Enantioselective total synthesis of the potent anti-inflammatory (+)-myrrhanol A

Article abstract of DOI:10.1021/jo901011m

(Chemical Equation Presented) The first total synthesis of potent anti-inflammatory polypodanes (+)-myrrhanol A (1), (+)-myrrhanone A (2), (+)-myrrhanone B (3), and (+)-myrrhanol B (4) has been achieved. Key steps in our convergent, highly stereocontrolle

Full text of DOI:10.1021/jo901011m

pubs.acs.org/joc
Enantioselective Total Synthesis of the Potent Anti-inflammatory
(þ)-Myrrhanol A
Victoriano Domingo, Lucia Silva, Horacio R. Dieguez, Jesus F. Arteaga,
†
‡
†
§
ꢀ
ꢀ
ꢀ
ꢀ
Jose F. Quı
´
lez del Moral,*,† and Alejandro F. Barrero*,†
†Department of Organic Chemistry, Institute of Biotechnology, University of Granada, Avda. Fuentenueva,
‡
18071 Granada, Spain, Department of Chemistry, University of Beira Interior, Rua Marque^s d’Avila e
ꢀ
§
Bolama, 6200-Covilha, Portugal, and Department of Chemical Engineering, Physical Chemistry and
~
Organic Chemistry, Faculty of Experimental Sciences, University of Huelva, Campus el Carmen, 21071
Huelva, Spain
jfquilez@ugr.es; afbarre@ugr.es
Received May 14, 2009
The first total synthesis of potent anti-inflammatory polypodanes (þ)-myrrhanol A (1), (þ)-myr-
rhanone A (2), (þ)-myrrhanone B (3), and (þ)-myrrhanol B (4) has been achieved. Key steps in our
convergent, highly stereocontrolled route are a Ti(III)-mediated radical cyclization of a chiral
monoepoxide to furnish a bicyclic synthon that combines stereospecifically with an acyclic vinyl iodide
via an intermolecular B-alkyl Suzuki-Miyaura cross-coupling.
Introduction
(þ)-Myrrhanol A (1), (þ)-myrrhanone A (2), (þ)-myr-
rhanone B (3), and (þ)-myrrhanol B (4) are polypodane
triterpenes isolated from guggul-gum resin.1 Although most
of the triterpenes contain a tetra- or pentacyclic skeleton as a
result of cascade cyclizations and rearrangements of the
acyclic precursors squalene (S) and 2,3-oxidosqualene
(OS), these bicyclic polypodane triterpenes derive from
incomplete cyclization of S or OS. Compounds 1-4 could
be then encompassed in a group of triterpenes defined as
“unusually cyclized triterpenes”, characterized by deriving
from cyclization proccesses different from those leading to
tetra- and pentacyclic triterpenes. It is worth mentioning that
there has been an increase in the description of this kind of
natural compound in the past few years.2
The resin from B. mukul is used in several alternative-
medicine preparations including products prescribed or sold
for the prevention of inflammation, lowering cholesterol,
and reduction of plaque buildup in the arteries. In connec-
tion with this, myrrhanol A (1) and myrrhanone A (2) were
shown to display a potent anti-inflammatory effect on
exudative pouch fluid, angiogenesis, and granuloma weights
in adjuvant-induced air-pouch granuloma of mice, their
effects being more marked than those of hydrocortisone.1
Moreover, myrrhanol A (1), myrrhanone A (2), and
myrrhanol B (4) were characterized as significant NO pro-
duction inhibitors due to their inhibitory activities against
(1) (a) Kimura, I.; Yoshikawa, M.; Kobayashi, S.; Sugihara, Y.; Suzuki,
M.; Oominami, H.; Murakami, T.; Matsuda, H.; Doiphode, V. Bioorg. Med.
Chem. Lett. 2001, 11, 985–989. (b) Matsuda, H.; Morikawa, T.; Ando, S.;
Oominami, H.; Murakami, T.; Kimura, I.; Yoshikawa, M. Bioorg. Med.
Chem. 2004, 12, 3037–3046.
(2) For reviews, see: (a) Domingo, V.; Arteaga, J. F.; Quilez , J. F.;
Barrero, A. F. Nat. Prod. Rep. 2008, 26, 115–134. (b) Xu, R.; Fazio, G. C.;
Matsuda, S. P. T. Phytochemistry 2004, 65, 261–291.
DOI: 10.1021/jo901011m
r
Published on Web 07/06/2009
J. Org. Chem. 2009, 74, 6151–6156 6151
2009 American Chemical Society

Domingo et al.
