Diastereoselective Synthesis of (±)-Ambrox by Titanium(III)-Catalyzed Radical Tandem Cyclization

Article abstract of DOI:10.1055/s-0035-1560594

A synthesis of (±)-ambrox, a compound with delicious ambergris-type scent, is presented. The key step is a highly diastereoselective titanocene(III)-catalyzed radical tandem cyclization of a farnesol derivative.

Full text of DOI:10.1055/s-0035-1560594

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–F
letter
A
A. Rosales et al.
Letter
Synlett
Diastereoselective Synthesis of (±)-Ambrox by Titanium(III)-Cata-
lyzed Radical Tandem Cyclization
Antonio Rosales*a,b
L. A. R. Foleyc
Natalia M. Padialc
Juan Muñoz-Bascónc
Iris Sancho-Sanzc
OAc
homologation
carbocationic
cyclization
Esther Roldan-Molinac
Laura Pozo-Moralesa
Adriana Irías-Álvareza
Roman Rodríguez-Maeckerb
Ignacio Rodríguez-Garcíad
J. Enrique Oltra*c
TiIII-mediated
diastereoselective
cyclization
O
O
+
H
NaCN
(
)-ambrox
a Department of Chemical and Environmental Engineer-
ing, Escuela Politécnica Superior, University of Sevilla,
41011 Sevilla, Spain
arosales@us.es
b Petrochemical Engineering, Universidad de las Fuerzas
Armadas-ESPE, 050150 Latacunga, Ecuador
c Department of Organic Chemistry, Faculty of Sciences,
University of Granada, 18071 Granada, Spain
joltra@ugr.es
d Química Orgánica, CeiA3, Universidad de Almería, 04120
Almería, Spain
Dedicated to Prof. Emilio Diaz Ojeda
Received: 06.07.2015
Accepted after revision: 23.10.2015
Published online: 09.12.2015
dients, with a market price well above $500/kg for the en-
antiomerically pure product and an annual worldwide pro-
duction of several tens of tons.3
DOI: 10.1055/s-0035-1560594; Art ID: st-2015-b0508-l
Abstract A synthesis of (±)-ambrox, a compound with delicious am-
bergris-type scent, is presented. The key step is a highly diastereoselec-
tive titanocene(III)-catalyzed radical tandem cyclization of a farnesol
derivative.
O
O
OH
H
H
O
Key words ambrox, natural products, titanocene, radical chemistry,
diastereoselective synthesis
ambrox (1)
OH
O
OH
Ambrox (1) is one of the natural components of amber-
gris (Figure 1) and, additionally, one of the commercially
most important products for providing ambergris-type
odor in fine perfumery.1 Ambergris is a solid, waxy sub-
stance produced by photooxidation of ambrein, a substance
accumulated in the gut of sperm whales (Physeter macro-
cephalus L.), which has been used in the past as a valuable
constituent of fine fragrances due to its exceptional fixative
and scent properties.2 Nevertheless, ambergris itself is no
longer used almost anywhere, because natural sources do
not meet the increasing demand for perfume ingredients
with ambergris-type odor. As a consequence, synthetic am-
brox constitutes the most important commercial substitute
with the desirable ambergris-type scent. Ambrox (1) is
considered to be one of the most expensive fragrance ingre-
H
H
H
Figure 1 Naturally occurring terpene derivatives isolated from amber-
gris
Since the first synthesis of this compound was de-
scribed more than sixty years ago,4 a considerable number
of different synthetic procedures have been reported. These
procedures include both semisynthetic methods via oxida-
tive degradation of naturally occurring products, such as
sclareol, manool, ambrein, and communic acids,5 and bio-
mimetic cyclizations of precursors, such as homofarnesic
acid, (E)-β-farnesene, homofarnesol, farnesylacetic acid and
analogues.6 Nevertheless, many of these procedures are ex-
pensive and laborious and/or provide yields that are nor-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

B
A. Rosales et al.
Letter
Synlett
mally susceptible of being improved. Therefore, novel pro-
cedures for the synthesis of ambrox are needed for a sus-
tainable production of this valuable product.
selective formation of the tetrahydrofuran ring. The desired
stereochemistry of ambrox (1) may also be obtained from
the tetrasubstituted endocyclic double bond (4-endo).12 Ac-
cording to the Markovnikov rule, only the tertiary cation
would be formed under protic treatment of the exocyclic
double bond in 4. In contrast, in the case of the endocyclic
olefins which are more commonly obtained from cationic
cyclizations or through other approaches, this selectivity is
often difficult to achieve and, usually, mixtures of isomeric
tetrahydrofurans are obtained.
