Titanium-catalyzed enantioselective synthesis of α-ambrinol

Article abstract of DOI:10.1002/adsc.200700511

We describe the first enantioselective synthesis of the odorant compound (-)-α-ambrinol (96% ee) from commercial geranylacetone. The key steps are a Jacobsen's asymmetric epoxidation and a titanium-catalyzed stereoselective cyclization initiated by radical epoxide opening. The oxirane ring opening proceeds with retention of configuration at the epoxide chiral center, giving a secondary alcohol which can be advantageously exploited to raise the ee provided by the synthetic sequence. We also synthesized (+)-α-ambrinol by a closely related procedure, showing the synthetic versatility of combining titanium-catalyzed cyclization with Jacobsen's epoxidation reactions.

Full text of DOI:10.1002/adsc.200700511

FULL PAPERS
DOI: 10.1002/adsc.200700511
Titanium-Catalyzed Enantioselective Synthesis of a-Ambrinol
JosØ Justicia,a,* Araceli G. CampaÇa,a Btissam Bazdi,a Rafael Robles,a
Juan M. Cuerva,a,* and J. Enrique Oltraa,*
a
Department of Organic Chemistry, University of Granada, Faculty of Sciences, Campus Fuentenueva s/n, 18071 Granada,
Spain
Fax : (+34)-958-248-437; e-mail: joltra@ugr.es or jjusti@ugr.es
Received: October 23, 2007; Published online: February 26, 2008
Abstract: We describe the first enantioselective syn- ee provided by the synthetic sequence. We also syn-
thesis of the odorant compound (À)-a-ambrinol thesized (+)-a-ambrinol by a closely related proce-
(96% ee) from commercial geranylacetone. The key dure, showing the synthetic versatility of combining
steps are a Jacobsenꢀs asymmetric epoxidation and a titanium-catalyzed cyclization with Jacobsenꢀs epoxi-
titanium-catalyzed stereoselective cyclization initiat- dation reactions.
ed by radical epoxide opening. The oxirane ring
opening proceeds with retention of configuration at
the epoxide chiral center, giving a secondary alcohol Keywords: a-ambrinol; asymmetric epoxidation; cat-
which can be advantageously exploited to raise the alysis; titanium; total synthesis
Introduction
of all mammalian steroids and triterpenoids. The car-
bocationic character of the enzyme-catalyzed cycliza-
Between 1988 and 1994 RajanBabu and Nugent intro- tion of oxidosqualene is well established.[14] Neverthe-
duced the use of bis(cyclopentadienyl)titanium chlo- less, Breslow, Pattenden and other authors have
ride (Cp2TiCl)[1] for the homolytic opening of epox- shown that radical cascade cyclizations, initiated by
ides.[2] This reagent has since become a powerful tool different means, can advantageously compete with
in organic synthesis,[3] especially after the catalytic carbocationic cyclizations in organic synthesis.[15] In-
version developed by Gansäuer et al., which uses spired by these observations, we deemed that a com-
2,4,6-collidine hydrochloride as titanocene-regenerat- bined strategy of enantioselective epoxidation of com-
ing agent.[4] Subsequently we developed an alternative mercial polyprenes, followed by Ti-catalyzed radical
titanocene-regenerating agent, a mixture of Me3SiCl cyclization of the epoxy derivative obtained, might fa-
and 2,4,6-collidine,[5] which has been used both by us cilitate the enantioselective synthesis of cyclic terpe-
and other authors for the total synthesis of several C- noids, including those lacking any OH group at C-3.