SCHEME 1. Retrosynthetic Analysis Based on a Ti(III)-Promoted Radical Cyclization and a B-Alkyl Suzuki-Miyaura Cross-Coupling
JOCArticle
SCHEME 2. Synthesis of Bicyclic Synthon 11
iNOS induction in LPS-activated macrophages, which
substantiates the traditional effects of this herbal medicine
for the treatment of inflammation.1,3 The unusual triterpe-
noid structures of these compounds together with their
potent biological activities prompted us to address their
total synthesis.4
Results and Discussion
In designing a synthetic route toward (þ)-myrrhanol A
(1) we envisioned a convergent approach based on the
coupling of a chiral synthon C16, namely, 11 with a
polyprenated (E)-vinyl iodide, 15, based on the retrosyn-
thetic analysis outlined in Scheme 1. In our opinion, this
approach will overcome the steric hindrance posed by C-11
in carbon-carbon coupling when the bicyclic synthon
possesses 15 carbon atoms. In this regard, preliminary
tests carried out in our laboratories proved the steric
problems associated with the C15 þ C15 coupling of
related derivatives.
(3) Meselhy, M. R. Phytochemistry 2003, 62, 213–218.
(4) (a) Nishizawa, M.; Takao, H.; Kanoh, N.; Asoh, K.; Hatakeyama, S.;
Yamada, H. Tetrahedron Lett. 1994, 35, 5693–5696. (b) Kinoshita, M.;
Nakamura, D.; Fujiwara, N.; Akita, H. J. Mol. Catal. B: Enzym. 2003, 22,
161–172.
(5) For pioneering work in this field, see: (a) Nugent, W. A.; RajanBabu,
T. V. J. Am. Chem. Soc. 1988, 110, 8561–8562. (b) RajanBabu, T. V.; Nugent,
W. A. J. Am. Chem. Soc. 1989, 111, 4525–4527. (c) RajanBabu, T. V.;
Nugent, W. A.; Beattie, M. S. J. Am. Chem. Soc. 1990, 112, 6408–6409.
(d) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994, 116, 986-997. For
€
reviews, see: (e) Gansauer, A.; Bluhm, H. Chem. Rev. 2000, 100, 2771–2788.
€
(f ) Gansauer, A.; Pierobon, M. In Radicals in Organic Synthesis; Renaud, P.,
Sibi, M. P., Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 2, pp 207-220.
€
€
(g) Gansauer, A.; Rinker, B. Tetrahedron 2002, 58, 7017–7026. (h) Gansauer, A.;
€
Narayan, S. Adv. Synth. Catal. 2002, 344, 465–475. (i) Gansauer, A.; Rinker, B.
In Titanium and Zirconium in Organic Synthesis; Marek, I., Ed.; Wiley-VCH:
Weinheim, Germany, 2002; pp 435-450. (j) Gansauer, A.; Lauterbach, T.;
Narayan, S. Angew. Chem., Int. Ed. 2003, 42, 5556–5573. (k) Cuerva, J. M.;
Justicia, J.; Oller-Lopez, J. L.; Bazdi, B.; Oltra, J. E. Mini-Rev. Org. Chem. 2006,
3, 23–35. (l) Cuerva, J. M.; Justicia, J.; Oller-Lopez, J. L.; Oltra, J. E. Top. Curr.
Chem. 2006, 264, 63–91. (m) Barrero, A. F.; Quilez del Moral, J. F.; Sanchez, E.
M.; Arteaga, J. F. Eur. J. Org. Chem. 2006, 1627–1641. For references of the
The key steps involved a Ti(III)-mediated cyclization5 of a
chiral monoepoxide 6 and a B-alkyl Suzuki-Miyaura cou-
pling of the synthons 11 and 15.6
As shown in Scheme 2, the synthesis of the required
boronate precursor 11 was projected in accordance with
€
€
catalytic version, see: (n) Gansauer, A.; Bluhm, H. Chem. Commun. 1998, 2143–
€
2144. (o) Gansauer, A.; Pierobon, M.; Bluhm, H. Angew. Chem., Int. Ed. 1998,
€
37, 101–103. (p) Gansauer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem. Soc. 1998,
(6) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
(b) Chemler, S. R.; Trauner, D.; Danishefsky, S. Angew. Chem., Int. Ed.
2001, 40, 4544–4568.
120, 12849–12859. (q) Barrero, A. F.; Rosales, A.; Cuerva, J. M.; Oltra, J. E. Org.
Lett. 2003, 5, 1935–1938.
6152 J. Org. Chem. Vol. 74, No. 16, 2009

Domingo et al.
JOCArticle
SCHEME 3. Synthesis of Acyclic Synthon 15
SCHEME 4. Palladium-Catalyzed Cross-Coupling Reaction
the absolute configuration found in the natural polypo-
danes, that is, 3S,5R,8R,9R,10S (myrrhanol A numbering).