Titanium is one of the most abundant metals on Earth
(the second among transition metals), and most of the tita-
nium compounds are degraded in nature to TiO2, which is
not toxic.7 In the last years Cp2TiCl has emerged as a formi-
dable tool in organic synthesis.8 In fact, this single-electron
transfer (SET) reagent has reported to be capable of pro-
moting and/or catalyzing very important transformations
in organic chemistry, such as radical-opening reactions,
radical cascade cyclizations, coupling reactions, THF-ring-
formation reactions, H-atom transfer, Barbier-type reac-
tions, deoxygenation of alcohols, umpolung reactions, and
polymerization reactions.
The synthesis of scarce natural products constitutes one
of the most demanding tests to prove the utility of new
methods or reagents in organic synthesis. As part of our
contributions to the synthesis of natural compounds,9 we
were interested in the development of a new concise syn-
thesis of ambrox (1). In the present report we describe a
novel, concise, safe, and environmental friendly diastereo-
selective synthesis of (±)-ambrox, the key step of which is a
radical tandem cyclization catalyzed by Cp2TiCl.
Our synthesis of 1 (Scheme 2) started with the selective
epoxidation of farnesyl acetate following a previously de-
scribed method13 which yields the epoxyfarnesol 2. Epoxy-
farnesol acetate (3) was obtained quantitatively from 2 by
acetylation.14 The cyclization of compound 3 catalyzed by a
catalytic quantity of Cp2TiCl (0.1 equiv), using the couple
TMSCl/2,4,6-collidine developed in our laboratory as a tita-
nocene-regenerating agent,9a afforded the trans-fused
decalin 4 bearing a crucial exocyclic double bond on C-8.15
Although the bicyclic compound 4 was obtained in a mod-
erate 40% yield, starting material 3 was recovered in a 40%
yield, and the cyclization process underwent a rigid stereo-
chemical control imposed by the geometry of the stereo-
genic center of epoxide 3. Bicyclic compound 4 was ob-
tained previously with similar yield when Cp2TiCl (0.2
equiv) was used.11a Therefore, the yield can be regarded as
satisfactory considering that the main compound has four
stereocenters with a single relative configuration. Previous-
ly, theoretical and experimental evidences indicated that
this radical tandem cyclization proceeds through a noncon-
certed fashion via discrete carbon-centered radicals. Con-
sidering the nonconcerted nature of this radical tandem cy-
clization, the stereoselectivity observed can be explained in
terms of Beckwith–Houk rules describes elsewhere.16 This
cyclization reaction proceed with high stereoselectivity and
only one of the many possible stereoisomers was isolated.
Similar results were previously reported.9b With enantio-
merically pure epoxyfarnesol 3 that was described by Spi-
nella et al.17 1 could be prepared enantiomerically pure. The
termination step of this tandem cyclization is a β-elimina-
tion leading to an olefin. The exocyclic location of the dou-
ble bond on C-8 in compound 4 is compulsory in order to
complete the proposed synthesis of ambrox (1). Saponifica-
tion of the acetate 4 gave isodrimenediol (5),18 a microbial
metabolite previously synthesized by Breslow et al.19 and
Compared to conventional cationic cyclizations,10 radi-
cal cyclization of epoxypolyisoprenes is a complementary
method because the generation of radicals proceeds under
milder conditions. Therefore, many functional groups are
tolerated that are not compatible with the cationic condi-
tions. Here we present a synthetic strategy for the prepara-
tion of ambrox by exploiting the advantages of the titano-
cene(III)-catalyzed radical tandem cyclizations, such as the
high diastereoselectivity,11a,9b the readily availability of the
starting materials and catalysts, and the regioselective for-
mation of an exocyclic olefin during the termination of the
process.11,9b,f This last point is of paramount importance for
the completion of the synthesis of ambrox as discussed lat-
er. Scheme 1 shows the retrosynthetic analysis of (±)-am-
brox (1) from epoxyfarnesol (2).