3 hydroxylated terpenoids in racemic form, including To check our hypothesis we chose a-ambrinol (1) as
monoterpenoids such as karahanaenone,[6] sesquiter- synthetic target.
penoids such as trans-4(11),8-daucadiene,[6] isodri->
menediol,[7] and 3b-hydroxydihydroconfertifolin,[7] di-
terpenoids such as 3b-hydroxymanool,[8] rostratone,[9] Results and Discussion
barekoxide,[6] laukarlaool,[6] and sclareol oxide,[10] mer-
oterpenoids such as zonarone and zonarol,[11] and tri- The levorotatory enantiomer of a-ambrinol (À)-1 is
terpenoids
such
as
3b-hydroxymalabarica- one of the most characteristic components of amber-
14(26),17E,21-triene[8] and achilleol A.[12] In contrast, gris, a concretion formed in the intestinal tract of
Cp2TiCl has scarcely been used for the enantioselec- some whales, and is very sought after in perfumery.[16]
tive synthesis of natural products.[13]
The dextrorotatory enantiomer (+)-1 is also an appre-
In mammals the enzyme-catalyzed enantioselective ciated odorant because of its strong dry, earthy, musty
epoxidation of squalene followed by cascade-cycliza- smell, quite different from that of the natural enantio-
tion of (S)-2,3-oxidosqualene leads to enantiomeri- mer.[16c] There are some procedures described for the
cally pure triterpenoids and steroids.[14] Thus, the synthesis of a-ambrinol (1) in racemic form.[16a,17] To
enzyme squalene epoxidase may be regarded not only the best of our knowledge, however, an enantioselec-
as being responsible for the hydroxy group located at tive total synthesis for either (À)-1 or (+)-1 has not
C-3 in sterols but also for the absolute configuration
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JosØ Justicia et al.
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been described,[18] in spite of the known influence of the regioselective formation of the exocyclic double
chirality on odorant properties.[16c,18,19]
bond.[8] Deoxygenation of 6 according to the Barton–
The retrosynthetic analysis depicted in Scheme 1 McCombie procedure[20] gave a 90% yield of protect-
suggested to us that (À)-a-ambrinol might be ob- ed ketone 8. Finally, deprotection of the masked
tained in relatively few steps from commercial gera- ketone 8 followed by Prins-type[21] stereoselective cy-
nylacetone (4). The key steps of the synthesis would
clization of 2 was accomplished in only one step and a
be the enantioselective epoxidation of protected gera- 79% yield of 1 was obtained by simple acid catalysis.
nylacetone followed by the diastereoselective Ti-cata- In this way we obtained racemic 1 in seven steps, in
lyzed cyclization of epoxide 3.
31% overall yield.
Once we were confident about the viability of the
synthesis described in Scheme 2, we decided to at-
tempt the enantioselective version of the process.
Vidari et al.[22] have described an efficient, highly
enantioselective dihydroxylation of geranyl acetate
(92% yield, 98% ee) employing the AD-mix system
developed by Sharpless and co-workers.[23] In our
case, however, treatment of 5 with AD-mix-a gave
only a 10% yield of diol (À)-9 (Scheme 3), which still
had to be transformed into epoxide 3. This low yield
prompted us to discard this procedure and assay
other methods for the single-step synthesis of optical-
ly active 3.
Scheme 1. Retrosynthetic analysis for (À)-1.
To check our retrosynthetic analysis we first pre-
pared racemic a-ambrinol (1) starting from commer-
cially available geranylacetone (4) (Scheme 2), which
was transformed into epoxide 3 in three steps using a
well-established procedure.[8] Stereoselective Ti-cata-
lyzed cyclization of 3 afforded a 61% yield of alcohol
6.[8] It should be noted that neither regioisomers with
an endocyclic double bond nor stereoisomers of 6
were detected. Theoretical and experimental evidence
Scheme 3. Asymmetric dihydroxylation of 5 employing AD-
mix-a.