The element of enantiocontrol in the synthesis was based
on the Sharpless asymmetric terminal dihydroxylation7 of
E,E-farnesyl acetate to access enantioselectively key bicyc-
lic 7, already reported by us in our asymmetric synthesis
of onocerane triterpenes.8 This reaction proceeded with
acceptable selectivity and efficiency to diol 5 in a 43% yield
based on recovered starting material. The enantiopurity of
this alcohol was established as 96% on the basis of the 1H
NMR spectrum of the corresponding (S)-Mosher ester 5a.9
Chiral diol 5 was efficiently converted into the isodrimene-
diol skeleton 7 via Ti(III)-mediated radical cyclization of
the corresponding oxirane as previously described by us.8
Protection of the 3-hydroxyl group of bicyclic 7 as its tert-
butyldimethylsilylether and deprotection of the primary
acetoxy group led to alcohol 8 in a 93% yield. Oxidation
of the exocyclic double bond by MCPBA followed by
reductive opening with LiAlH4 of the oxirane ring gener-
ated the quaternary stereocenter at C-8 with the appro-
priate configuration, thus affording diol 9 in an 82% yield
as the only diastereoisomer detected. The primary alcohol
in 9 was selectively acetylated, whereas the tertiary hydro-
xyl group was protected as its MEM ether. At this point, the
presence of orthogonal protecting groups at C-3, C-8, and
C-11 positions provides the opportunity to extend the chain
at C11 via a selective acetoxy-deprotection of the latter.
Swern oxidation of the primary alcohol 10 and Wittig
olefination of the corresponding sterically hindered alde-
hyde allowed us to achieve the required one-carbon homo-
logation to afford the bicyclic synthon 11 in an 85% yield
over two steps.
of Corey, allylic bromide 12 was obtained from geranyl
acetate.10
Three carbons were then introduced via coupling with
1-trimethylsilyl propargyl lithium, which after deprotection
gave 13 in a 70% overall yield. The E-vinyl iodide key
intermediate 15 was then installed by a Negishi carbometala-
tion.11 This protocol proved to proceed with remarkably
high regio- and stereoselectivity.
The target (þ)-myrrhanol A was efficiently assembled as
follows. Treatment of olefin 11 with 9-BBN in THF under
reflux, followed by addition of Pd(dppf)Cl2 and the geometri-
cally pure vinyl iodide 15, afforded the desired coupling product
16 in a 90% isolated yield as shown in Scheme 4. As expected,
the alkene geometry of the acyclic partner was maintained in
the Suzuki coupling product. Harsh conditions were necessary
in the hydroboration reaction due to the sterically congested
environment of the vinyl group in 11 (Scheme 4).
Concomitant deprotection of the three ethers present in 15
was achieved in only one step after treating this compound
with a mixture of AcOH and HCl in THF to afford (þ)-
myrrhanol A (1). Considerable experimentation was needed
to avoid both alkene isomerization and dehydration of the
tertiary alcohol. MS and 1H and 13C NMR of our synthetic
coincide completely with those of the natural product. The
sign of the optical rotation [R]D of both synthetic (þ8.2°,
c 1.0, MeOH) and natural myrrhanol A (þ12.2°, c 1.0,
MeOH) matched, thus confirming the absolute configura-
tion of the natural compound.
Turning our attention to the synthesis of the synthon 15,
we started the linear sequence from the commercially
available geranyl acetate (Scheme 3). Based on the work
Once the enantioselective synthesis of (þ)-myrrhanol A
was achieved, we decided to address the synthesis of its
congeners (þ)-myrrhanone A (2), (þ)-myrrhanone B (3),
and (þ)-myrrhanol B (4) (Scheme 5), which although present
in the resin of B. mukul in minor concentration also presen-
ted a significant NO production inhibitory activity. Thus,
regioselective protection of the primary alcohol in 1 as its
corresponding tert-butyldimethylsilylether and subsequent
(7) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.
J. Org. Chem. 1992, 10, 2768–2771.
(8) For the preparation of racemic 7: (a) Barrero, A. F.; Cuerva, J. M.;
Herrador, M. M.; Valdivia, M. V. J. Org. Chem. 2001, 66, 4074–4078.
(b) Justicia, J.; Rosales, A.; Bunuel, E.; Oller-Lopez, J. L.; Valdivia, M.;
Haidour, A.; Oltra, J. E.; Barrero, A. F.; Cardenas, D. J.; Cuerva, J. M.