The key step is the titanium(III)-catalyzed cyclization of
epoxide 3 to the decalin derivative 4, which is the crucial
intermediate for the preparation of ambrox (1). On the basis
of our experience, this cyclization will proceed with high
regio- and stereoselectivity.11a This retrosynthetic analysis
also addresses the important issues of the regio- and stereo-
OAc
OH
OAc
O
HO
O
O
H
H
exo-4
endo-4
3
2
1
Scheme 1 Retrosynthetic analysis of (±)-ambrox (1)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

C
A. Rosales et al.
Letter
Synlett
OH
OAc
OAc
OR
a
c
b
HO
HO
O
O
H
H
3
2
4
5 R = OH
d
6 R = OMs
R1
CN
e
O
i
O
f
h
HO
HO
HO
H
H
H
H
8 R1 = CHO
9 R1 = CH2OH
7
g
1
10
Scheme 2 Synthesis of ambrox (1) from epoxyfarnesol (2). Reagents and conditions: (a) DMAP (1.25 equiv), Ac2O (1.1 equiv), CH2Cl2, r.t., 1 h, quant.;
(b) Cp2TiCl (0.1 equiv), THF, r.t., 12 h, 40%; (c) K2CO3 (1.12 equiv), MeOH, r.t., 30 min, 95%; (d) DMAP (0.1 equiv), MsCl (1.05 equiv), pyridine, r.t., 2 h,
95%; (e) NaCN (5 equiv), DMSO, 100 °C, 12 h, 49%; (f) DIBAL-H (1.19 equiv), toluene, –78 °C, 30 min, 85%; (g) NaBH4 (1.3 equiv), MeOH, 0 °C, 30 min,
95%; (h) PTSA (1.3 equiv), MeNO2, r.t., 2 h, 60%; (i) (a) DMAP (3.0 equiv), C6F5OC(S)Cl (2.0 equiv), CH2Cl2, 4 h; (b) AIBN (0.2 equiv), n-Bu3SnH (2.5
equiv), benzene, reflux, 3 h, 74% (two steps).
isolated from Polyporus arcularius20 and Funalia trogii.21
Subsequently, mesylation of compound 5 with MsCl in Et3N
at –40 °C afforded a 95% yield of the compound 6,22 which
was treated with NaCN in dimethyl sulfoxide (DMSO) to af-
ford the nitrile compound 7 in a 49% yield23 along with 11
(30%)23 (Scheme 3). This result can be explained consider-
ing that under these experimental reaction conditions two
competing processes can take place. On the first hand, the
mesylate group can be substituted by the nitrile group
through an SN2 process to give the compound 7, while on
the second hand it can suffer elimination to give the diene
11 (Scheme 3). The C-1 elongation is crucial to the synthesis
of the THF ring in ambrox (1), and the nitrile group was
confirmed by a detailed analysis of its spectroscopic prop-
erties, specially the presence of a signal at δ = 120.0 ppm in
its 13C NMR spectrum.
9 in 95% yield.25 The conversion of the key intermediate 4 to
ambrox (1) has been previously reported using similar con-
ditions from the deoxy series and tributylsilylether deriva-
tive by Miyake et al.,26 Kinoshita et al.,27 Mori et al.,28 and
Heissler et al.29
The PTSA-mediated cyclization of 9 proved to be regio-
and stereoselective, affording the THF derivative 10, as only
isolated product, in a 60% yield.30 Finally, using the Barton–
McCombie deoxygenation method,31 the alcohol 8 could
also be easily transformed in ambrox (1). In fact, conversion
of the alcohol 10 into its trifluoromethoxythiocarbonyl de-
rivative followed by radical reduction with Bu3SnH, afford-
ed ambrox (1) in a gratifying 74% yield.32 Spectroscopic data
for synthetic ambrox (1) were identical to those previously
reported for the natural product.5e
In summary, we have developed a concise diastereose-
lective route to ambrox (1) using the titanium(III)-catalyzed
radical cyclization of epoxypolyprene 3 as the key step. At
the moment we are working on the synthesis of superam-
brox33 that will be reported in due course.
E2
HO
OMs
11 (30%)
MsOH
HO
H
MsO–
CN
CN–
Acknowledgment
6
HO
The Spanish MICINN (Projects CTQ2008-06790, CTQ2010-17115, and
CTQ2011-24443) and the Regional Government of Andalucia (Proj-
ects P07-FQM-3213 and P10-FQM-6050) are greatly acknowledged
for financial support. A. Rosales acknowledges University of the Sevil-
la for his position as professor and to Prof. A. Gansäuer for his collabo-
ration in the redaction of this manuscript.
H
SN2
7
(49%)
Scheme 3 NaCN-mediated transformation of 6 to 7 and 11
Reduction of
7 with diisobutylaluminum hydride
(DIBAL-H) in toluene furnished the aldehyde 8 in a 85%
yield,24 which was further reduced with NaBH4 to give diol
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

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Supporting Information
(f) Rosales, A.; Muñoz-Bascón, J.; Roldán-Molina, E.; Rivas-
Bascón, N. M.; Padial, N.; Rodríguez-Macker, R.; Rodríguez-
García, I.; Oltra, J. E. J. Org. Chem. 2015, 80, 1866.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560594.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(10) (a) Abe, I.; Rhomer, M.; Prestwich, G. D. Chem. Rev. 1993, 93,
2189. (b) Wendt, K. U.; Schulz, G. E.; Corey, E. J.; Liu, D. R. Angew.
