Total Synthesis of the Labdane Diterpenes Galanal A and B from Geraniol

Article abstract of DOI:10.1021/acs.joc.6b02766

The first total synthesis of galanal A and B has been achieved from naturally occurring geraniol. Key steps in this synthesis are the use of a Lewis acid assisted chiral Br?nsted acid (chiral LBA) mediated cationic polyene cyclization and a titanocene-mediated radical cyclization for the asymmetric assembly of the "AB" ring and the construction of the all-carbon quaternary center at the junction of the "BC" ring, respectively.

Full text of DOI:10.1021/acs.joc.6b02766

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Article
Total Synthesis of the Labdane Diterpenes
Galanal A and Galanal B from Geraniol
Shih-Che Lin, and Rong-Jie Chein
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02766 • Publication Date (Web): 30 Dec 2016
Downloaded from http://pubs.acs.org on December 30, 2016
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The Journal of Organic Chemistry
Total Synthesis of the Labdane Diterpenes Galanal A and Galanal B from Geraniol
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Shih-Che Lin† and Rong-Jie Chein*,
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† Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program (TIGP),
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Academia Sinica, Taipei 115, Taiwan
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‡ Department of Chemistry, National Taiwan University, Taipei 106, Taiwan
§Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan
rjchein@chem.sinica.edu.tw
SYNOPSIS TOC:
Abstract: The first total synthesis of galanal A and galanal B has been achieved from naturally occurring
geraniol. Key steps in this synthesis are the use of a Lewis-acid assisted chiral Brønsted acid (chiral LBA)-
mediated cationic polyene cyclization and a titanocene-mediated radical cyclization for the asymmetric
assembly of the “AB” ring and the construction of the all-carbon quaternary center at the junction of the
“BC” ring, respectively.
■ INTRODUCTION
In recent decades, an increasing number of natural plant products with unique and remarkable
biological activities have been discovered.1 One class of these products is labdane-type diterpenes and
their derivatives, which exhibit important pharmaceutical activities and serve as useful materials for
chemical transformations.2 In 1986, the tricyclic labdane-type diterpenes galanal A and galanal B were
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first isolated from Zingiberaceae seeds (Alpinia galanga), and their structures were subsequently
established by Morita et al.3 In 2003, these dietary ginger constituents were also isolated from myoga
(Zingiber mioga Roscoe) by Miyoshi et al., who determined that these compounds were novel anti-
cancer agents by revealing that they induce apoptosis in p53-mutated Jurkat cells.4 In 2004, Abe et al.
reported that galanal A and galanal B from myoga exhibited antimicrobial activities against Gram-
positive bacteria and yeasts.5 In 2014, Yamamoto et al. demonstrated that galanal A was an effective
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IDO1 inhibitor that inhibits the expression of IDO1 mRNA induced by the IFN--dependent pathway.6
Although studies have proven that galanals are important natural products, little research has addressed
the synthesis of these products. Recently, our research group reported the first semi-synthesis of galanal
A and galanal B from sesquiterpene (+)–sclareolide.7 Here, as part of our ongoing interest in the
synthesis of labdane-type diterpenes with biological and pharmaceutical activities, we disclose the first
total synthesis of galanal A and galanal B from monoterpene geraniol. Different from our previous work
using a chiral natural product as the starting material, all the stereogenic centers in this work are
introduced asymmetrically through a biomimetic synthetic strategy.
Previous work: The first semi-synthesis of galanal A and B from (+)–sclareolide
* Stereogenic centers derived from chiral pool
This work: The first total synthesis of galanal A and B from geraniol
* Asymmetric introduction of stereogenic centers through Yamamoto’s methodology
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■ RESULTS AND DISCUSSION
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Biomimetic Synthetic Strategy. It has been established that diterpene cyclase is responsible for
the cyclization of (E,E,E)-geranylgeranyl diphosphate; the resulting labdadienyl diphosphate is then
elaborated into the large superfamily of labdane-type diterpenoids.8 Accordingly, we speculated that
galanal A and galanal B are downstream products of labdadienyl diphosphate in their natural
biosynthetic pathway (Scheme 1, left column). This hypothesis led us to utilize a biomimetic synthetic
strategy, as presented in the right column of Scheme 1. Ring C of galanals could be constructed at a late
stage of the synthesis using a titanocene-mediated cyclization followed by functionalizations. The
formation of the A and B rings could be accomplished biomimetically via a polycyclic cascade reaction.