Chem.;Eur. J. 2004, 10, 1778–1788. (c) Justicia, J.; Oltra, J. E.; Cuerva,
J. M. J. Org. Chem. 2005, 70, 8265-8272. For the enantioselective preparation
of 7, see: Barrero, A. F.; Herrador, M. M.; Quilez del Moral, J. F.; Arteaga, P.;
Arteaga, J. F.; Piedra, M.; Sanchez, E. M. Org. Lett. 2005, 7, 2301–2304.
(9) Zhang, J.; Corey, E. J. Org. Lett. 2001, 3, 3215–3216.
(10) Corey, E. J.; Tius, M. A.; Das, J. J. Am. Chem. Soc. 1980, 102, 1742–
1744.
(11) Negishi, E.; Van Horn, D. E.; Yoshida, T. J. Am. Chem. Soc. 1985,
107, 6639–6647.
J. Org. Chem. Vol. 74, No. 16, 2009 6153

Domingo et al.
JOCArticle
SCHEME 5. Synthesis of(þ)-Myrrhanone A (2), (þ)-Myrrhanone
Experimental Section
B (3), and (þ)-Myrrhanol B (4)
(R,2E,6E)-10,11-Dihydroxy-3,7,11-trimethyldodeca-2,6-dienyl
Acetate (5). To a mixture of tert-butanol (225 mL) and water
(225 mL) were added 40.05 g of AD-mix-β (85.65 mmol K3Fe-
(CN)6, 85.65mmol of K2CO3, 0.04 mmol of [K2OsO2(OH)4], and
0.3 mmol of (DHQD)2-PHAL ligand (hydroquinidine 1,4-
phthalazinediyl diether). The resulting mixture was stirred me-
chanically at 25 °C until two clear phases were obtained. Then,
CH3SO2NH2 (2.715 g, 28.50 mmol) was added, and the mixture
was cooled to 0 °C. The resulting heterogeneous slurry was
stirred vigorously at 0 °C, as farnesyl acetate (7.50 g, 28.50 mmol)
was added at once. Stirring was continued at 0 °C for 24 h. At this
time the oxidation was completed, and solid sodium sulphite
(37.20 g) was added. The mixture was allowed to warm to room
temperature and stirred until two clear phases were obtained.
Ethyl acetate (150 mL) and water (45 mL) were added, and after
separation of the layers, the aqueous phase was further extracted
with ethyl acetate (3ꢀ100 mL). The combined organic extract
was washed with a 2 N aqueous NaOH solution (100 mL), dried
(Na2SO4), and concentrated under reduced pressure. This crude
product was purified by flash chromatography (hexane/
t-BuOMe, 1:3) to afford 1.5 g (5.71 mmol) of starting material
and2.97 g (9.9mmol) of 5 as a clear colorless viscousoil. [R]20
=
D
þ12.1 (c 1.0, CHCl3).14 IR (film) 3446, 2971, 2930, 1735, 1717,
1437, 1365, 1229, 1159, 1074, 1022 cm-1; 1H NMR (500 MHz,
CDCl3) δ 5.31 (dt, J = 7.2, 1.2 Hz, 1H), 5.14 (dt, J = 6.8, 0.9 Hz,
1H), 4.56 (d, J = 6.8 Hz, 2H), 3.32 (dd, J = 10.5, 1.8 Hz, 1H),
2.40 (d, J = 4.5 Hz, 1H), 2.25-2.18 (m, 1H), 2.13-2.0 (m, 4H),
2.03 (s, 3H), 1.67 (s, 3H), 1.59 (s, 3H), 1.58-1.53 (m, 1H), 1.42-
1.34 (m, 1H), 1.17 (s, 3H), 1.13 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 171.1, 141.8, 135.2, 124.2, 118.4, 78.0, 72.9, 61.3, 39.3,
36.6, 29.5, 26.3, 25.9, 23.2, 20.9, 16.3, 15.8. HRFABMS: calcd for
C17H30O4Na [MþNa]þ 321.2042, found 321.2071.
(S)-MTPA Ester 5a. To a solution of 5 (9 mg, 0.03 mmol) in
dry CH2Cl2 (1.2 mL) were added (S)-(þ)-methoxy-
R-(trifluoromethyl)phenylacetyl chloride (11 μL, 0.06 mmol)
and DMAP (15 mg, 1.2 mmol). The resulting mixture was then
stirred for 1 h at rt. The mixture was diluted with CH2Cl2 and
then passed through a column of silica gel. The eluent was
concentrated to give the desired (S)-MTPA ester 5a (15 mg,
0.029 mmol) as a colorless oil. 1H NMR (C6D6, 500 MHz),
R enantiomer δ 7.82 (bd, J=7.8 Hz, 2H), 7.09 (bt, J=7.8 Hz,
2H), 7.02 (bt, J=7.3 Hz, 1H), 5.40 (bt, J=6.8 Hz, 1H), 5.08 (bt,
J= 6.8 Hz, 1H), 5.00 (dd, J=9.7, 2.4 Hz, 1H), 4.58 (d, J=7.0 Hz,
2H); 3.51 (s, 3H), 2.02 (m, 2H), 1.94-1.84 (m, 4H), 1.66 (s, 3H),
1.55-1.40 (m, 2H), 1.46 (s, 3H), 1.38 (s, 3H), 0.98 (s, 3H), 0.89 (s,
3H); S enantiomer δ 3.44 (s, 3H).
