mL) was added
dropwise at 0 °C to a solution of MeONHMe‚HCl (6.1 mmol,
0.6 g) in dry CH2Cl2 (10 mL). After the mixture was stirred at
room temperature for 1 h, the reaction mixture was cooled to
-50 °C, and a solution of 15 (1.4 g, 3.0 mmol) in dry CH2Cl2
(2 mL) was added. The reaction was stirred at room temper-
ature overnight. The reaction was cooled to 0 °C, quenched
with 1 M aqueous tartaric acid, and stirred vigorously for 1 h.
The mixture was extracted with CH2Cl2 (3×), washed with
water and brine, dried over MgSO4, and concentrated. The
residue was purified over silica gel using hexanes/EtOAc (8:
2, then 7:3) to give amide 16 (1.03 g, 98%) as a colorless oil:
1
MS m/z (CI) 475 (M + H)+; H NMR (CDCl3) δ 7.68 (dd, 2H),
7.38 (m, 3H), 5.33 (bs, 1H), 3.77 (m, 1H), 3.59 (m, 1H), 1.49
(br s, 3H), 1.05 (s, 9H), 0.85 (s, 3H), 0.83 (s, 3H), 0.72 (s, 3H);
13C NMR (CDCl3) δ 135.6, 135.0, 134.0, 129.5, 127.6, 122.1,
65.4, 50.4, 50.1, 42.3, 39.0, 36.4, 33.1, 32.9, 30.1, 26.9, 23.7,
21.9, 21.8, 19.1, 18.7, 13.5; HRSM (CI) calcd for C32H47OSi [M
+ H]+ 475.3396, found 475.3385.
(1S,4a S,8a S)-1,4,4a ,5,6,7,8,8a -Oct a h yd r o-2,5,5,8a -t et -
r a m eth yl-1-n a p h th a len eth a n ol (13). To a solution of silyl
ether 12 (2.32 mmol, 1.1 g) in dry THF (10 mL) was added
TBAF (7 mmol, 7 mL, 1 M in THF). The reaction was heated
at reflux for 1 h and concentrated. The residue was extracted
with ether, washed with water and brine, dried over MgSO4,
and concentrated. Purification over silica gel using hexanes/
EtOAc (8:2) gave compound 13 (537 mg, 98%) as a colorless
Rf 0.14 (hexanes/EtOAc, 8:2); [R]20 -2.3 (c 0.31; CHCl3); MS
D
m/z (CI) 352 (MH+); 1H NMR (CDCl3) δ 5.40 (bs, 1H), 3.95 (m,
1H), 3.69 (s, 3H), 3.41 (bs, 1H, OH), 3.19 (s, 3H), 2.87 (m, 1H),
1.66 (s, 3H), 1.20 (d, J ) 7.2 Hz, 3H), 0.87 (s, 3H), 0.85 (s,
3H), 0.75 (s, 3H); 13C NMR (CDCl3) δ 178.1, 135.1, 122.7, 71.8,
61.6, 60.3, 50.1, 49.9, 42.2, 39.9, 39.0, 36.3, 33.2, 33.0, 32.3,
31.9, 23.9, 22.5, 21.9, 18.8, 13.6, 10.6; HRMS (CI) calcd for
oil: Rf 0.27 (hexanes/EtOAc, 7:3); [R]D -11.5 (c 0.74, CHCl3),
lit.12 [R]20 -11.8 (c 0.9, CHCl3); MS m/z (CI) 237 (MH+); H
C
21H38O3N [M + H]+ 352.2852, found 352.2854.
(2S,3R)-3-(ter t-Bu tyldim eth ylsilyloxy)-2-m eth yl-4-[(1S,-
1
D
NMR (CDCl3) δ 5.41 (bs, 1H), 3.78 (m, 1H), 3.56 (dt, J ) 9.5,
8.2 Hz, 1H), 1.67 (s, 3H), 0.88 (s, 3H), 0.85 (s, 3H), 0.77 (s,
3H); 13C NMR (CDCl3) δ 134.5, 122.7, 64.4, 50.7, 50.1, 42.2,
4a S,8a S)-1,4,4a ,5,6,7,8,8a -octa h yd r o-2,5,5,8a -tetr a m eth yl-
1-n a p h th a len yl]bu ta n -1-[-N-m eth yl-N′-m eth oxy-a m id e]

7268 J . Org. Chem., Vol. 66, No. 22, 2001
Poigny et al.