The asymmetric epoxidation of 5 by Shiꢀs proce-
reported by our group suggest that this reaction pro- dure[24] gave (+)-3 in 33% yield and a moderate enan-
ceeds via stereoselective 6-endo cyclization of the ter- tiomeric excess (32% ee). Finally, the enantioselective
tiary radical generated by the Ti-catalyzed epoxide epoxidation of 5 with the aid of the Mn-based Jacob-
opening and, under anhydrous conditions, ends with senꢀs catalyst (À)-(10)[25] provided (À)-3 ([a]D20: À5.2)
in a moderate 39% yield, a medium 55% ee,[26] and an
excellent regioselectivity. What is more, 50% of the
starting diene 5 was recovered unchanged. Its treat-
ment under Jacobsen epoxidation conditions again
raised the overall yield of epoxide (À)-3 to 63%
(Scheme 4). Ti-catalyzed cyclization of (À)-3 gave al-
cohol (À)-6 ([a]D20: À4.4) with a 55% ee[26] identical to
that of the starting epoxide. This observation confirms
that the Ti-catalyzed cyclization of 3 to 6 occurs with
retention of configuration at the epoxide chiral
center. This supports our hypothesis that a judicious
combination of asymmetric epoxidation and Ti-cata-
lyzed radical cyclization reactions might be advanta-
geously exploited for the enantioselective synthesis of
cyclic terpenoids.
At this point we realized that (1S)-(À)-camphanic
chloride (11) reacted much faster with (+)-6 than
with (À)-6, providing an effective tool to raise the ee
of the levorotatory alcohol. Thus, treatment of the
Scheme 2. Synthesis of racemic a-ambrinol (1).
enantioenriched mixture of (À)-6 and (+)-6 (77.5/22.5
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Titanium-Catalyzed Enantioselective Synthesis of a-Ambrinol
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Scheme 4. Enantioselective synthesis of (À)-1.
ratio) with a substoichiometric proportion of 11 cobsenꢀs complex (À)-10. As the antipode (+)-10 is
(0.25 equiv.), followed by addition of acetic anhydride also commercially available, we could furthermore
gave (in a one-pot reaction) a mixture of camphanate prepare unnatural (+)-a-ambrinol, taking advantage
12 and acetate 13 (Scheme 4), which are easily separa- of this catalyst as depicted in Scheme 5. Thus, as we
ble by flash chromatography.[27] Simple saponification expected, the enantioselective epoxidation of 5 with
of 13 regenerated alcohol (À)-6 ([a]2D0: À7.8) with a the aid of catalyst (+)-10 gave a 60% yield (two turn-
95% ee.[26] Finally, following the same procedure de- overs) of (+)-3 with a 55% ee.[26]
picted in Scheme 2, (À)-6 was converted into (À)-a-
In this way we were able to accomplish the total
ambrinol ([a]2D0: À122.2) (96% ee).[26] Thus, the total synthesis of enantioenriched[28] (+)-1 ([a]2D0: +81.8)
synthesis of (À)-1 from commercial geranylacetone from commercial 4 in only six steps, with an overall
(4) was completed in eight steps and afforded an yield of 25%. More importantly, we thus showed that
overall yield of 18%.
the combination of Jacobsenꢀs asymmetric epoxida-
Mimicking what occurs in nature, in the synthetic tion and Ti-catalyzed cyclization reactions constitutes
sequence depicted in Scheme 4 enantioselection was a versatile procedure which might be used for the
introduced at the epoxidation step catalyzed by Ja- enantioselective synthesis of both optical antipodes of
cyclic terpenoids with or without an OH group at C-3.
Conclusions
We describe here the first enantioselective synthesis
of the odorant (À)-a-ambrinol (96% ee), by combin-
ing Jacobsenꢀs asymmetric epoxidation and Ti-cata-
lyzed stereoselective cyclization reactions. The cycli-
zation reaction was initiated by radical epoxide open-
ing and proceeded with retention of configuration at
the epoxide chiral center to give a secondary alcohol
that can be advantageously exploited to raise the ee
provided by the synthetic sequence. We also describe
the synthesis of the unnatural enantiomer (+)-a-am-
brinol by a closely related procedure, thus showing
the synthetic versatility of this method. At the
moment we are trying to extend this strategy to the
enantioselective synthesis of other marine terpenoids
Scheme 5. Enantioselective synthesis of (+)-1.
with biological activity.
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Experimental Section
Synthesis of Alcohol (À)-6
Following the procedure described above but using epoxide
(À)-3 as starting material, alcohol (À)-6 was obtained as a
colorless oil; yield: 59%; [a]2D0: À4.4 (c 1.2, CHCl3); 55%
ee.[26]
General Details
Deoxygenated solvents and reagents were used for all reac-
tions involving Cp2TiCl. THF was freshly distilled from Na,
while CH2Cl2 and benzene were freshly distilled from CaH2.