(2S,4aS,5S)-Decahydro-2-hydroxy-1,1,4a-trimethyl-6-methyl-
enenaphthalen-5-yl)methyl Acetate (7). A mixture of Cp2TiCl2
(276 mg, 1.11 mmol) and Mn dust (2438 mg, 44.32 mmol) in
strictly deoxygenated THF (70 mL) and Ar atmosphere was
stirred at rt until the red solution turned green. Then, a solution
of 1550 mg (5.54 mmol) of epoxide 4 and 2,4,6-collidine (5.1 mL,
38.78 mmol) and Me3SiCl (2.8 mL, 22.16 mmol) were added.
The reaction mixture was stirred for 2 h (TLC monitoring),
quenched with 1 N HCl, extracted with t-BuOMe, washed with
brine, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was dissolved in THF (20 mL)
and stirred with Bu4NF (6.7 mL, 6.67 mmol) for 3 h. Then, THF
was removed, and the mixture was diluted with t-BuOMe,
washed with brine, and dried over anhydrous Na2SO4 and the
solvent was removed. The resulting crude was purified by
column chromatography on silica gel (hexane/t-BuOMe, 1:1)
to afford 732 mg (47%) of 7.9
Dess-Martin oxidation at C3 provided after TBAF depro-
tection (þ)-myrrhanone A (2) (Scheme 5). From myrrha-
none A, the synthesis of (þ)-myrrhanone B (3) requires the
oxidation of the primary allylic alcohol to carboxylic acid.
This transformation was uneventfully achieved using the
Dess-Martin periodinane to afford the corresponding alde-
hyde, which was oxidized to the desired carboxylic acid 3
with sodium chlorite.12 Finally, chemo- and stereoselective
reduction of 3 afforded the target (þ)-myrrhanol B (4).
Conclusion
In summary, we report a brief and convergent first total
synthesis of the potent anti-inflammatory (þ)-myrrhanol A
and its also bioactive congeners (þ)-myrrhanone A (2), (þ)-
myrrhanone B (3), and (þ)-myrrhanol B (4), starting from
commercially available geranyl and farnesyl acetate. The
synthesis of these unusually cyclized triterpenes illustrates
the versatility of the Ti(III)-mediated radical cyclization of
asymmetric monoepoxides of polyprenes in the enantio-
selective synthesis of polycyclic natural structures. In our
opinion, this radical approach complements conveniently
the cationic version of these cyclizations used by Corey and
others in the synthesis of polycyclic triterpenes.13
(12) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37,
2091–2096.
(13) Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 8865–8869.
(14) Vidari, G; Dapiaggi, A.; Zanoni, G.; Gaslaschelli, L. Tetrahedron
Lett. 1993, 34, 6485–6488.
6154 J. Org. Chem. Vol. 74, No. 16, 2009

Domingo et al.
JOCArticle
(2E,6E,10E)-11-Iodo-2,6,10-trimethylundeca-2,6,10-trien-1-ol (14).
To a solution of zirconocene dichloride (125 mg, 428 mmol) in
CH2Cl2 (3.4 mL) at rt under an argon atmosphere was added
dropwise a solution of trimethylaluminum in heptane (2 M in
heptane, 2.6 mL, 5.14 mmol). After 15 min, the solution was cooled
to 0 °C, and a solution of alkyne 13 (325 mg, 1.69 mmol) dissolved in
CH2Cl2 (3.4 mL) was added to the above lemon yellow solution. The
reaction mixture was stirred at 0 °C for 6 h and then cooled to -30 °C.
Iodine (869 mg, 3.42 mmol) was added as a solution in 2 mL of THF.