(17). To a cooled (-78 °C) solution of amide 16 (2.48 mmol,
870 mg) in dry CH2Cl2 (10 mL) was added 2,6-lutidine (600
µL, 2 equiv), followed by TBDMSOTf (630 µL, 1.1 equiv). The
mixture was stirred at -78 °C for 1 h and warmed to -10 °C.
The reaction was quenched with MeOH (1 mL), and the solvent
was evaporated under reduced pressure. The residue was
extracted with ether, washed with 0.5 N aqueous HCl, water,
saturated NaHCO3, and brine, dried over MgSO4, and con-
centrated. Flash chromatography on silica gel using hexanes/
EtOAc (9:1) gave 17 (1.13 g, 98%) as a colorless oil: Rf 0.27
(hexanes/EtOAc, 9:1); [R]20D +3.9 (c 0.49, CHCl3); MS m/z (CI)
466 (M + H)+; 1H NMR (CDCl3) δ 5.35 (bs, 1H), 4.01 (m, 1H),
3.63 (s, 3H), 3.12 (s, 3H), 2.81 (m, 1H), 1.66 (s, 3H), 1.11 (d, J
) 6.9 Hz, 3H), 0.87 (s, 9H), 0.82 (s, 3H), 0.81 (s, 3H), 0.67 (s,
3H), 0.02 (s, 3H), -0.02 (s, 3H); 13C NMR (CDCl3) δ 176.1,
135.6, 122.4, 73.7, 61.3, 50.5, 48.3, 43.3, 42.5, 39.0, 36.5, 34.3,
33.1, 32.1, 26.3, 25.6, 23.9, 23.0, 21.9, 18.8, 18.3, 13.9, -2.0,
-3.9; HRMS (CI) calcd for C27H52O3NSi [M + H]+ 466.3716,
found 466.3708.
colorless oil, which was used in the next step without further
characterization: Rf 0.44 (hexanes/EtOAc, 9:1). To a solution
of sulfone 20 (1.34 mmol, 730 mg) in MeOH (10 mL) was added
NiCl2‚xH2O (0.268 mmol, 35 mg) at 0 °C. The mixture was
stirred for 10 min, and then NaBH4 (4 mmol, 152 mg) was
added. After being stirred at 0 °C for 3 h, the reaction mixture
was diluted with ether. The organic layer was washed with
water and brine, dried over MgSO4, and evaporated. Chroma-
tography on silica gel using hexanes/EtOAc (90:10) gave
sulfone 21 (673 mg, 92%) as a colorless oil: Rf 0.44 (hexanes/
EtOAc, 9:1); [R]20 +20.5 (c 1.0, CHCl3); MS m/z (CI) 547 (M
D
+ H)+; H NMR (CDCl3) δ 7.89-7.50 (m, 5H), 5.34 (bs, 1H),
1
3.64 (m, J ) 14, 2.7 Hz, 1H), 3.12 (m, 2H), 1.57 (bs, 3H), 0.86
(d, J ) 8.3 Hz, 3H), 0.84 (s, 3H), 0.82 (s, 3H), 0.75 (s, 9H),
0.62 (s, 3H), -0.01 (s, 3H), -0.09 (s, 3H); 13C NMR (CDCl3) δ
139.0, 134.8, 133.5, 129.1, 128.0, 122.7, 75.9, 55.5, 50.4, 48.7,
42.4, 39.2, 38.9, 36.5, 33.1, 32.9, 29.6, 28.1, 25.9, 23.9, 23.7,
22.6, 21.7, 18.7, 16.3, 13.5, -1.9, -2.4; HRMS (CI) calcd for
C
32H55O3SSi [M + H]+ 547.3641, found 547.3646.