Products were purified by flash chromatography on Merck
silica gel 50 (eluents are given in parenthesis). Yields refer
to analytically pure samples. IR spectra were recorded using
a Satellite FTIR spectrometer. Optical rotations were mea-
sured in a Perkin–Elmer 341 digital polarimeter and are re-
ported as follows: [a]rD:t: (c in cg per 1 mL solvent). NMR
spectra were recorded in a Variant 400 L900 NMR spec-
Synthesis of Alcohol (+)-6
Following the procedure described above but using epoxide
(+)-3 as starting material, alcohol (+)-6 was obtained as a
colorless oil; yield: 60%; [a]2D0: +4.4 (c 1.6, CHCl3).
Enantioselective Discrimination between Alcohols
(+)-6 and (À)-6 by (1S)-(À)-Camphanic Chloride
1
trometer. H NMR: CDCl3 (d=7.26 ppm) in the indicated
solvent as internal standard in the same solvent. 13C NMR:
CDCl3 (d=77.16 ppm) as internal standard in the same sol-
vent; coupling constants measured in Hz and always given
as JH,H coupling constants. Enantiomeric excesses were mea-
sured employing an HPLC Waters 2690 apparatus using a
Waters PAD 996 detector and a Daicel Chiral Pak AD
0.46 cm”25 cm column. Compound 5 has been previously
described.[29] Racemic 3 was obtained as described in a pre-
vious paper.[8]
DMAP (47 mg, 0.39 mmol), pyridine (31 mL), and (1S)-(À)-
camphanic chloride (21.6 mg, 0.1 mmol) were added to a so-
lution of enantioenriched alcohol (À)-6 (55% ee) (100 mg,
0.39 mmol) in CH2Cl2 (6 mL). The solution was stirred for
24 h at room temperature. Subsequently, Ac2O (37 mL,
0.39 mmol) was added and the mixture was stirred for 2 h at
room temperature. The solvent was then removed and the
residue was submitted to flash chromatography (hexane:
EtOAc, 8:2) to yield camphanate 12 (yield: 37 mg, 22%)
and acetate 13 (yield: 85 mg, 74%).
Synthesis of Epoxide (À)-3
1
Compound 12: Colorless oil; H NMR (400 MHz, CDCl3):
d=4.85 (br s, 1H), 4.80 (dd, J=11.6, 4.3 Hz, 1H), 4.64 (br s,
1H), 3.95 (m, 4H), 1.33 (s, 3H), 1.15 (s, 3H), 1.10 (s, 3H),
1.01 (s, 3H), 0.97 (s, 3H), 0.82 (s, 3H).
m-Chloroperbenzoic acid (MCPBA, 70% purity) (380 mg,
1.7 mmol) was added to a mixture of compound 5 (200 mg,
0.84 mmol), 4-methylmorpholine N-oxide (NMO) (564 mg,
4.2 mmol), and catalyst (À)-10 (34 mg) in CH2Cl2 (10 mL) at
À408C. The mixture was stirred for 8 h at À408C. CH2Cl2
(20 mL) was then added and the solution was washed with
aqueous NaOH (2N), dried over anhydrous Na2SO4 and the
solvent removed. The residue was submitted to flash chro-
matography (hexane: EtOAc, 8:2) to yield epoxide (À)-3 as
a colorless oil; yield: 134 mg (63% after 2 turnovers); [a]2D0:
À5.2 (c 1.33, CHCl3); 55% ee;[26] 1H and 13C NMR spectra
matched those described in a previous paper.[8]
1
Compound 13: Colorless oil; H NMR (400 MHz, CDCl3):
d=4.87 (br s, 1H), 4.62 (br s, 1H), 4.28 (dd, J=11.5, 4.3 Hz,
1H), 3.93 (m, 4H), 2.43 (dt, J=13.0, 4.6 Hz, 1H), 2.05 (s,
3H), 1.33 (s, 3H), 0.99 (s, 3H), 0.79 (s, 3H).