The resulting brown slurry was warmed to 0 °C and poured slowly
with stirring into an iced saturated aqueous NaHCO3. The aqueous
layer was extracted with ether (3ꢀ20 mL). The combined organic
layer was washed with saturated aqueous NaHCO3 and dried over
Na2SO4. Concentration followed by flash chromatography on silica
gel with 1:2 hexane/ether as eluent provided the desired product 14 as
a colorless oil (464 mg, 1.39 mmol, 82%). IR 3419, 2919, 2850, 1644,
1442 cm-1. 1H NMR (CDCl3, 500 MHz) δ 5.86 (s, 1 H), 5.37 (t, J =
6.9 Hz, 1H), 5.07 (t, J= 6.9 Hz, 1H), 3.99 (s, 2H), 2.22 (t, J=7.9Hz,
2H), 2.10 (m, 4H), 2.01 (t, J = 7.2 Hz, 2H), 1.83 (s, 3H), 1.66 (s, 3H),
1.57 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 148.5, 136.4, 135.5,
126.6, 123.9, 75.1, 69.3, 39.6, 39.4, 28.2, 26.3, 24.1, 16.1, 13.7.
HRFABMS: calcd for C14H23IONa [MþNa]þ 357.0691, found
357.0698.
25.1, 23.7, 20.2, 16.2, 16.0, 15.5, 15.3, 13.7. HRFABMS: calcd
for C30H52O3Na [M þ Na]þ 483.3813, found 483.3825.
(þ)-Myrrhanone A (2). To a stirred solution of (þ)-myrrhanol
A (73 mg, 0.159 mmol) in DMF (3 mL) were added imidazole
(16 mg, 0.238 mmol) and TBSCl (36 mg, 0.238 mmol) at rt. The
reaction progress was monitored by TLC, and after consump-
tion of the starting product (20 min), the mixture was diluted
with t-BuOMe and water and extracted with t-BuOMe. The
combined organic layer was washed with 2 N HCl and brine,
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The resulting crude was dissolved in dry CH2Cl2 (4.1mL)
under Ar, and Dess-Martin reagent (118 mg, 0.278 mmol) was
added. After 2 h at rt the reaction was quenched with a saturated
solution of Na2S2O3-NaHCO3 that was added slowly to the
mixture. The combined organic layer was washed with brine,
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The resulting crude was dissolved in THF (2 mL) and
stirred with TBAF 1 M (0.25 mL, 0.25 mmol) for 30 min (TLC
monitoring). Then, THF was removed, the mixture was diluted
with t-BuOMe, washed with brine, and dried over anhydrous
Na2SO4, and the solvent removed. The resulting crude was
purified by column chromatography on silica gel (hexane/
t-BuOMe, 1:1) to afford 45 mg (61% over three steps) of (þ)-
myrrhanone A (2). Colorless oil, [R]25D = þ6.9 (c 1.0, MeOH); IR
Compound 16. To olefin 11 (240 mg, 0.527 mmol) was added a
solution of 9-BBN (3.16 mL, 0.5 M in THF), and the solution
was stirred at reflux for 4 h. This solution was transferred by
cannula to another flask containing a mixture of vinyl iodide
15 (292 mg, 0.652 mmol), Pd(dppf)Cl2, CH2Cl2 (53 mg,
0.065 mmol), AsPh3 (29 mg, 0.097 mmol), Cs2CO3 (664 mg,
2.04 mmol), and water (0.375 mL, 15 mmol) in DMF (7.5 mL).
After 30 min, the brown reaction mixture was diluted with water
and extracted three times with t-BuOMe. The organic layer was
washed with water and brine and dried over Na2SO4. Concen-
tration followed by silica gel flash-chromatography (hexane/
t-BuOMe, 12:1) yielded 368 mg (90%) of 16. [R]20D =þ1.5
(c 1.0, CH2Cl2); IR (film) 2952, 2930, 2856, 1598, 1448, 1253,
1101, 1067, 1039, 835, 773 cm-1; 1H NMR (500 MHz, CDCl3)
δ 5.38 (t, J = 7.0 Hz, 1H), 5.14 (t, J = 7.2 Hz, 1H), 5.11 (t, J =
7.1 Hz, 1H), 4.86 (t, J = 7.7 Hz, 1H), 4.73 (t, J = 7.7 Hz, 1H),
3.99 (s, 2H), 3.74-3.62 (m, 2H), 3.54 (t, J = 4.8 Hz, 2H), 3.38 (s,
3H), 3.19 (dd, J = 11.2, 4.5 Hz, 1H), 2.14-1.90 (m, 10H), 1.70-
0.84 (m, 12H), 1.60 (s, 3H), 1.59 (s, 6H), 1.18 (s, 3H), 0.90 (s, 9H),
0.88 (s, 12H), 0.80 (s, 3H), 0.71 (s, 3H), 0.05 (s, 6H), 0.04 (s, 3H),
0.03 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 134.7, 134.4, 134.2,
125.2, 124.4, 124.4, 88.8, 80.2, 79.3, 71.9, 68.7, 66.4, 59.2, 58.9,
54.9, 40.1, 39.7, 39.4, 39.3, 38.6, 38.0, 31.4, 28.5, 27.5, 26.7, 26.2,
26.1, 26.0 (3C), 25.9 (3C), 20.7, 19.9, 18.4, 18.1, 16.1, 16.0, 15.9,
15.8, 13.4, -3.8, -4.9, -5.3 (2C). HRFABMS: calcd for
C46H88O5Si2Na [M þ Na]þ 799.6067, found 799.6054.