1,4-Diben zyloxy-2-(3-m eth yl-2-bu ten yl)ben zen e (23).
(2S,3R)-3-(ter t-Bu tyldim eth ylsilyloxy)-2-m eth yl-4-[(1S,-
4a S,8a S)1,4,4a ,5,6,7,8,8a -octa h yd r o-2,5,5,8a -tetr a m eth yl-
1-n a p h th a len yl]bu ta n a l (18). To a cooled solution of amide
17 (1.12 g, 2.41 mmol) in dry THF (10 mL) was added DIBALH
(1 M in THF, 7.23 mmol, 7.23 mL) in a dropwise manner. The
reaction was stirred at -78 °C for 30 min and quenched with
saturated aqueous sodium potassium tartrate (10 mL). The
mixture was stirred vigorously at room temperature for 1 h.
The reaction was extracted with ether (3×), washed with water
and brine, dried over MgSO4, and concentrated. Flash chro-
matography on silica gel using hexanes/EtOAc (98:2, then 95:
5) gave aldehyde 18 (970 mg, 99%) as white crystals: Rf 0.72
To a solution of 22 (14.04 mmol, 2.5 g), in anhydrous DMF
(42 mL) at 0 °C, was added NaH (35.1 mmol, 1.4 g in oil) in
small portions. The mixture was stirred for 15 min, and then
benzyl bromide (42 mmol, 5 mL) was added dropwise. The
solution was stirred at room temperature overnight, and
ethanol (1 mL) was added at 0 °C. The DMF was evaporated
under reduced pressure, and the residue was extracted twice
with ether. The organic layer was washed with brine, dried
over MgSO4, and concentrated. Flash chromatography using
hexanes/EtOAc (98:2) gave 23 (4.88 g, 97%) as a colorless oil:
Rf 0.68 (hexanes/EtOAc, 95:5); MS m/z (CI) 359 (M + H)+; 1H
NMR (CDCl3) δ 7.42-7.27 (m, 10H), 6.88-6.69 (m, 3H), 5.29
(t large, J ) 7.3 Hz, 1H), 4.97 (d, J ) 7,6 Hz, 4H), 3.35 (d, J
) 7.3 Hz, 2H), 1.72 (s, 3H), 1.63 (s, 3H); 13C NMR (CDCl3) δ
153.0, 150.8, 137.6, 137.4, 132.7, 131.9, 128.5, 128.4, 127.8,
127.6, 127.5, 127.2, 122.2, 117.0, 115.8, 112.7, 111.7, 70.7, 70.5,
28.6, 25.8, 17.7; HRMS calcd for C25H27O2 [M + H]+ 359.2010,
found 359.2012.
(EtOAc/hexanes); mp 114-116 °C (pentane); [R]20 +73.6 (c
D
0.63, CHCl3); MS m/z (CI) 407 (M + H)+; H NMR (CDCl3) δ
1
9.90 (s, 1H), 5.38 (m large, 1H), 4.08 (m, 1H), 2.58 (m, 1H),
1.62 (bs, 3H), 1.02 (d, J ) 6.8 Hz, 3H), 0.88 (s, 9H), 0.84 (s,
3H), 0.83 (s, 3H), 0.67 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H); 13C
NMR (CDCl3) δ 205.5, 134.5, 123.1, 73.8, 53.1, 50.4, 49.1, 42.4,
39.1, 36.6, 33.1, 33.0, 31.3, 29.7, 25.9, 23.9, 22.7, 21.8, 18.7,
13.5, 9.1, -1.8, -2.5; HRMS (CI) calcd for C25H47O2Si [M +
H]+ 407.3345, found 407.3352.
(E)-4-(2,5-Diben zyloxy)-2-m eth yl-2-bu ten -1-ol (25). A
solution of 23 (12.1 mmol, 4.33 g) in dry CH2Cl2 (25 mL) was
added dropwise to a solution of SeO2 (0.242 mmol, 27 mg),
salicylic acid (1.21 mmol, 167 mg), and t-BuOOH (80%, 43.56
mmol, 5.48 mL) in 25 mL of CH2Cl2. The mixture was stirred
for 48 h at room temperature. Toluene (50 mL) was added.