Chem. Int. Ed. 2000, 39, 2812. (c) Yoder, R. A.; Johnston, J. N.
Chem. Rev. 2005, 105, 4730.
References and Notes
(11) (a) Justicia, J.; Rosales, A.; Buñuel, E.; Oller-López, J. L.; Valdivia,
M.; Haïdour, A.; Oltra, J. E.; Barrero, A. F.; Cárdenas, D. J.; Cuerva,
J. M. Chem. Eur. J. 2004, 10, 1778. (b) Gansäuer, A.; Lauterbach,
T.; Geich-Gimbel, D. Chem. Eur. J. 2004, 10, 4983. (c) Justicia, J.;
Oller-López, J. L.; Campaña, A. G.; Oltra, J. E. Cuerva J. M.;
Buñuel, E.; Cárdenas, D. J. J. Am. Chem. Soc. 2005, 127, 14911.
(d) Gansäuer, A.; Worgull, D.; Knebel, K.; Huth, I.;
Schnakenburg, G. Angew. Chem. Int. Ed. 2009, 48, 8882.
(12) Verstegen-Haaksma, A. A.; Swarts, H. J.; Jansen, B. J. M.; Groot, A.
Tetrahedron 1994, 50, 10095.
(1) Ambrox is the registered trademark of Firmenich for compound 1.
(2) Sell, C. Chem. Ind. (London) 1990, 20, 516.
(3) Sell, C. S. In Kirk-Othmer Chemical Technology of Cosmetics; John
Wiley & Sons: Hoboken, 2013, 354.
(4) Stoll, M.; Hinder, M. Helv. Chim. Acta 1950, 33, 1251.
(5) (a) Schenk, H. R.; Gutman, H.; Jeger, O.; Ruzicka, L. Helv. Chim.
Acta 1954, 37, 543. (b) Cambie, R. C.; Joblin, K. N.; Preston, A. F.
Aust. J. Chem. 1971, 24, 583. (c) de Pascual-Teresa, T.; Urones, J.;
Montaña, P.; Basabe, P. Tetrahedron Lett. 1985, 26, 5717.
(d) Koyama, H.; Kaku, Y.; Ohno, M. Tetrahedron Lett. 1987, 28,
2863. (e) Xie, Y.-P.; Li, B.-G.; Luo, Y.-G.; Chen, X.-Z.; Zhang, G.-L.
Helv. Chim. Acta 2008, 91, 734.
(6) (a) Barrero, A. F.; Altarejos, J.; Álvarez-Manzaneda, E. J.; Ramos,
J. M.; Salido, S. J. Org. Chem. 1996, 61, 2215. (b) Ishihara, K.;
Ishibashi, H.; Yamamoto, H. J. Am. Chem. Soc. 2002, 124, 3647.
(c) Snowden, R. L.; Eichenberger, J. C.; Linder, S. M.; Sonnay, P.;
Vial, C.; Schulte-Elte, K. H. J. Org. Chem. 1992, 57, 955. (d) Shenvi,
R. A.; Corey, E. J. Org. Lett. 2010, 12, 3548. (e) Barrero, A. F.;
Cuerva, J. M.; Herrador, M. M.; Valdivia, M. V. J. Org. Chem. 2001,
66, 4074. (f) Barrero, A. F.; Herrador, M. M.; Quílez del Moral, J.
F.; Arteaga, P.; Arteaga, J. F.; Piedra, M.; Sánchez, E. M. Org. Lett.
2005, 7, 2301. (g) Justicia, J.; Oltra, J. E.; Barrero, A. F.; Guadaño,
A.; González-Coloma, A.; Cuerva, J. M. Eur. J. Org. Chem. 2005,
712. (h) Domingo, V.; Silva, L.; Diéguez, H. R.; Arteaga, J. F.;
Quílez del Moral, J. F.; Barrero, A. F. J. Org. Chem. 2009, 74, 6151.
(i) Chapuis, C. Helv. Chim. Acta 2014, 97, 197.
(13) Snyder, S. A.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 740.