1
(film) 3406, 2935, 2862, 1702, 1456, 1385, 1078, 1006 cm-1; H
NMR (500 MHz, CDCl3) δ 5.31 (t, J = 7.0 Hz, 1H), 5.08 (t, J =
7.2 Hz, 1H), 5.04 (t, J = 6.8 Hz, 1H), 3.9 (s, 2H), 2.51 (ddd, J =
16.0, 11.7, 7.0 Hz, 1H), 2.32 (ddd, J = 16.0, 6.3, 3.4 Hz, 1H), 2.08-
1.80 (m, 11H), 1.58-1.21 (m, 8H), 1.58 (s, 3H), 1.52 (s, 6H), 1.11
(s, 3H), 1.04 (t, J = 3.9 Hz, 1H), 1.02 (s, 3H), 0.94 (s, 3H), 0.87 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 216.9, 135.4, 134.7, 134.6,
125.9, 124.8, 124.5, 73.7, 68.9, 60.3, 55.1, 47.5, 43.8, 39.6, 39.3,
38.6, 38.3, 33.9, 31.1, 26.5, 26.3, 26.1, 25.7, 23.6, 21.4, 21.3, 16.2,
16.0, 14.81, 13.7. HRFABMS: calcd for C30H50O3Na [M þ Na]þ
481.3657, found 481.3667.
(þ)-Myrrhanone B (3). To a mixture of (þ)-myrrhanone A
(37 mg, 0.080 mmol) in CH2Cl2 (2 mL) under Ar was added
Dess-Martin reagent (67 mg, 0.16 mmol). After 2 h at rt the
reaction was quenched with a saturated solution of Na2S2O3-
NaHCO3 that was added slowly to the mixture, and the com-
bined organic layer was washed with brine, dried over anhy-
drous Na2SO4, and concentrated under reduced pressure.
Filtration on silica gel (hexane/t-BuOMe 1:2) afforded the
allylic aldehyde, which was dissolved in 2 mL of tert-butyl
alcohol and 1 mL of 2-methyl-2-butene. A solution of sodium
chlorite (29 mg, 0.32 mmol) and sodium dihydrogenphosphate
(33 mg, 0.24 mmol) in 0.5 mL of water was added dropwise over
a 10 min period. The pale yellow reaction mixture was stirred at
room temperature overnight. Volatile components were then
removed under vacuum. The residue was dissolved in 30 mL of
water and extracted with two 15 mL portions of hexane. The
aqueous layer was acidified to pH 3 with HCl and extracted with
three 20 mL portions of ether. The combined ether layers were
washed with 50 mL of cold water, dried, and concentrated. The
resulting crude was purified by column chromatography on
silica gel (hexane/t-BuOMe, 2:1) to give 30 mg (79% overall
yield) of (þ)-myrrhanone B (3). Colorless oil, [R]25D = þ7.1 (c
(þ)-Myrrhanol A (1). To a solution of 12 (211 mg, 0.271
mmol) and 80% aqueous AcOH (4.2 mL) in THF (2.8 mL) was
gradually added 2 M HCl (0.7 mL) at room temperature for
30 min, and the whole mixture was stirred for 3.5 h at the same
temperature. The reaction mixture was diluted with brine and
extracted with t-BuOMe. The organic layer was washed with 7%
aqueous NaHCO3 and dried over Na2SO4. Evaporation of the
organic solvent gave a residue, which was chromatographed
on silica gel (hexane/t-BuOMe, 1:2) to give (þ)-myrrhanol A (1)
(99 mg, 80%). Colorless oil, [R]25D = þ8.2 (c 1.0, MeOH);
1.0, MeOH); IR (film) 3423, 2936, 1687, 1643, 1457, 1385 cm-1
;
1H NMR (500 MHz, CDCl3) δ 6.76 (bt, J = 7.3 Hz, 1H), 5.06 (t,
J = 7.0 Hz, 1H), 5.04 (t, J = 6.8 Hz, 1H), 2.53 (ddd, J = 16.0,
11.7, 7.0 Hz, 1H), 2.33 (ddd, J = 16.0, 6.4, 3.5 Hz, 1H), 2.24 (q,
J = 7.1 Hz, 2H), 2.05-1.76 (m, 9H), 1.76 (s, 3H), 1.57-1.14 (m,
8H), 1.54 (s, 3H), 1.52 (s, 3H), 1.16 (s, 3H), 1.08 (t, J = 3.9 Hz,
1H), 1.04 (s, 3H), 0.96 (s, 3H), 0.89 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 216.6, 171.4, 134.6, 144.1, 133.4, 126.9, 125.4, 125.1,
74.4, 60.4, 55.1, 47.4, 43.6, 39.3, 38.6, 38.2, 37.9, 33.9, 31.3, 26.8,
26.2, 25.9, 25.7, 23.5, 21.3 (2 C), 16.0, 15.7, 14.7, 12.0. HRFABMS:
calcd for C30H48O4Na [M þ Na]þ 495.3450, found 495.3441.
