Synthesis of (-)-astrogorgiadiol

Article abstract of DOI:10.1016/j.tet.2011.10.027

Astrogorgiadiol is a naturally occurring Vitamin D analogue that, in cell culture, downregulates the production of the cytokine osteopontin (OPN). OPN has been implicated in virulent asthma, and OPN knockout mice do not develop osteoporosis. As we have pursued whole animal studies with astrogorgiadiol, we have increased the scale of the synthesis. We report an improved preparation of the A-ring synthon and the scale-up of the diasteromerically pure D-ring/sidechain chiron.

Full text of DOI:10.1016/j.tet.2011.10.027

Tetrahedron 67 (2011) 10229e10233
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of (ꢀ)-astrogorgiadiol
*
Douglass F. Taber , David M. Raciti
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Astrogorgiadiol is a naturally occurring Vitamin D analogue that, in cell culture, downregulates the
production of the cytokine osteopontin (OPN). OPN has been implicated in virulent asthma, and OPN
knockout mice do not develop osteoporosis. As we have pursued whole animal studies with as-
trogorgiadiol, we have increased the scale of the synthesis. We report an improved preparation of the
A-ring synthon and the scale-up of the diasteromerically pure D-ring/sidechain chiron.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 14 September 2011
Received in revised form 8 October 2011
Accepted 10 October 2011
Available online 19 October 2011
Keywords:
Rh catalyst
CeH insertion
Robinson annulation
Epoxide opening
Dianion alkylation
1. Introduction
We have described1,2 the total syntheses of astrogorgiadiol 2
(Eq. 1) and calicoferol B 3.3 Remarkably, while the active metabolite
of Vitamin D, 1a,25-dihydroxy Vitamin D3 (calcitriol) 1 upregulates
the cytokine osteopontin (OPN) in cell culture, 30 nM 2 down-
regulates OPN.3 This is the first small molecule known to down-
regulate this cytokine. Osteopontin has been shown to play
a significant role in the development of virulent asthma,4 and OPN
knockout mice do not develop osteoporosis.5 As we have pursued
whole animal studies of astrogorgiadiol 2, we have needed a more
robust supply. We describe here a second generation preparation of
the A-ring synthon 5 (Scheme 1), and a scale-up of the diaster-
omerically pure D-ring/sidechain chiron 4, which are combined1
via Robinson annulation to make 2.
Scheme 1. Synthesis of astrogorgiadiol.
2. Results and discussion
Passage of the diazo ketone 9 through a plug of silica gel was suf-
ficient to prepare it for Rh-mediated cyclization.
2.1. Preparation of the b-ketoester 4
We were pleased to observe that 10.1 g of the diazo ketone 9
prepared in this manner cyclized smoothly to the previously ob-
The D-ring/sidechain chiron 4 was prepared as before (Scheme
2) from commercial (R)-citronellal 6. It is not necessary to purify
either the citronellol from the LiAlH4 reduction nor the benzene-
sulfonate 7 prepared from it. Exposure of the crude benzenesulfo-
served1 70:30 mixture of
b-ketoesters 4 and 10, using just
0.02 mol % of the Hashimoto7 catalyst Rh2(S)-PTPA4. We had pre-
viously1 cyclized chromatographically-purified 9 with the Hashi-
moto7 catalyst on a 2.0 g scale using 0.48 mol % of the catalyst. The
diastereomers 4 and 10 do not separate on TLC, but direct crystal-
lization of the chromatographed mixture from the cyclization of
10.1 g of the diazo ketone delivered 2.73 g of the pure crystalline 4.
nate to an excess of the dianion6 of methyl acetoacetate led to the
b-
ketoster 8, that was purified as before by short path distillation.
* Corresponding author. E-mail address: taberdf@udel.edu (D.F. Taber).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.027

10230
D.F. Taber, D.M. Raciti / Tetrahedron 67 (2011) 10229e10233
Scheme 2. Preparation of the b-ketoester 4.
Scheme 3. Previous preparation of the ketone 5.