The solvents were evaporated in vacuo. The residue was
diluted with ether, washed with 10% aqueous KOH, water,
and brine, dried over MgSO4, and concentrated. The crude
mixture of aldehyde 24 and alcohol 25 thus obtained was
dissolved in MeOH (50 mL) and cooled to 0 °C. To this was
added NaBH4 (12.1 mmol, 460 mg) in small portions. The
reaction was stirred for 30 min, quenched carefully by the
addition of acetone (5 mL), and concentrated. The residue was
dissolved in ether, washed successively with saturated
NH4Cl, water, and brine, dried over MgSO4, and concentrated.
Purification over silica gel using hexanes/EtOAc (8:2) gave
alcohol 25 (2.45 g, 54%) as a colorless oil: Rf 0.3; MS m/z (CI)
Cr ysta l Da ta for 18. Colorless needle (0.06 × 0.20 × 0.66
mm). C25 H46 O2 Si, Mw ) 406.71. Orthorhombic system, space
group P212121, Z ) 4, a ) 6.701(5) Å, b ) 17.617(8) Å, c )
22.128(30) Å, V ) 2612.2 Å3, dc ) 1.034 g cm-3, F(000) ) 904,
λ(Cu KR) ) 1.5418 Å, µ ) 0.90 mm; 5280 data measured on a
Nonius-CAD4 diffractometer upto θ ) 68° (-8 e h e 8, k )
0-21, l ) 0-26) reduced to 4603 unique reflections (Rint
)
0.078) of which 3572 were considered as observed with I g
2.0 σ(I); semiempirical absorption corrections. Absolute con-
figuration deduced from the differences of Bijvoe¨t pairs.
Structure solved with program SHELXS8618 and refined with
program SHELXL93.19 Refinement converged to R1(F) )
0.0497 for the 3572 observed Fo and wR2(F2) ) 0.1353 for all
the 4603 data with goodness of fit S ) 1.018. In the final
difference map, the residual electron density was found to be
between -0.17 and 0.20 e Å-3. Further details on the crystal
structure may be obtained from the Cambridge Crystal-
lographic Data Centre, 12 Union Road, GB-Cambridge CB2
1EZ (UK).
1
375 (M + H)+; H NMR (CDCl3) δ 7.41-7.26 (m, 10H), 6.8-
6.7 (m, 3H), 5.54 (t, J ) 6.3 Hz, 1H), 4.97 (d, 4H), 3.96 (bs,
2H), 3.38 (d, J ) 7.3 Hz, 2H), 1.66 (s, 3H), 1.57 (bs, 1H); 13C
NMR (CDCl3) δ 152.9, 150.8, 137.4, 137.3, 135.8, 131.0, 128.4,
128.3, 127.8, 127.7, 127.4, 127.2, 123.7, 117.0, 112.7, 111.9,
70.6, 70.4, 68.7, 28.3, 13.6; HRMS calcd for C25H27O3 [M + H]+
375.1960, found 375.1969.