Scheme 1. Hypothetical biosynthetic pathway and rational design
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Cationic Polycyclization of Diene 2. Based on the strategy mentioned above, 2-
(homogeranyl)anisole 2 was synthesized from geraniol via geraniol phosphate 1, using a modified
procedure (Scheme 2).9 The diene substrate 2 was then subjected to several cationic polycyclization
conditions followed by methyl ether cleavage to afford phenol 4, as indicated in Table 1. Polycyclic
cyclization occurred rapidly when diene 2 was treated with an excess amount of chlorosulfonic acid at -
78 °C.10 After ether cleavage of the resulting product with BBr3 in dichloromethane at 0 °C, 4 was
isolated in 58% yield in 2 steps (entry 1). The yield was further improved to 76% when diene 2 was
placed under a Ru (III)-catalyzed intramolecular electrophilic hydroarylation condition (entry 2).11
Interestingly, we found that BBr3 could initiate both polyene cyclization and demethylation in a one-pot
manner, with a moderate yield of 4 (61%, entry 3). With less amount of BBr3, both 3 and 4 were
isolated from the reaction, which implies the faster polycyclization process than the demethylation one
in this conversion.
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Scheme 2. Synthesis of Diene 2
Reagents and conditions: (a) (C2H5O)2POCl, py., (C2H5)2O, -15 °C to rt, 3 h; (b) 1-(bromomethyl)-2-
methoxybenzene, Mg, THF, -40 °C to rt, 12 h.
Table 1. Cationic polycyclization of diene 2
yield for 4 (%)a
entry
1
condition
(i) 5.0 equiv. ClSO3H, EtNO2, -78 °C, 30 min;
(ii) 1.2 equiv. BBr3, CH2Cl2, 0 °C, 2 h
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(i) 1 mol% RuCl3*xH2O, 2 mol% AgOTf, (CH2)2Cl2, 60 °C, 4h
(ii) 1.2 equiv. BBr3, CH2Cl2, 0 °C, 2 h
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2.4 equiv. BBr3, CH2Cl2, 0 °C, 4 h
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a Isolated yield.
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Enantioselective Cationic Polycyclization of Diene 2. After completion of the racemic
polycyclization of diene 2, an attempt on asymmetric polycyclization of 2 was then made based on
Yamamoto’s report of Lewis-acid assisted chiral Brønsted acid (chiral LBA).12 As summarized in Table
2, reaction of 2 with a mixture of SnCl4 and BINOL (L1) in toluene gave a mixture of desired product
(+)-3 (33% ee) and the monocyclized products 3a and 3b in 50% yield (entry 1). The employ of 3,3’-
dichloro-BINOL (L2) as the chiral Brønsted acid improved the ee of (+)-3 to 44% (entry 2). When the
monobenzylether derivative of BINOL (L3) was used, the ee of (+)-3 increased to 60% with 91% yield
of the mixing products (Entry 3), which were further treated with SnCl4 and CF3COOH in EtNO2 at -78
°C to afford the fully cyclized product (+)-3 in 86% total yield with 57% ee (Scheme 3). Similar ee was
observed when the chiral Brønsted acid was changed to L4 (Entry 5). Unfortunately, when the 3 and 3’
positions of BINOL were equipped with bulkier phenyl or tripheyl silyl group (L5-L6), the reactivity
was much diminished (entry 7-10). The phenylalkynyl group at the ortho position (L7) gave similar ee
as entry 1 (entry 11). Besides Yamamoto’s protocol, Corey’s method using SbCl5 to promote Brønsted
acid L2 was also tested in the screening, but only racemic 3 was obtained in 50% yield (entry 12).13
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Table 2. Enantioselective polycyclization with BINOL-related ligand Screening
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yield (%) [ratio of 3, 3a, and 3b]a
ee of 3b
entry