Saponification of Acetate 13
K2CO3 (200 mg, 1.45 mmol) was added to a solution of ace-
tate 13 (85 mg, 0.29 mmol) in MeOH (5 mL) and the mix-
ture was stirred for 7 h at room temperature. The solvent
was then removed, water was added and the mixture was ex-
tracted with EtOAc. The organic layer was dried over anhy-
drous Na2SO4, and the solvent removed. The residue was
submitted to flash chromatography (hexane: EtOAc, 7:3) to
afford alcohol (À)-6 as a colorless oil; yield: 72 mg (98%);
[a]2D0: À7.8 (c 0.8, CHCl3); 95% ee.[26]
Synthesis of Epoxide (+)-3
Following the procedure described above but using (+)-10
instead of (À)-10 as catalyst, epoxide (+)-3 was obtained as
a colorless oil; yield: 60%; [a]2D0: +5.2 (c 1.54, CHCl3); 55%
ee.[26]
Ti-Catalyzed Cyclization of 3
Preparation of Thionocarbonate 7
Deoxygenated THF (20 mL) was added to a mixture of
Cp2TiCl2 (98 mg, 0.39 mmol) and Mn dust (860 mg,
15.7 mmol) under an argon atmosphere and the suspension
was stirred at room temperature until it turned green (about
15 min). A solution of epoxy alkene 3 (500 mg, 1.96 mmol)
and 2,4,6-collidine (1.8 mL) in THF (5 mL) and Me3SiCl
(1.0 mL) were then added simultaneously and the mixture
was stirred at room temperature for 1.5 h. Brine was added
and the mixture was extracted with EtOAc. The organic
layer was dried over anhydrous Na2SO4 and the solvent re-
moved. The residue was submitted to flash chromatography
(hexane: EtOAc, 85:15) giving alcohol 6 as a colorless oil;
yield: 305 mg (61%); 1H and 13C NMR spectra matched
those previously described.[8]
Pentafluorophenyl
chlorothionoformate
(150 mg,
0.57 mmol) was added to a solution of 6 (70 mg, 0.28 mmol)
and DMAP (102 mg, 0.84 mmol) in CH2Cl2 (8 mL) at 08C
and the solution was stirred at room temperature for 5 h.
Fresh CH2Cl2 (40 mL) was then added and the mixture was
washed with brine. The organic layer was dried over anhy-
drous Na2SO4, and the solvent removed. The residue was
submitted to flash chromatography (hexane: EtOAc, 95:5)
to afford thionocarbonate 7 as a colorless oil; yield: 130 mg
(97%); IR (film): umax =2954, 2877, 1523, 1378, 1306, 1144,
1059, 998, 954 cmÀ1 1H NMR (400 MHz, CDCl3): d=5.12
;
(dd, J=11.7, 4.2 Hz, 1H), 4.95 (bs, 1H), 4.71 (bs, 1H), 3.94
(m, 4H), 2.42–2.34 (m, 1H), 2.12–2.02 (m, 2H), 1.86–1.38
(m, 6H), 1.31 (s, 3H), 1.08 (s, 3H), 0.91 (s, 3H); 13C NMR
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Titanium-Catalyzed Enantioselective Synthesis of a-Ambrinol
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(100 MHz, CDCl3): d=191.7 (C), 145.9 (C), 110.6 (CH2),
110.4 (C), 93.0 (CH), 64.9 (CH2), 64.8 (CH2), 52.2 (CH),
40.3 (C), 38.2 (CH2), 31.3 (CH2), 27.5 (CH2), 26.2 (CH3),
24.1 (CH3), 20.1 (CH2), 18.1 (CH3) (some signals were not
observed); HR-FAB-MS: m/z=503.1288, calcd. for
C22H25F5O4SNa: 503.1291.
Synthesis of (+)-a-Ambrinol
Following the procedure described above but starting from
ketal (+)-8, (+)-a-ambrinol was obtained as a colorless oil;
yield: 76%; [a]2D0: +81.8 (c 0.9, CHCl3).