(2S,3R)-3-Meth yl-5-p h en ylsu lfon yl-1-[(1S,4a S,8a S)-1,4,-
4a ,5,6,7,8,8a -octa h yd r o-2,5,5,8a -tetr a m eth yl-1-n a p h th a -
len yl]p en ta n -2-(ter t-bu tyld im eth ylsilyl oxy) (21). To a
suspension of NaH (3.27 mmol, 78 mg) in dry THF (5 mL) was
added (EtO)2OPCH2SO2Ph (19) (3.27 mmol, 954 mg) in dry
THF (4 mL) at 0 °C. The mixture was stirred at this
temperature for 30 min. To this was added a solution of
aldehyde 18 (2.182 mmol, 886 mg) in dry THF, and the
reaction was stirred at room temperature for 2 h. The mixture
was extracted twice with ether, washed with brine, and dried
over MgSO4. Flash chromatography on silica gel using hex-
anes/EtOAc (95:5 and 9:1) gave sulfone 20 (834 mg, 70%) as a
2-[(E)-4-Br om o-3-m et h yl-2-b u t en yl]-1,4-d ib en zyloxy-
ben zen e (26). To a solution of alcohol 25 (4 mmol, 1.5 g) in
dry CH2Cl2 (10 mL) was successively added CBr4 (5.18 mmol,
1.72 g) and triphenylphosphine polymer bound (6 mmol, 2 g)
at 0 °C. The suspension was stirred at this temperature for 4
h and then filtered. Solvent was evaporated under reduced
pressure, and the excess of CBr4 was removed in high vacuum
to give the pure bromide 26 (1.73 g, 99%) as a colorless oil: Rf
0.46 (hexanes/EtOAc, 95:5); MS m/z (CI) 453 (MH + CH4)+;
1H NMR (CDCl3) δ 7.43-7.28 (m, 10H), 6.83-6.73 (m, 3H),
5.74 (t, J ) 7.2 Hz, 1H), 5.00 (d, J ) 5.6 Hz, 4H), 3.98 (bs,
2H), 3.37 (d, J ) 7.4 Hz, 2H), 1.78 (s, 3H); 13C NMR (CDCl3)
(18) Sheldrick, G. M. Acta Crystallogr., Sect. A 1990, 46, 467-473.
(19) Sheldrick, G. M. SHELXL93: Program for the Refinement of
Crystal Structures; University of Go¨ttingen: Germany, 1993.

Synthesis and Configuration of Coscinosulfate
J . Org. Chem., Vol. 66, No. 22, 2001 7269
δ 152.9, 150.8, 137.4, 137.3, 132.9, 130.1, 129.1, 128.5, 127.8,
127.7, 127.5, 127.2, 116.9, 112.8, 112.4, 70.7, 70.5, 41.5, 29.1,
14.7; HRMS (CI) calcd for C26H30O2Br [MH + CH4]+ 453.1429,
found 453.1435.
(2R,3R,7E)-9-(2,5-Dih ydr oxyph en yl)-3,7-dim eth yl-1-[(1S,-
4a S,8a S)-1,4,4a ,5,6,7,8,8a -octa h yd r o-2,5,5,8a -tetr a m eth yl-
1-n a p h th a len yl]-7-n on en -2-ol (30). A freshly prepared so-
lution of lithium naphthalenide (2.31 mmol, 2.31 mL, 1 M in
THF) was added dropwise to a solution of 29 (0.231 mmol, 150
mg) in dry THF (3 mL) at -78 °C. The reaction was stirred at
this temperature for 1 h, quenched with saturated NH4Cl, and
extracted with ether. The organic layer was washed with water
and brine, dried over MgSO4, and concentrated. The residue
was purified by flash chromatography to give triol 30 (90 mg,
(2R,3R,7E)-9-(2,5-Diben zyloxyp h en yl)-3,7-d im eth yl-1-
[(1S,4a S,8a S)-1,4,4a ,5,6,7,8,8a -oct a h yd r o-2,5,5,8a -t et r a -
m eth yl-1-n a p h th a len yl]-7-n on en -2-(ter t-bu tyld im eth yl-
silyloxy) (28). To a solution of sulfone 21 (0.37 mmol, 200
mg) and bromide 26 (0.444 mmol, 194 mg) in dry THF (3 mL)
at -78 °C was added LDA (1.11 mmol, freshly prepared from