The progress of the crystallization was followed by monitoring the
enough astrogorgiadiol 2 to support the ongoing whole animal
studies.
ratio of the 1H NMR doublet at
d 2.95 (4) to the doublet at d 2.97
(10). Selective RuBINAP-mediated hydrogenation8 of 10 in the re-
sidual mixture of 4 and 10 as we have described1 allowed the
separation of additional quantities of pure crystalline 4.
4. Experimental section
4.1. General
2.2. Preparation of the ketone 5
1H NMR and 13C NMR spectra were recorded, as solutions in
deuteriochloroform (CDCl3) unless otherwise indicated, at
400 MHz and 100 MHz, respectively. 13C multiplicities were de-
termined with the aid of a JVERT pulse sequence, differentiating the
signals for methyl and methine carbons as ‘d’ from methylene and
quaternary carbons as ‘u’. The infrared (IR) spectra were de-
termined as neat oils. Rf values indicated refer to thin layer chro-
The previous preparation1 of 5 is outlined in Scheme 3. The Ni-
catalyzed coupling was not perfectly clean, giving a product that
was about 5% desmethyl. Although this could be removed by
recrystallizing 5, on scale-up 5 was found to be unstable. We were
not able to find alternative conditions that gave acceptably clean
methylation of 16.
We therefore envisioned a new approach to 5, based on the
addition (Scheme 4) of the Grignard reagent derived from 25 to the
epoxide 20.9 Gram quantities of the epoxide 20 were readily pre-
pared by dehydrohalogenation10 of the commercial bromide 11,
followed by epoxidation.
The preparation of the alcohol 24 by reduction of the cyclic ether
23 had been described.11 We prepared the requisite m-methoxy
phenethyl alcohol by reduction of the commercial acid 21. In our
hands, cyclization of the derived MOM ether gave 23 contaminated
by about 5% of 22, that had to be separated by column chroma-
tography. Reduction of 23 with LiAlH4/AlCl3 then gave 24, as had
previously been described.11
matography (TLC) on 2.5ꢁ10 cm, 250
mm analytical plates coated
with silica gel GF and developed in the solvent system indicated. All
glassware was oven dried and rinsed with dry solvent before use.
THF was distilled from sodium metal/benzophenone ketyl under
dry nitrogen. Toluene, dichloromethane, and acetonitrile were
distilled from calcium hydride under dry nitrogen. CH2Cl2 is
dichloromethane, MTBE is methyl-tertbutyl ether and PE is petro-
leum ether. All reactions were conducted under N2 and stirred
magnetically.
4.1.1. Methyl (1R,5R)-2-oxo-5-((1R)-1,5-dimethyl-4-hexenyl)cyclo-
pentanecarboxylate (4).
Conversion12 of the alcohol 24 to the bromide 25 proceeded
smoothly, as did Grignard formation and addition to the epoxide 20
to give 26. Using this approach, we routinely prepare several
hundred milligrams of clean alcohol 26 in a run. As we had pre-
viously observed, the ketone 5 was only marginally stable. It was
best to carry out the oxidation13 and purification quickly, as needed,
then directly take 5 into the Robinson annulation.
4.1.1.1. Preparation of citronellol. Powdered LiAlH4 (2.50 g,
65.8 mmol) was introduced into a 1 L round bottom flask that
contained 400 mL of dry THF. The system was mechanically stirred,
kept at 0 ꢂC, and under constant N2. Citronellal 6 (20.0 g, 130 mmol)
was added neat over 10 min, and the residue was rinsed and added
with a few mL of THF. The slurry was allowed to stir for approxi-
mately 1 h (followed by TLC). The system was quenched14 by the
dropwise addition of water, 15% aqueous NaOH and water, with
stirring after each addition. The reaction mixture was filtered
through Na2SO4 and the solids were rinsed with MTBE. After con-
centration, the crude residue was distilled to yield citronellol
(18.3 g, 91%) as a clear oil, TLC Rf (10% MTBE/PE)¼0.09. 1H NMR
3. Conclusion
We have scaled up the cyclization to prepare the diasteromeri-
cally pure D-ring/sidechain chiron 4 (Scheme 1) and have de-
veloped a more robust synthetic route to the A-ring synthon 5.