(14) Preparation of Acetate 3
DMAP (153 mg, 1.25 mmol) and Ac2O (0.1 mL, 1.1 mmol) were
added to 2 (252 mg, 1.06 mmol) in CH2Cl2 (8 mL), and the
resulting mixture was stirred at r.t. for 1 h. The mixture was
then diluted with Et2O and washed with 2 N HCl, a sat. solution
of NaHCO3, and brine. The organic layer was dried (anhydrous
Na2SO4) and the solvent removed. The residue was purified by
flash chromatography (hexane–EtOAc, 9:1) to yield 270 mg of
1
the compound 3 (100%). H NMR and 13C NMR spectra of com-
pound 3 were consistent with that of the original isolation liter-
ature.34
(15) Cp2TiCl-Catalyzed Cyclization of 3
Strictly deoxygenated THF (15 mL) was added to a mixture of
[Cp2TiCl2] (25 mg, 0.1 mmol) and Mn dust (440 mg, 8.0 mmol)
under Ar, and the suspension was stirred at r.t. until it turned
green (about 15 min). Then a solution of 2,4,6-collidine (0.9 mL,
7.0 mmol) and TMSCl (0.5 mL, 4.0 mmol) in THF (5 mL) was
added, the mixture was stirred for 5 min, a solution of 3 (280
mg, 1 mmol) in THF (5 mL) was finally added, and the mixture
was stirred at r.t. for 12 h. Then 2 N HCl was added, and the
mixture was extracted with Et2O. The combined organic layers
were dried with anhydrous Na2SO4, and the solvent was
removed. The residue was dissolved in THF, and 1 M solution of
TBAF in THF (1.2 mmol) was added. The new mixture was
stirred for 30 min, diluted with Et2O, and washed with brine.
The organic layer was dried with anhydrous Na2SO4 and the
solvent removed. The residue was purified by flash chromatog-
raphy (hexane–EtOAc, 9:1) to yield 112 mg of the cyclization
compound 4 (40%), and 112 mg of starting material 3 was
recovered (40%). Only the isomer 4 was isolated. 1H NMR and
13C NMR spectra of compound 4 were consistent with that of
the original isolation literature.11a
(7) Ramón, D. J.; Yus, M. Chem. Rev. 2006, 106, 2126.
(8) For relevant reviews, see: (a) Gansäuer, A.; Bluhm, H. Chem. Rev.
2000, 100, 2771. (b) Gansäuer, A.; Rinker, B. Tetrahedron 2002,
58, 7017. (c) Gansäuer, A.; Narayan, S. Adv. Synth. Catal. 2002,
344, 465. (d) Gansäuer, A.; Lauterbach, T.; Narayan, S. Angew.
Chem. Int. Ed. 2003, 42, 5556. (e) Cuerva, J. M.; Justicia, J.; Oller-
López, J. L.; Bazdi, B.; Oltra, J. E. Mini-Rev. Org. Chem. 2006, 3, 23.
(f) Cuerva, J. M.; Justicia, J.; Oller-López, J. L.; Oltra, J. E. Top. Curr.
Chem. 2006, 264, 63. (g) Gansäuer, A.; Justicia, J.; Fan, C.-A.;
Worgull, D.; Piestert, F. Top. Curr. Chem. 2007, 279, 25.
(h) Justicia, J.; Álvarez de Cienfuegos, L.; Campaña, A. G.; Miguel,
D.; Jakoby, V.; Gansäuer, A.; Cuerva, J. M. Chem. Soc. Rev. 2011,
40, 3525. (i) Rosales, A.; Rodríguez-García, I.; Muñoz-Bascón, J.;
Roldan-Molina, E. M.; Padial, N.; Pozo-Morales, L.; García-
Ocaña, M.; Oltra, J. E. Eur. J. Org. Chem. 2015, 21, 4567.
(j) Rosales, A.; Rodríguez-García, I.; Muñoz-Bascón, J.; Roldan-
Molina, E. M.; Padial, N.; Pozo-Morales, L.; García-Ocaña, M.;
Oltra, J. E. Eur. J. Org. Chem. 2015, 21, 4592.
(16) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions; VCH: Weinheim, 1995.
(9) (a) Barrero, A. F.; Rosales, A.; Cuerva, J. M.; Oltra, J. E. Org. Lett.
2003, 5, 1935. (b) Gansäuer, A.; Justicia, J.; Rosales, A.; Worgull,
D.; Rinker, B.; Cuerva, J. M.; Oltra, J. E. Eur. J. Org. Chem. 2006, 18,
4115. (c) Rosales, A.; Estévez, R. E.; Cuerva, J. M.; Oltra, J. E.