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ligand
L1
solvent
toluene
t (h)
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50 [1.0 : 1.4 : 1.9]
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L2
L3
L3
L4
L4
L5
L5
L6
L6
L7
L2
toluene
toluene
CH2Cl2
toluene
CH2Cl2
toluene
CH2Cl2
toluene
CH2Cl2
toluene
CH2Cl2
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96
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88 [7.0 : 10.0 : 5.0]
91 [1.0 : 3.8 : 5.0]
86 [4.0 : 3.0 : 1.0]
86 [3.0 : 10.0 : 5.0]
83 [6.0 : 1.0 : 0]
no reaction
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no reaction
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12c
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a The ratio was determined by 1H-NMR. b ee of cyclized product 3 was determined by HPLC analysis
with chiralcel OD-H column. c SbCl5 was used instead of SnCl4 according to Corey’s method.
Scheme 3. Enantioselective synthesis of (+)-3
Reagents and conditions: (a) SnCl4, L3, toluene, -78 °C, 24 h; (b) SnCl4, CF3COOH, EtNO2, -78 °C, 4 h;
(c) BBr3, CH2Cl2, 0 °C, 2 h.
After ether cleavage of compound 3 with BBr3, the resulting phenol 4 was treated with Raney
nickel under a high-pressure H2 atmosphere to provide a mixture of hydrogenation products 5 and 614 in
the 1:5 ratio and 79% yield (Scheme 4). Following sequential pyridinium chlorochromate (PCC)
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oxidation and Baeyer-Villiger rearrangement, the mixture was transformed into lactone 8 in 75% yield
(in two steps) and then converted to hydroxyl carboxamide 9 via Nelson’s method15 in 90% yield. After
reviewing the literature, we found that Swern oxidation can be applied to substrate 9 for the dehydration
of carboxamide in combination with the oxidation of the secondary alcohol.16 Thus, 9 was subjected to
Swern oxidation, and the reaction proceeded smoothly to afford ketone nitrile 10 in 73% yield. The
transformation of 10 via the Corey-Chaykovsky reaction stereoselectively afforded epoxynitrile 11,
which is a suitable precursor for the construction of the all-carbon quaternary center at the ring junction
of the B and C rings.17
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Scheme 4. Synthesis of epoxynitrile 11
Reagents and conditions: (a) Raney Ni, H2 (550 psi), EtOH, 180 °C, 2 d; (b) PCC, DCM, rt, 5 h; (c)
mCPBA, NaHCO3, rt, overnight; (d) Me2AlNH2, Cl2CHCH2Cl, 80 °C, 1 h; (e) (COCl)2, DMSO, Et3N,
78 °C to rt, overnight; (f) NaH, (CH3)3SI, DMSO/THF, rt, 3 h.
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Construction of the All-carbon Quaternary Center at the “BC” Ring Junction. In 1988,
Nugent and RajanBabu introduced a Ti (III)-mediated radical cyclization of epoxyolefins that was
subsequently used by Fernandez-Mateo et al. to generate bicyclic -hydroxycycloalkanones from
epoxynitriles.18 With epoxynitrile 11 in hand, we could proceed to the key titanocene-mediated
intramolecular radical cyclization step. To our delight, upon treating epoxynitrile 11 with Ti(III) species
generated in situ from Cp2TiCl2 and Zn in THF at room temperature, the homolytic regioselective
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cleavage of the oxirane ring and the following equatorial-oriented 6-exo-dig radical cyclization through
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intermediate II proceeded smoothly. Following an acidic work-up, -hydroxycycloalkanone 12 was
isolated in 80% yield with the desired stereochemistry. The structural connectivities of 11 and 12, which
are depicted in Scheme 5, were confirmed by X-ray crystallographic analysis.