Using the materials so prepared, we have been able to produce
(CDCl3,
d): 5.10 (m, 1H), 3.66 (m, 2H), 2.1e1.8 (m, 3H), 1.68 (s, 3H),
1.7e1.5 (m, 2H), 1.60 (s, 3H), 1.4e1.3 (m, 2H), 1.17 (m, 1H), 0.90 (d,

D.F. Taber, D.M. Raciti / Tetrahedron 67 (2011) 10229e10233
10231
cannula under positive N2 pressure and the mixture was allowed
to stir at rt for 1 h. The mixture was quenched cautiously by
pouring into saturated aqueous NH4Cl, then partitioned between
MTBE and, sequentially, H2O and brine. The combined organic
extracts were dried (Na2SO4) and concentrated to yield a brown-
ish oil. This was distilled bulb-to-bulb at 0.7 Torr. At a bath tem-
perature of 100 ꢂC a clear oil distilled over and was discarded. The
product 8 distilled at 140e160 ꢂC. The
b-ketoester 8 (26.1 g, 75%)
was isolated as clear yellow oil, TLC Rf (10% MTBE/PE)¼0.39, TLC Rf
(7.5%:7.5% MTBE/DCM/PE)¼0.41, 1H NMR (CDCl3,
d): 5.08 (m, 1H),
3.74 (s, 3H), 3.45 (s, 2H), 2.52 (t, J¼7.34 Hz, 2H), 1.96 (m, 2H), 1.68
(s, 3H), 1.60 (s, 3H), 1.6e1.2 (m, 6H), 1.13 (m, 1H), 0.87 (d,
J¼6.85 Hz, 3H). 13C NMR (CDCl3,
d): (u) 202.6, 167.5, 130.9, 48.8,
43.2, 36.8, 36.1, 25.3, 20.8; (d) 124.7, 52.1, 32.1, 25.6, 19.2, 17.5. IR
(cmꢀ1): 2925, 1748, 1716.
Alternatively, the product could be purified by column chro-
matography, allowing concomitant recovery of unreacted cit-
ronellyl benzenesulfonate. A unique mobile phase was used, 1:1
MTBE/CH2Cl2 in PE. This ternary mobile phase allowed for in-
creased resolution between the 7 and 8.
4.1.1.4. Diazo ketone 9. Acetoacetate 8 (26.1 g, 102 mmol) was
taken up in 115 mL of acetonitrile in a 250 mL round bottom flask.
While stirring, triethylamine (34.8 mL, 251 mmol) and mesyl
azide15 (14.8, 122 mmol) were added neat sequentially. After
overnight stirring half of the solvent was removed in vacuo, then
the reaction mixture was partitioned between PE and, sequentially,
10% NaOH, and brine. The combined organic extract was dried
(Na2SO4) and concentrated, and the residue was filtered through
a plug of silica gel to yield the diazo ketone 9 (22.1 g, 78.9 mmol,
61% yield from citronellal), TLC Rf (10% MTBE/PE)¼0.42, TLC Rf
(7.5%:7.5% MTBE/DCM/PE)¼0.50. 1H NMR (CDCl3,
d): 5.09 (m, 1H),
Scheme 4. New preparation of the ketone 5.
3.84 (s, 3H), 2.83 (t, J¼7.85 Hz, 2H), 1.96 (m, 2H), 1.68 (s, 3H), 1.60 (s,
3H), 1.7e1.5 (m, 2H), 1.5e1.3 (m, 3H), 1.15 (m, 2H), 0.88 (d,
J¼6.49 Hz, 3H). 13C NMR (CDCl3,
d): (u) 193.0, 161.8, 131.1, 40.5, 36.9,
J¼6.66 Hz, 3H). 13C NMR (CDCl3,
d
): (u) 131.2, 61.0, 39.8, 37.1, 25.4;
36.4, 25.5, 21.9; (d) 124.9, 52.1, 32.2, 25.7, 19.4, 17.6. IR (cmꢀ1): 2914,
2133, 1725, 1659, 1309. This substance was not stable to analysis by
mass spectrometry.