Angew. Chem. Int. Ed. 2005, 44, 319. (d) Justicia, J.; Álvarez de
Cienfuegos, L.; Estévez, R. E.; Paradas, M.; Lasanta, A. M.; Oller-
López, J. L.; Rosales, A.; Oltra, J. E. Tetrahedron 2008, 64, 11938.
(e) Rosales, A.; Muñóz-Bascón, J.; Morales-Álcázar, V. M.;
Castilla-Alcalá, J. A.; Oltra, J. E. RSC Adv. 2012, 2, 12922.
(17) D’Acunto, M.; Della Monica, C.; Izzo, I.; De Petrocellis, L.; di
Marzo, V.; Spinella, A. Tetrahedron 2010, 66, 9785.
(18) Saponification of 4
Compound 4 (224 mg, 0.8 mmol) was dissolved in MeOH (2
mL), K2CO3 (124 mg, 0.9 mmol) was added, and the solution was
stirred for 30 min. The mixture was then diluted with Et2O and
washed with 2 N HCl solution. The organic layer was dried
(anhydrous Na2SO4), and the solvent was removed. The residue
was purified by flash chromatography (hexane–EtOAc, 85:15)
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to yield 181 mg of compound 5 (95%). 1H NMR and 13C NMR
spectra of compound isodrimenediol (5) were consistent with
those of the original isolation literature (see ref. 20).
(19) Breslow, R.; Olin, S. S.; Groves, J. T. Tetrahedron Lett. 1968, 9,
1837.
(20) Fleck, W. F.; Schlegel, B.; Hoffmann, P.; Ritzau, M.; Heinze, S.;
Gräfe, U. J. Nat. Prod. 1996, 59, 780.
(21) Ding, J. H.; Feng, T.; Li, Z. H.; Si, J.; Yu, H. Y.; Zhang, H. B.; Liu, J. K.
J. Asian Nat. Prod. Res. 2013, 15, 828.
The organic layer was washed with sat. brine, dried over anhy-
drous Na2SO4, and the solvent was removed. The residue was
purified by flash chromatography (hexane–EtOAc, 9:1) to yield
212 mg of the aldehyde 8 (85%) as waxy mass.
Analytical Data for aldehyde 8
1H NMR (500 MHz, CDCl3): δ = 9.64 (dd, J = 3.1, 0.9 Hz, 1 H), 4.84
(s, 1 H), 4.41 (s, 1 H), 3.28 (dd, J = 11.6, 4.5 Hz, 1 H), 2.52 (ddd,
J = 16.8, 10.8, 3.2 Hz, 1 H), 2.46–2.40 (m, 2 H), 2.35–2.30 (m, 1
H), 2.09 (td, J = 13.1, 5.0 Hz, 1 H), 1.81–1.51 (m, 5 H), 1.42 (qd,
J = 13.0, 4.3 Hz, 1 H), 1.21 (dd, J = 12.5, 2.8 Hz, 1 H), 1.02 (s, 3 H),
0.80 (s, 3 H), 0.72 (s, 3 H). 13C NMR (126 MHz, CDCl3): δ = 203.0
(CH), 147.9 (C), 108.4 (CH2), 78.6 (CH), 54.3 (CH), 50.6 (CH), 39.8
(CH2), 39.1 (C), 38.6 (C), 37.3 (2 × CH2), 28.3 (CH3), 27.7 (CH2),
23.5 (CH2), 15.4 (CH3), 14.6 (CH3).
(22) Synthesis of Mesylate 6
To a solution of isodrimenediol (5, 238 mg, 1.0 mmol) and
DMAP (12 mg, 0.1 mmol) in pyridine (4 mL) was added MsCl
(81 μL, 1.05 mmol), and the whole mixture was stirred for 2 h at
r.t. The reaction mixture was diluted with sat. brine and
extracted with Et2O. The organic layer was washed with 2 N aq
HCl, 7% aq NaHCO3, dried with anhydrous Na2SO4, and the
solvent was removed. The residue was purified by flash chro-
matography (hexane–EtOAc, 9:1) to yield 300 mg of mesylate 6
(95%), isolated as a waxy mass.
(25) Preparation of Alcohol 9
To a solution of 8 (187 mg, 0.75 mmol) in MeOH (3.7 mL) was
added NaBH4 (37 mg, 0.98 mmol) at 0 °C. The mixture of reac-
tion was stirred for 30 min at the same temperature. After addi-
tion of acetone (0.6 mL), the reaction mixture was condensed to
give a residue, which was diluted with sat. brine and extracted
with Et2O. The organic layer was dried with anhydrous Na2SO4,
and the solvent was removed. The crude of reaction was puri-
fied by flash chromatography (hexane–EtOAc, 85:15) to yield
179 mg of the alcohol 9 (95%) isolated as waxy mass.