n-BuLi (1.6 M) in hexane and diisopropylamine) in a dropwise
manner. The reaction was stirred at this temperature for 2 h,
warmed to 0 °C, and stirred for 2 h. The reaction was extracted
with ether, washed with water and brine, dried over MgSO4,
and concentrated. Purification over silica gel using hexanes/
EtOAc (95:5, then 90:10) gave 27 (254 mg, 76%), which was
used in the next step without further characterization. To a
solution of 27 (0.281 mmol, 254 mg) in dry MeOH (12 mL)
was added 20 equiv of sodium-mercury amalgam (Na-Hg,
10%). The suspension was stirred overnight at room temper-
ature and then filtered, and the solvent was evaporated under
reduced pressure. Flash chromatography on silica gel using
hexanes/EtOAc (95:5) gave 28 (198 mg, 70% from 21) as a
83%) as a colorless oil: Rf 0.26 (hexanes/EtOAc, 75:25); [R]20
D
+1.3 (c 1.51, CHCl3); MS m/z (CI) 469 (MH+); 1H NMR (CDCl3)
δ 6.66-6.53 (m, 3H), 6.35 (bs, 1H, OH), 5.40 (bs, 1H), 5.30 (t,
J ) 7.0 Hz, 1H), 5.27 (bs, 1H, OH), 3.68 (m, 1H-12), 3.28 (d, J
) 7.4 Hz, 2H), 1.66 (s, 3H), 1.62 (bs, 3H), 0.88 (d, J ) 6.9 Hz,
3H), 0.87 (s, 3H); 0.85 (s, 3H), 0.73 (s, 3H); 13C NMR (CDCl3)
δ 149.8, 147.4, 137.8, 134.8, 128.2, 122.7, 121.9, 116.1, 113.4,
76.2, 50.6, 49.9, 42.1, 39.6; 39.2, 39.1, 36.2, 33.0, 32.9, 32.5,
32.4, 28.4, 25.0, 23.8, 22.3, 21.8, 18.7, 15.7, 13.6, 13.3; HRMS
(CI) calcd for C31H49O3 [MH+] 469.3681, found 469.3685.
Coscin osu lfa te 1. To a solution of triol 30 (0.021 mmol,
10 mg) in dry 1,2-dichloroethane (1 mL) was added PhI(OAc)2
(0.023 mmol, 8 mg). The reaction was stirred at room tem-
perature for 1 h. To this was added SO3‚pyridine (0.0965 mmol,
15.3 mg). The mixture was stirred for 2 h at reflux. The solvent
was evaporated under reduced pressure, and the residue was
dissolved in MeOH (3 mL) followed by careful addition of
NaBH4 (0.386 mmol, 15 mg) in portions. The reaction was
stirred at room temperature for 30 min and concentrated in
vacuo. The residue thus obtained was extracted with butanol-
1, washed with water, and dried over Na2SO4, and the sol-
vent was evaporated under reduced pressure. The residue
was purified over C-18 reverse phase using CH3CN/H2O (4:6)
as eluent to give 1 (7 mg, 58%) as a white solid: Rf 0.28
colorless oil: Rf 0.55 (hexanes/EtOAc, 95:5); [R]20 +14.8 (c
D
2.04, CHCl3); MS m/z (EI) 762 (M+); 1H NMR (CDCl3) δ 7.45-
7.31 (m, 10H), 6.86-6.71 (m, 3H), 5.39 (bs, 1H), 5.32 (t, J )
7.2 Hz, 1H), 5.01 (d, J ) 9.3 Hz, 4H), 3.69 (dt, J ) 2.5, 10.3
Hz, 1H-12), 3.37 (d, J ) 7.2 Hz, 2H), 1.66 (s, 3H), 1.65 (s, 3H),
0.90 (s, 9H), 0.88 (s, 3H), 0.87 (s, 3H), 0.86 (d, 3H), 0.06 (s,
3H), 0.04 (s, 3H); 13C NMR (CDCl3) δ 153.0, 150.9, 137.7, 137.4,
137.0, 135.7, 132.0, 128.5, 128.4, 127.8, 127.6, 127.5, 127.2,
122.4, 121.7, 116.9, 112.8, 111.7, 76.6, 70.7, 70.5, 50.5, 49.2,
42.5, 40.3, 40.1, 39.0, 36.6, 33.2, 33.0, 30.1, 28.9, 28.5, 26.7,
26.1, 24.0, 22.8, 21.9, 18.8, 18.1, 16.2, 15.9, 13.6, -1.9, -2.5;
HRMS (EI) calcd for C51H74O3Si (M+) 762.5407, found 762.5418.