(d) 124.6, 29.1, 25.6, 19.4, 17.6. IR (cmꢀ1): 3331 (b), 2927, 1454, 1377,
1058. MS (m/z, %): 55 (64), 69 (100), 82 (44), 95 (33), 109 (14), 123
(18), 138 (6), 156 (6). HRMS calcd for C10H20O: 156.1514, found
156.1514. ½a 1D7
ꢃ
þ3.74 (c 1.02, EtOH).
4.1.1.5. Cyclization of 9. To the ester 9 (10.1 g, 39.5 mmol) in
a 1 L round bottom flask was added 550 mL of dry CH2Cl2
(passed through K2CO3).The Rh2(S)-PTPA4 (100 mg, 0.02 mol %)
in 30 mL of dry CH2Cl2 was added16 rapidly dropwise and the
reaction was stirred overnight. The solvent was evaporated and
the residual green oil was chromatographed to give cyclized
products 4 and 10 (70:30, respectively) (8.5 g, 33.7 mmol, 85%
yield). TLC Rf (10% MTBE/PE)¼0.28. Moist crystals were observed
upon standing. Recrystallization was performed by taking up
5.0 g of moist crystals in PE, then slowly evaporating by exposing
to a steady air flow. Thin crystals are observed and the PE was
removed from air flow and allowed to evaporate slowly over-
night. The crystals that formed overnight were triturated with PE
resulting in 1.5 g of a 16:1 ratio of diastereomers. Further crys-
tallization yielded a total of 2.73 g (10.8 mmol, 18% yield from
citronellal) of crystalline ester 4. The spectroscopic data matched
that reported.1
4.1.1.2. Benzenesulfonate 7. A solution of the above crude cit-
ronellol (18.3 g, 118 mmol) in 250 mL of CH2Cl2 in a 500 mL round
bottom flask at 0 ꢂC was stirred. Triethylamine (36.1 mL, 260 mmol)
was added in one portion, followed by 4-dimethylaminopyridine
(123 mg, 1.01 mmol). Finally benzenesulfonyl chloride (25.0 g,
140 mmol) was added dropwise via pipette. The mixture was stir-
red at 0 ꢂC for 2 h. The slurry was partitioned between 10%MTBE/PE
and, sequentially, 5% aqueous HCl, water, and brine. The organic
extract was dried (Na2SO4) and concentrated to leave citronellyl
benzenesulfonate 7 (40.3 g) as thick yellow oil, TLC Rf (10% MTBE/
PE)¼0.41, (7.5%:7.5% MTBE/DCM/PE)¼0.53. 1H NMR (CDCl3,
d): 7.92
(m, 2H), 7.66 (m, 1H), 7.56 (m, 2H), 5.03 (m, 1H), 4.09 (m, 2H), 1.91
(m, 2H), 1.68 (m, 1H), 1.67 (s, 3H), 1.57 (s, 3H), 1.52 (m, 1H), 1.44 (m,
1H), 1.24 (m, 1H), 1.11 (m, 1H), 0.81 (d, J¼6.49 Hz, 3H). 13C NMR
(CDCl3, d): (u) 136.1, 131.4, 69.2, 36.6, 35.5, 25.1; (d) 133.6, 129.1,
127.7, 124.2, 28.7, 25.6, 18.9, 17.5. IR (cmꢀ1): 2914, 1449, 1360, 1188,
944.
4.1.2. 2-(2-Phenoxyethyl)-oxirane (20). Bromide 19 (9.1 g, 40 mmol)
and HMPA (8.96 g, 50 mmol) were combined in a 50 mL round
bottom flask, then heated to 200 ꢂC for 60 min. The solution was
cooled to rt and partitioned between 15% MTBE/PE and H2O. The
combined organic extract was dried (Na2SO4) and concentrated.