Analytical Data for Alcohol 9
Analytical Data for Mesylate 6
1H NMR (500 MHz, CDCl3): δ = 4.92 (s, 1 H), 4.62 (s, 1 H), 4.45
(dd, J = 10.0, 3.9 Hz, 1 H), 4.34 (dd, J = 9.8, 8.9 Hz, 1 H), 3.26 (dd,
J = 11.7, 4.2 Hz, 1 H), 2.98 (s, 3 H), 2.43 (ddd, J = 13.2, 4.3, 2.4 Hz,
1 H), 2.11 (dd, J = 8.6, 3.2 Hz, 1 H), 2.02 (td, J = 13.0, 4.8 Hz, 1 H),
1.78–1.69 (m, 3 H), 1.66–1.54 (m, 2 H), 1.45–1.35 (m, 2 H), 1.13
(dd, J = 12.5, 2.8 Hz, 1 H), 1.00 (s, 3 H), 0.78 (s, 3 H), 0.76 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 145.1 (C), 108.0 (CH2), 78.3 (CH),
66.4 (CH2), 54.8 (CH), 54.2 (CH), 39.1 (C), 38.9 (C), 37.6 (CH3),
37.2 (CH2), 37.0 (CH2), 28.2 (CH3), 27.5 (CH2), 23.3 (CH2), 15.4
(CH3), 15.2 (CH3).
1H NMR (500 MHz, CDCl3): δ = 4.87 (br s, 1 H), 4.56 (br s, 1 H),
3.74 (ddd, J = 10.1, 7.3, 4.3 Hz, 1 H), 3.53 (dt, J = 10.1, 7.0 Hz, 1
H), 3.27 (dd, J = 11.8, 4.3 Hz, 1 H), 2.41 (ddd, J = 12.8, 4.3, 2.5 Hz,
1 H), 2.00 (td, J = 13.0, 5.1 Hz, 1 H), 1.82–1.56 (m, 7 H), 1.55–
1.45 (m, 2 × OH), 1.40 (dd, J = 12.8, 4.2 Hz, 1 H), 1.21 (m, 1 H),
1.13 (dd, J = 12.5, 2.8 Hz, 1 H), 1.00 (s, 3 H), 0.78 (s, 3 H), 0.70 (s,
3 H). 13C NMR (126 MHz, CDCl3): δ = 148.2 (C), 106.8 (CH2), 78.8
(CH), 62.4 (CH2), 54.6 (CH), 52.5 (CH), 39.1 (C), 39.1 (C), 38.1
(CH2), 37.1 (CH2), 28.3 (CH3), 27.9 (CH2), 27.2 (CH2), 23.9 (CH2),
15.41 (CH3), 14.5 (CH3).
(23) Preparation of Nitrile 7
To a solution of mesylate 6 (252 mg, 0.8 mmol) in DMSO (5 mL)
was added NaCN (196 mg, 4 mmol), and the mixture of reaction
was stirred for 12 h at 100 °C. The reaction mixture was diluted
with sat. brine and extracted with Et2O. The organic layer was
dried with anhydrous Na2SO4, and the solvent was removed.
The residue was purified by flash chromatography (hexane–
EtOAc, 9:1) to yield 97 mg of the nitrile 7 (49%) and 53 mg of the
diexo-olefin 11 (30%), both isolated as waxy mass.
(26) Miyake, T.; Uda, K.; Kinoshita, M.; Fujii, M.; Akita, H. Chem.
Pharm. Bull. 2008, 56, 398.
(27) Kinoshita, M.; Ohtsuka, M.; Nakamura, D.; Akita, H. Chem.
Pharm. Bull. 2002, 50, 930.
Analytical Data for Nitrile 7
(28) Mori, K.; Tamura, H. Liebigs Ann. Chem. 1990, 361.
(29) Raeppel, F.; Weibel, J.-M.; Heissler, D. Tetrahedron Lett. 1999, 40,
6377.
1H NMR (401 MHz, CDCl3): δ = 4.96 (s, 1 H), 4.62 (s, 1 H), 3.25
(dd, J = 11.6, 4.3 Hz, 1 H), 2.56–2.40 (m, 2 H), 2.34 (dd, J = 16.7,
10.6 Hz, 1 H), 2.17–2.00 (m, 2 H), 1.80–1.50 (m, 4 H), 1.45–1.28
(m, 2 H), 1.12 (dd, J = 12.5, 2.6 Hz, 1 H), 1.00 (s, 3 H), 0.77 (s, 3
H), 0.68 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 145.7 (C), 120.0
(C), 108.2 (CH2), 78.2 (CH), 54.1 (CH), 52.9 (CH), 39.1 (C), 39.0
(C), 37.1 (CH2), 37.0 (CH2), 28.2 (CH3), 27.5 (CH2), 23.3 (CH2),
15.4 (CH3), 14.0 (CH2), 13.7 (CH3).