(2R,3R,7E)-9-(2,5-Diben zyloxyp h en yl)-3,7-d im eth yl-1-
[(1S,4a S,8a S)-1,4,4a ,5,6,7,8,8a -oct a h yd r o-2,5,5,8a -t et r a -
m eth yl-1-n a p h th a len yl]-7-n on en -2-ol (29). To a solution of
silyl ether 28 (0.293 mmol, 224 mg) in dry THF (5 mL) was
added a solution of TBAF (1 M) in THF (1.465 mmol, 1.46 mL).
The reaction was heated at reflux for 48 h. The solvent was
evaporated under reduced pressure and extracted with ether.
The organic layer was washed with water and brine, dried over
MgSO4, and concentrated. The residue was purified over silica
gel using hexanes/EtOAc (9:1) to give 29 (177 mg, 93%) as a
colorless oil: Rf. 0.37 (hexanes/EtOAc, 9:1); [R]20D +10.7 (c 0.67;
CHCl3); MS m/z (CI) 649 (MH+); 1H NMR (CDCl3) δ 7.44-
7.28 (m, 10H), 6.86-6.71 (m, 3H), 5.41 (bs, 1H), 5.33 (t, J )
7.3 Hz, 1H), 5.01 (d, J ) 7.3 Hz, 4H), 3.62 (m, 1H-12), 3.38 (d,
J ) 7.3 Hz, 2H), 1.65 (s, 2 × 3H), 0.93 (s, 3H), 0.89 (d, 3H),
0.87 (s, 3H), 0.75 (s, 3H); 13C NMR (CDCl3) δ 152.9, 150.8,
137.6, 137.3, 136.6, 135.1, 131.9, 128.5, 128.4, 127.8, 127.6,
127.4, 127.1, 122.5, 122.0, 116.9, 112.6, 111.6, 75.3, 70.6, 70.4,
50.6, 50.0, 42.2, 39.9, 39.4, 39.2, 36.2, 33.1, 32.9, 32.5, 28.4,
25.8, 23.8, 22.3, 21.8, 18.7, 16.0, 13.9, 13.6; HRMS calcd for
(CH2Cl2/MeOH, 8:2); mp 127-129 °C, lit. 129-130 °C; [R]20
D
+4.8 (c 0.25, MeOH), natural coscinosulfate [R]20 +5 (c 1.4,
D
1
MeOH); MS m/z (FAB) 593 (M + Na+); H NMR (CD3OH) δ
6.57 (d, J ) 8.54, 1H, H-6′), 6.55 (d, J ) 2.98, 1H, H-3′), 6.42
(dd, J ) 8.54, J ) 2.98, 1H, H-4′), 5.36 (bs, 1H, H-7), 5.32 (t,
J ) 7.35, 1H, H-18), 4.5 (dd, J ) 11.15, J ) 1.61, 1H, H-12),
3.23 (d, J ) 7.33, 1H, H-19), 1.71 (s, 3H, CH3-22), 1.70 (s, 3H,
CH3-25), 0.94 (d, J ) 7.01, 3H, CH3-24), 0.89 (s, 3H, CH3-21),
0.85 (s, 3H, CH3-20), 0.75 (s, 3H, CH3-23); 13C NMR 150.9,
147.9, 136.7, 135.4, 128.8, 123.2, 121.6, 116.4, 115.8, 113.2,
82.1, 50.3, 48.3, 42.5, 39.5, 38.8, 38.3, 36.9, 36.7, 33.2, 32.8,
28.3, 25.7, 27.2, 24.5, 22.4, 21.2, 19.3, 15.7, 13.6, 13.2; HRMS
(FAB) calcd for C31H47SO5Na2 [M + Na+] 593.2883, found
593.2887.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 1, 2, 5, 7, 9, 12, 13, 15, 16, 17, 18, 21,
25, 26, 28, 29, and 30 and X-ray crystallographic data for 18.
This material is available free of charge via the Internet at
http://pubs.acs.org.
C
45H61O3 (MH+) 649.4620, found 649.4611.
J O010154C