The crude residue was dissolved in 100 mL of CH2Cl2 in a 250 mL
round bottom flask. With stirring, 70% commercial MCPBA (15 g,
61 mmol) was added. The mixture was stirred overnight, then
partitioned between CH2Cl2 and aqueous 5% NaOHþ5% Na2SO3. The
4.1.1.3. Keto ester 8. Sodium hydride (21.8 g, 60% in mineral oil,
545 mmol) was dispersed in 350 mL of dry THF that was stirring
in a 1 L round bottom flask at 0 ꢂC under N2. Next methyl ace-
toacetate (35.0 g, 300 mmol) was added dropwise via syringe.
After stirring for 10 min n-butyl lithium (136 mL, 2.0 M) was
added rapidly dropwise via syringe. After 10 min the crude cit-
ronellyl benzenesulfonate 7 (40.3 g, 136 mmol) was introduced via

10232
D.F. Taber, D.M. Raciti / Tetrahedron 67 (2011) 10229e10233
organic layer was dried (Na2SO4) and concentrated. The crude
residue was distilled bulb-to-bulb, (pot¼80e100 ꢂC, 1.0 mmHg) to
give 20 (2.83 g, 43% from bromide) as a clear colorless oil. 1H NMR
4.1.5.2. Alcohol 26. Magnesium (120 mg, 5.0 mmol) was added
to a dried 25 mL round bottom flask equipped with a stir bar and an
N2 adapter. The apparatus was rinsed three times with 5 mL of
THF.THF (8 mL) was added followed by bromide 25 (590 mg,
2.6 mmol). An I2 flake was added, turning the solution a deep yel-
low brown. The solution was heated to reflux and a color discharge
was observed. After reflux subsided the solution was heated again
in the same manner and allowed to subside and stir for 30 min. The
solution was warmed to reflux one more time and then the solution
was chilled to ꢀ30 ꢂC. CuBr$Me2S was added (dissolved in 1 mL of
THF) and stirring was continued for 5 min. Epoxide 20 (580 mg,
3.50 mmol) was diluted in a few mL of THF and added to the
Grignard solution. The cooling bath was removed and the solution
was allowed to warm to rt. The solution was then diluted with 5%
aqueous HCl and extracted with ethyl acetate. The organic extract
was dried (Na2SO4) and concentrated. The organic extract was then
removed in vacuo and the remaining oil was chromatographed to
yield the phenoxy alcohol 26 (340 mg, 42% from bromide) as a clear
(CDCl3,
d
): 7.32 (m, 2H), 6.98 (t, J¼7.6 Hz, 2H), 6.94 (m, 1H), 4.14 (d,
J¼7.6 Hz, 2H), 3.19 (m, 1H), 2.86 (t, J¼4.5 Hz, 1H), 2.62 (dd, J¼2.8,
4.5 Hz, 1H), 2.13 (m, 1H), 1.98 (m, 1H). 13C NMR (CDCl3,
d): (u) 64.5,
47.2, 32.5; (d) 129.5, 120.9, 114.5, 49.8. IR (cmꢀ1): 3047, 2998, 2929,
2870, 1590, 1491. HRMS calcd for C10H16NO2 (MþNH4): 182.1181,
found 182.1183.
4.1.3. 6-Methoxyisochroman (23). To 3-methoxyphenylacetic acid
21 in 50 mL THF containing 10 drops of MeOH was added BH3$Me2S
in portions (foams!). After the reaction had subsided, MeOH
(20 mL) was added cautiously (foams!). The solvent was removed
on the rotary evaporator, then the MeOH addition and evaporation
were repeated two more times. The residue was then distilled bulb-
to-bulb (pot¼100e120 ꢂC, 1.0 mmHg) to give 5.47 g of crude 2-(3-
methoxyphenyl)ethanol.