(30) Synthesis of Tetrahydrofuran Derivative 10
To a solution of 9 (100 mg, 0.39 mmol) in MeNO2 (10 mL) was
added PTSA (87 mg, 0.5 mmol). The mixture of reaction was
stirred for 2 h at r.t. The reaction was quenched with aq NaHCO3
(10%) and extracted with Et2O. The organic layer was washed
with sat. brine, dried over anhydrous Na2SO4, and the solvent
was removed. The residue was purified by flash chromatogra-
phy (hexane–EtOAc, 80:20) to yield 10 (60 mg, 60%) as a waxy
mass. Only the isomer 10 was isolated. 1H NMR and 13C NMR
spectra of compound 10 were consistent with that of the origi-
nal isolation literature.35
Analytical Data for Diexo-olefin 11
1H NMR (500 MHz, CDCl3): δ = 4.81 (t, J = 2.1 Hz, 1 H), 4.77 (s, 1
H), 4.67 (s, 1 H), 4.53 (s, 1 H), 3.25 (dd, J = 10.3, 4.2 Hz, 1 H), 2.47
(br d, J = 12.6 Hz, 1 H), 2.15–2.06 (m, 1 H), 1.82–1.49 (m, 6 H),
1.12 (dd, J = 12.5, 2.5 Hz, 1 H), 1.00 (s, 3 H), 0.95 (s, 3 H), 0.83 (s,
3 H). 13C NMR (126 MHz, CDCl3): δ = 160.9 (C), 149.4 (C), 109.3
(CH2), 103.5 (CH2), 78.8 (CH), 51.7 (CH), 39.9 (C), 39.4 (C), 35.6
(CH2), 35.3 (CH2), 28.3 (CH3), 27.7 (CH2), 22.3 (CH2), 20.8 (CH3),
15.5 (CH3).
(31) (a) Barton, D. H. R.; Ferreira, J. A.; Jaszberenyi, J. C. Free Radical
Deoxygenation of Thiocarbonyl Derivatives of Alcohols, In Prepar-
ative Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel Dekker:
New York, 1997, 151. (b) Crich, D.; Quintero, L. Chem. Rev. 1989,
89, 1413.
(24) Synthesis of Aldehyde 8
To a solution of nitrile 7 (247 mg, 1.0 mmol) in toluene (3 mL)
was added 1 M DIBAL in toluene (1.19 mL, 1.19 mmol) at –78
°C. The mixture of reaction was stirred for 30 min at the same
temperature. After addition of acetone (0.75 mL), the reaction
mixture was diluted with 2 M aq HCl and extracted with Et2O.
(32) Barton–McCombie Deoxygenation of Alcohol 10
DMAP (110 mg, 0.9 mmol) and O-pentafluorophenyl chlorothio-
noformate (160 mg, 0.6 mmol) were added to a solution of
alcohol 10 (80 mg, 0.3 mmol) in CH2Cl2 (10 mL) at 0 °C, and the
mixture was stirred at r.t. for 4 h. The reaction was quenched
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

F
A. Rosales et al.
Letter
Synlett
with H2O, the mixture extracted with EtOAc, the organic layer
dried (anhydrous MgSO4), and the solvent removed to give a
residue (120 mg), which was dissolved in benzene (10 mL) and
slowly added to a mixture of HSnBu3 (220 mg, 0.76 mmol) and
AIBN (10 mg) in benzene (10 mL). This mixture was refluxed for
3 h, the solvent was removed, and the residue was submitted to
flash chromatography (hexane–EtOAc, 85:15) to yield 1 (50 mg,
74%) as a white solid. Its 1H NMR and 13C NMR data matched
those previously reported for ambrox (see ref. 36).
(33) Fehr, C.; Farris, I. Angew. Chem. Int. Ed. 2006, 45, 6904.
(34) Tsangarakis, C.; Arkoudis, E.; Raptis, C.; Stratakis, M. Org. Lett.
2007, 9, 583.
(35) Janson, J. R.; Truneh, A. Phytochemistry 1996, 42, 1021.
(36) Ohloff, G.; Giersch, W.; Pickenhagen, W.; Furrer, A.; Frei, B. Helv.
Chim. Acta 1985, 68, 2022.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F