1
IR(film) 3429, 2928, 1640, 1448, 1364, 1037 cm-1; H NMR
(500 MHz, CDCl3) δ 5.39 (t, J = 7.0 Hz, 1H), 5.16 (t, J = 7.1 Hz,
1H), 5.11 (t, J=7.0 Hz, 1H), 3.99 (s, 2H), 3.21 (dd, J=11.4,
4.6 Hz, 1H), 2.15-1.86 (m, 10H), 1.83 (bd, J=11.6 Hz, 1H),
1.73-1.08 (m, 9H), 1.65 (s, 3H), 1.60 (s, 3H), 1.55 (s, 3H), 1.12 (s,
3H), 1.02 (t, J = 3.7 Hz, 1H), 0.98 (s, 3H), 0.89 (bd, J = 11.2 Hz,
1H), 0.79 (s, 3H), 0.75 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
135.1, 134.7, 134.6, 126.0, 125.0, 124.5, 78.7, 73.9, 68.9, 61.2,
55.0, 44.4, 39.6, 39.3, 38.81 (2C), 37.8, 31.3, 28.1, 27.1, 26.5, 26.1,
J. Org. Chem. Vol. 74, No. 16, 2009 6155

Domingo et al.
JOCArticle
(þ)-Myrrhanol B (4). To a solution of (þ)-myrrhanone B
(10 mg, 0.021 mmol) in dry MeOH was added NaBH4, and the
mixture was stirred for 2 h. The reaction was quenched with
acetone and concentrated under reduced pressure. The residue
was dissolved in 10 mL of water, and this was acidified to pH 3
with HCl and extracted with three 10 mL portions of EtOAc,
washed with brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The resulting crude was
purified by HPLC (hexane/t-BuOMe, 1:1) to afford 6 mg (60%)
of (þ)-myrrhanol B (4). Colorless oil, [R]28D = þ6.2 (c 1.0,
MeOH); IR (film) 3453, 2930, 2862, 1709, 1650, 1456, 1385,
1080, 1006 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.70 (bt, J =
7.2 Hz, 1H), 5.04 (t, J = 7.0 Hz, 1H), 5.02 (t, J = 7.1Hz, 1H), 3.18
(dd, J = 11.6, 4.6 Hz, 1H), 2.21 (q, J = 6.8 Hz, 2H), 2.08-1.72
(m, 9H), 1.74 (bs, 3H), 1.64-1.02 (m, 9H), 1.53 (s, 3H), 1.51 (s,
3H), 1.10 (s, 3H), 0.98 (t, J = 3.8 Hz, 1H), 0.92 (s, 3H), 0.84 (bd,
J = 11.9 Hz, 1H), 0.73 (s, 3H), 0.69 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ171.4, 143.6, 137.0, 133.2, 126.9, 125.5, 125.4, 78.8, 75.1,
61.4, 55.0, 44.3, 39.3, 38.8 (2C), 37.9, 37.8, 31.6, 28.1, 27.1, 26.5,
25.7, 25.6, 23.6, 20.2, 16.0, 15.7, 15.5, 15.3, 12.1. HRFABMS
calcd for C30H5O4Na [M þ Na]þ 497.3607, found 497.3625.
Acknowledgment. This research was supported by the
Spanish Ministry of Science and Technology, Project
CTQ2006-15575-C02-01. V.D. thanks the Spanish Ministry
of Science and Technology for a predoctoral grant enabling
him to pursue these studies.
Supporting Information Available: Experimental proce-
dures and spectroscopic data for compounds 6, 8-11, 13, 15,
and 1H and 13C NMR spectra of 1-11, and 13-16. This material is
available free of charge at http://pubs.acs.org.This material is
available free of charge via the Internet at http://pubs.acs.org.
6156 J. Org. Chem. Vol. 74, No. 16, 2009