The crude 2-(3-methoxyphenyl)ethanol (4.12 g), chloromethyl
methyl ether solution17 (16.6 M, 12 mL), and diisopropylethylamine
(11.4 g, 90 mmol) were combined in 40 mL of CH2Cl2. After 90 min,
the reaction mixture was partitioned between CH2Cl2 and 5%
aqueous HCl. The combined organic extracts were dried (Na2SO4)
and concentrated.
The residue was taken up in 30 mL of 1,2-dicholorethane, p-
toluenesulfonic acid (0.8 g) was added, and the mixture was heated
to reflux overnight. Water (3 mL) was added, and reflux was con-
tinued for 1 h. The cooled reaction mixture was partitioned be-
tween CH2Cl2 and 5% aqueous HCl. The combined organic extracts
were dried (Na2SO4) and concentrated, and the residue was chro-
matographed to give 23 (2.03 g, 81% yield from 21 based on alcohol
not recovered) as a colorless oil, TLC Rf (1:1:8 CH2Cl2/MTBE/PE)¼
0.45. The spectroscopic data matched that reported.11 This was
preceded by a small quantity of 22, not isolated, TLC Rf (1:1:8
CH2Cl2/MTBE/PE)¼0.56, and followed by recovered alcohol, 1.10 g,
TLC Rf (1:1:8 CH2Cl2/MTBE/PE)¼0.12.
pale yellow oil, TLC Rf (30% MTBE/PE)¼0.30. 1H NMR (CDCl3,
d): 7.31
(t, J¼7.3 Hz, 2H), 7.08 (d, J¼8.5 Hz,1H), 6.99 (t, J¼7.3 Hz,1H), 6.93 (d,
J¼7.3 Hz, 2H), 6.75 (d, J¼2.5 Hz,1H), 6.69 (dd, J¼2.5, 8.5 Hz,1H), 4.17
(m, 2H), 3.96 (m, 1H), 3.81 (s, 3H), 2.63 (m, 2H), 2.26 (s, 3H),1.96 (m,
2H), 1.81 (m, 1H), 1.64 (m, 2H). 13C NMR (CDCl3,
d): (u) 158.6, 157.8,
142.7, 128.1, 65.9, 37.4, 36.4, 33.5, 26.2; (d) 131.0, 129.5, 121.0, 114.5,
114.5, 111.1, 70.0, 55.3, 18.4. IR (cmꢀ1): 3410, 2927, 2870, 1598, 1498,
1467, 1297, 1246. HRMS calcd for C20H30NO3 (MþNH4): 332.2226,
found 332.2231.
4.1.6. 6-(5-Methoxy-2-methylphenyl)-1-hexen-3-one (5). The phe-
noxyalcohol 26 (124 mg, 0.39 mmol) was dissolved in 5 mL of CH3CN
in a 25 mL round bottom flask. Periodic acid (136 mg, 0.6 mmol) was
added followed bypyridiniumchlorochromate (10 mg, 0.046 mmol).