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Scheme 5. Ti (III)-mediated radical cyclization and X-ray crystallographic analysis of 11 and 12
(hydrogen atoms omitted for clarity)
Completion of the Syntheses of Galanal A and Galanal B. Following this stage, the remaining
steps to complete the total synthesis were ring expansion and the functionalization of the C ring. First,
12 was treated with 4 equiv of LiHMDS and 6 equiv of methyl cyanoformate to introduce the methyl
formate to the carbon  to the carbonyl group and to the primary alcohol to provide protection from
interference with the following transformations.19 The C ring of -keto ester 13 was then expanded to a
seven-membered ring via a Simmon-Smith cyclopropanation/ring-opening reaction cascade (Scheme
6).20 6,6,7-Tricyclic -ketoester 14 was subjected to a sequence of selenization, oxidation, and
elimination to generate the double bond in 15. This double bond was isomerized by DBU in refluxed
benzene to afford the more thermodynamically stable isomer 16.21 Density functional theory (DFT)
calculations at the RB3LYP/6-31G(d) level revealed that the Gibbs free energy of 16 is 2.45 kcal/mol
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lower than that of 15 (Figure 1). The double conjugation system in ring C of 15 is countervailed by the
ring strain, and the twisted ring conformation is converted to the chair-like conformation of 16 after
double bond migration to release this ring strain. The further reduction of 16 with DIBAL yielded diols
17 and 17 in a 1:3.5 ratio. Finally, the two primary alcohols of 17 and 17 were selectively
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oxidized using a mixture of TEMPO and NCS to generate galanal A ([]25 = -34.6 (c 0.8, CHCl3), 53%
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D
ee, lit. []25 = -65.3 (c 0.83, CHCl3)7) and galanal B ([]25 = -39.1 (c 1.0, CHCl3), 55% ee, lit. []25 = -
D
D
D
71.4 (c 0.97, CHCl3)7) in the same ratio.22
Scheme 6. Total synthesis of galanal A and galanal B
Reagents and conditions: (a) LiHMDS, NCCOOMe, THF, -78 °C to rt, overnight; (b) Et2Zn, CH2I2,
ClCH2CH2Cl, rt, 14 h; (c) LiHMDS, PhSeCl, THF, -78 °C, 3 h; then H2O2(aq), py., rt, 2h; (d) DBU, C6H6,
reflux, 3 h; (e) DIBAL, CH2Cl2, -78 °C to rt, 12 h; (f) TEMPO, TBACl, NCS,
CH2Cl2/NaHCO3(aq)/K2CO3(aq), rt, 12 h.
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15, G =-846044.33 kcal/mol
16, G = -846046.78 kcal/mol (2.45 kcal/mol lower than 15)
Figure 1. Calculated structures of 15 and 16 (hydrogen atoms omitted for clarity).
■ CONCLUSIONS
In summary, we completed the first total synthesis of galanal A and galanal B in 17 steps. This
synthesis features the use of a cationic polycyclization to assemble the “AB” ring and a Ti(III)-mediated
radical cyclization to construct the all-carbon quaternary center at the “BC” ring junction as the key
steps. We expect this new synthetic route to greatly facilitate bioactivity and SAR studies of galanal A
and galanal B and thereby contribute to pharmaceutical development related to these labdane-type
diterpenes in the future.