Thionocarbonate (À)-7
Following the procedure described above but starting from
(À)-6 (95% ee), thionocarbonate (À)-7 was obtained as a
colorless oil; yield: 90%; [a]2D0: À12.9 (c 5.5, CHCl3).
Acknowledgements
We thank the Spanish Ministry of Education and Science
(MEC)) for financial support (Project CTQ2005–08402). J. J.
thanks the Spanish MEC and the University of Granada for
his “Juan de la Cierva” contract. A. G. C. and B. B. thank
the Spanish MEC and MAE, respectively, for their fellow-
ships. We are also grateful to our English colleague Dr. J.
Trout for revising our English text.
Thionocarbonate (+)-7
Following the procedure described above but starting from
(+)-6 ([a]2D0: +4.4), thionocarbonate (+)-7 was obtained as a
colorless oil; yield: 97%; [a]2D0: +7.3 (c 1.17, CHCl3).
Synthesis of Ketal 8
References
AIBN (8 mg, 0.05 mmol) and HSn(n-Bu)3 (218 mg,
A
0.75 mmol) were added to a solution of thionocarbonate 7
(123 mg, 0.25 mmol) in benzene (20 mL) and the mixture
was stirred at reflux for 4 h. The solvent was then removed
and the residue was submitted to flash chromatography
(hexane: EtOAc, 95:5) to afford 8 as a colorless oil; yield:
[1] Bis(cyclopentadienyl)titanium(III) chloride (Nugentꢀs
G
reagent), generated in situ by stirring commercial
Cp2TiCl2 with Mn dust in anhydrous THF, exists as an
equilibrium mixture of the monomer Cp2TiCl and the
dinuclear (Cp2TiCl)2 species; see: a) R. J. Enemærke, J.
Larsen, T. Skrydstrup, K. Daasbjerg, J. Am. Chem. Soc.
2004, 126, 7853–7864; b) K. Daasbjerg, H. Svith, S.
Grimme, M. Gerenkamp, C. Muck-Lichtenfeld, A.
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2044; c) A. Gansäuer, A. Barchuk, F. Keller, M.
Schmitt, S. Grimme, M. Gerenkamp, C. Muck-Lichten-
feld, K. Daasbjerg, H. Svith, J. Am. Chem. Soc. 2007,
129, 1359–1371. For the sake of clarity, we represent
this complex herein as Cp2TiCl.
1
55 mg (93%); H and 13C NMR spectra matched those de-
scribed elsewhere.[30]
Ketal (À)-8
Following the procedure described above but starting from
thionocarbonate (À)-7, ketal (À)-8 was obtained as a color-
less oil; yield: 100%; [a]2D0: À14.6 (c 1.33, CHCl3).
Ketal (+)-8
[2] a) W. A. Nugent, T. V. RajanBabu, J. Am. Chem. Soc.
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Following the procedure described above but starting from
thionocarbonate (+)-7, ketal (+)-8 was obtained as a color-
less oil; yield: 95%; [a]2D0: +8.3 (c 0.67, CHCl3).
Synthesis of a-Ambrinol (1)
A sample of pTsOH (12 mg, 0.06 mmol) was added to a so-
lution of compound 8 (42 mg, 0.17 mmol) in 7 mL of wet
CH2Cl2, and the mixture was stirred for 24 h at room tem-
perature. Water was then added and the mixture was ex-
tracted with CH2Cl2. The organic layer was dried over
anhyd Na2SO4 and the solvent removed. The residue was
submitted to flash chromatography (hexane: EtOAc, 92:8),
affording a-ambrinol (1) as a colorless oil; yield: 27 mg
1
(79%); H and 13C NMR spectra matched those described
elsewhere.[17d]
Synthesis of (À)-a-Ambrinol
Following the procedure described above but starting from
ketal (À)-8, (À)-a-ambrinol was obtained as a colorless oil;
yield: 75%; [a]D20: À122.2 (c 0.83, CHCl3); 96% ee.[26]
[4] a) A. Gansäuer, H. Bluhm, Chem. Commun. 1998,
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