The mixture was stirred for 15 min. Flash silica (2 g) was added, and
the solvent was evaporated. The crude product was chromato-
graphed directly yielding 6-(5-methoxy-2-methylphenyl)-1-
phenoxy-3 hexanone 5 (51 mg, 42%) as a colorless oil, TLC Rf (20%
MTBE/PE)¼0.41. 1H NMR (CDCl3,
): 7.3 (m, 2H), 7.04 (d, J¼8.19 Hz,
d
4.1.4. 2-(2-Methyl-5-methoxyphenyl)ethanol (24). AlCl3 (3.5 g) was
added cautiously with ice/water cooling to LiAlH4 (0.50 g) in diethyl
ether (20 mL). The chroman 23 (2.51 g) in a little ether was added,
and a reflux condenser was attached. The reaction mixture was
stirred in an oil bath (T¼80 ꢂC) overnight, during which time the
ether evaporated. The resulting solid mass was partitioned between
ethyl acetate and saturated aqueous sodium potassium tartrate. The
combined organic extract was dried (Na2SO4) and concentrated, and
the residue was chromatographed to give 24 (1.12 g, 44% yield from
23) as a colorless oil, 1.10 g, TLC Rf (1:4 MTBE/CH2Cl2)¼0.55. The
spectroscopic data matched that reported.11
1H), 6.94 (t, J¼7.17 Hz,1H), 6.88 (d, J¼8.53 Hz, 2H), 6.69 (d, J¼2.73 Hz,
1H), 6.66 (dd, J¼8.19, 2.73 Hz,1H), 4.22 (t, J¼6.14 Hz, 2H), 3.76 (s, 3H),
2.86 (t, J¼6.14 Hz, 2H), 2.6 (m, 4H), 2.23 (s, 3H), 1.9 (m, 2H). 13C NMR
(CDCl3, d): (u) 208.3, 158.5, 157.7, 140.9, 128.0, 62.8, 42.8, 42.1, 32.6,
23.6, 18.3; (d) 130.9, 129.4, 120.9, 114.7, 114.4, 110.9, 55.2, 18.3. The
spectroscopic data matched that reported.1
Acknowledgements
We thank Dr. John Dykins for mass spectrometric measure-
ments, supported by the NSF (0541775), Dr. Shi Bai for NMR as-
sistance (NSF CRIF:MU, CHE 0840401) and the University of
Delaware Honors Program for financial support. This work is ded-
icated to Professor Gilbert Stork on the occasion of his 90th
birthday.
4.1.5. 6-(5-Methoxy-2-methylphenyl)-1-phenoxy-3-hexanol (26).
4.1.5.1. Bromide 25. 5-Methoxy-2-methyl benzeneethanol 24
(593 mg, 3.57 mmol) was dissolved in 15 mL of CH2Cl2 in a 50 mL
round bottom flask at 0 ꢂC Ph3P (1.31 g, 5.0 mmol) was added, and
the mixture was stirred until it dissolved. N-Bromosuccinimide
(801 mg, 4.5 mmol) was added in portions and the progress of the
reaction was followed by TLC. After completion (15 min), the re-
action was partitioned between CH2Cl2 and 5% aqueous NaOHþ5%
aqueous Na2SO3. The combined organic extract was dried (Na2SO4)
and concentrated, and the remaining oil was distilled bulb-to-bulb
from powdered CaH2 (bp pot¼80e100 ꢂC, 1.0 mmHg) to obtain the
bromide 25 (714 mg, 87%) as a clear faintly pink oil. 1H NMR (CDCl3,
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.10.027.
References and notes
1. Taber, D. F.; Malcolm, S. C. J. Org. Chem. 2001, 66, 944.
d
): 7.11 (d, J¼9.0 Hz, 1H), 6.75 (m, 2H), 3.82 (s, 3H), 3.54 (t, J¼7.6 Hz,
2. For the preparation of astrogorgiadiol from Vitamin D3, see Della Sala, G.; Izzo,
I.; De Riccardis, F.; Sodano, G. Tetrahedron Lett. 1998, 39, 4741.
3. Taber, D. F.; Jiang, Q.; Chen, B.; Zhang, W.; Campbell, C. L. J. Org. Chem. 2002, 67,
4821.
4. (a) Kurokawa, M.; Konno, S.; Takahashi, A.; Plunkett, B.; Rittling, S. R.; Matsui, Y.;
Kon, S.; Morimoto, J.; Uede, T.; Matsukura, S.; Kokubu, F.; Adachi, M.; Nishimura,
2H), 3.17 (t, J¼7.6 Hz, 2H), 2.29 (s, 3H). 13C NMR (CDCl3,
d): (u)
157.9, 138.2, 128.1, 37.2, 31.6; (d) 131.3, 115.2, 112.3, 55.3, 18.3. IR
(cmꢀ1): 2951, 2835, 1611, 1581, 1501, 1458. HRMS calcd for
C10H17BrNO(MþNH4): 246.0489, found 246.0493.

D.F. Taber, D.M. Raciti / Tetrahedron 67 (2011) 10229e10233
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