■ EXPERIMENTAL SECTION
General methods. All reactions using air-/moisture-sensitive reagents were performed in a flame-
dried apparatus, under an atmosphere of dry nitrogen, and standard syringe–septa techniques were
followed. Solvents were freshly dried and purified by conventional methods prior to use. The progress of
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all the reactions were monitored by TLC, using TLC glass plates precoated with silica gel. H and C
NMR spectra were recorded with 400 MHz, 500 MHz or N600 MHz spectrometers and chemical shifts
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were measured in δ (ppm) with residual solvent peaks as internal standards (CDCl3, δ 7.26 ppm in H
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NMR, δ 77.0 ppm in C NMR; CD3OD, δ 3.31 ppm in H NMR, δ 49.0 ppm in C NMR). Coupling
constants (J) are reported in Hz, and the splitting abbreviations used were: s, singlet; d, doublet; t, triplet;
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m, multiplet. HR MALDI (LR MALDI)-mass spectra were conducted on an Proteomics Analyzer
equipped with an Nd/YAG laser (335nm) operating at a repetition rate of 200 Hz. HR FAB (LR FAB)
and HR EI (LR EI)-mass spectra were recorded on a double focusing mass spectrometer with a
resolution of 8000(3000) (5% valley definition). HR (LR) ESI (Electrospray)-mass spectra were
recorded using dual ionization source options.
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(E)-3,7-dimethylocta-2,6-dienyl diethyl phosphate (1).9,23 To a solution of geraniol (8.8g, 57
mmol) and pyridine (13.8 ml, 171 mmol) in ether (30 ml) at -15 °C was added diethyl chlorophosphate
(14.8 g, 85.5 mmol) dropwise. The reaction mixture was allowed to warm slowly to rt over a course of
3h. Upon completion, the reaction was treated with 1N HCl (150 ml) and extracted with EA (3 × 100
mL). The combined organic layers were then washed with sat. NaHCO3 (2 × 60 mL) and brine (60 mL),
dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column
chromatography (gradient from 1:9 → 2:3 EtOAc:hexanes) to give 1 (15.6 g, 94%) as colorless oil.
Data for 1: 1H NMR (400 MHz, CDCl3) δ 5.39–5.35 (m, 1H), 5.07–5.03 (m, 1H), 4.54 (t, J = 7.6 Hz,
2H), 4.11–4.03 (m, 4H), 2.07–2.00 (m, 4H), 1.68 (s, 3H), 1.65 (s, 3H), 1.57 (s, 3H), 1.33–1.28 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 142.5, 131.8, 123.6, 118.9 (d, J = 6.3 Hz), 64.0 (d, J = 5.3 Hz),
63.5 (d, J = 5.5 Hz), 39.4, 26.2, 25.6, 17.6, 16.4, 16.0 (d, J = 6.5 Hz).
1-(bromomethyl)-2-methoxybenzene. A stirred solution of 2-methylanisole (6g, 49.7 mmol) and
NBS (8.8g, 49.7 mmol) in benzene (125 mL, 0.4M) was refluxed for 4h with irradiation by a 250W IR
lamp and a 250W white light lamp at a close distance. After cooling down to rt, the reaction crude was
diluted with hexanes, filtered through a pad of celite, and concentrated in vacuo. The crude was again
added hexane and filtered through a pad of celite. The filtrate was concentrated and the resulting 1-
(bromomethyl)-2-methoxybenzene (10g, 49.7 mmol) was used directly for the next step.
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(E)-1-(4,8-dimethylnona-3,7-dienyl)-2-methoxyben-zene (2).9 A solution of 1-(bromomethyl)-2-
methoxybenzene (10.0 g, 49.7 mmol) in THF (100 mL) was added dropwise to Mg turnings (2.4g, 98.7
mmol, flame-dried) under N2 at 0 °C. After 1h of stirring at 0 °C, the resultant magnesium bromide was
cooled to -40 °C and added quickly via cannula to a solution of 1 (7.2 g, 25.0 mmol) in THF (25 mL) at
-40 °C. The resulting reaction mixture was then allowed to warm slowly to room temperature over the
course of 4h, and then was stirred at room temperature for another 8h. The reaction contents were
quenched with sat. NH4Cl (100 mL) and extracted with (EtOAc:hexanes, 1:2, 3 × 150 mL). The
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combined organic layers were washed with sat. NaHCO3 (100 mL) and brine (100 mL), dried over
Na2SO4 and concentrated in vacuo. The residue was coated on silica gel and purified by flash column
chromatography (gradient from 0:1 → 2:98 EtOAc:hexanes) to give 2 (6 g, 94%) as colorless oil. Data
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for 2: IR (film) 2924, 2852, 1739, 1707, 1461, 1365, 1277, 1199, 1174 cm-1; H NMR (400 MHz,
CDCl3): δ 7.22–7.14 (m, 2H), 6.92–6.85 (m, 2H), 5.25 (t, J = 7.2 Hz, 1H), 5.14 (t, J = 7.2 Hz, 1H),
3.85 (s, 3H), 2.67 (t, J = 7.8 Hz, 2H), 2.30 (dd, J = 15.4 Hz, J = 7.4 Hz, 2H), 2.13–2.06 (m, 2H),
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2.03–1.99 (m, 2H), 1.72 (s, 3H), 1.64 (s, 3H), 1.60 (s, 3H); C NMR (100 MHz, CDCl3): δ 157.5,
135.4, 131.2, 130.8, 129.9, 126.9, 124.5, 124.1, 120.3, 110.2, 55.2, 39.7, 30.5, 28.2, 26.8, 25.7, 17.7,
15.9; HRMS (APCI) calcd for C18H27O [M+H]+: 259.2062, found: 259.2057.
(±)-(4aS)-8-methoxy-1,1,4a-trimethyl-1,2,3,4,4a,9,10, 10a-oc-tahydrophenanthrene (3).24 (Table
1, entry 1) To a solution of ClSO3H (3.9 mL, 58.05 mmol) in EtNO2 (80 mL) was added 2 (3.0 g,
11.61 mmol) in EtNO2 (40 mL) by low-temperature dropping funnel at -78 °C dropwise, and stirring
was continued for 30 minutes. The reaction was quenched by sat. NaHCO3(aq) (120 mL) and allowed to
warm to room temperature gradually. The phases were separated, and the aqueous layer was extracted
with ether (3 × 100 mL). The organic extracts were combined, washed with sat. NaHCO3(aq) (300 mL)
and brine (300 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash
column chromatography (gradient from 1:49 → 1:24 EtOAc:hexanes) to afford 3 (1.86 g, 62%) as a
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white solid. Data for 3: Mp 113–115 °C; IR (film) 3000, 2926, 2867, 2831, 1577, 1455, 1434, 1369,
1254, 1067, 1059, 1043 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.14 (t, J = 8.0 Hz, 1H), 6.93 (d, J = 8.0
Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 3.82 (s, 3H), 2.90 (dd, J = 18.0 Hz, J = 6.4 Hz, 1H), 2.66–2.56 (m.
1H), 2.33–2.26 (m, 1H), 1.98–1.90 (m, 1H), 1.83–1.57 (m, 3H), 1.53–1.45 (m, 1H), 1.40 (td, J = 13.0
Hz, J = 3.8 Hz, 1H), 1.33 (dd, J = 12.6 Hz, J = 2.1 Hz, 1H), 1.28–1.17 (m, 1H), 1.21 (s, 3H), 0.97 (s,
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3H), 0.95 (s, 3H); C NMR (100 MHz, CDCl3): δ 157.0, 151.6, 126.0, 124.3, 116.6, 106.3, 55.2,
49.9, 41.6, 39.0, 37.8, 33.4, 33.3, 24.7, 24.5, 21.6, 19.3, 18.4; HRMS (EI) calcd for C18H26O [M]+:
258.1984, found: 258.1983.
(±)-(4bS)-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octah-ydroph-enanthren-1-ol (4). (Table 1, entry
1): To a solution of 3 (3.0 g, 11.46 mmol) in CH2Cl2 (28 mL) was added BBr3 (1.3 mL, 13.75 mmol)
dropwise at 0 °C, and stirring was continued for 2h. The reaction was quenched by H2O (30 mL) and
allowed to warm to room temperature gradually. The phases were separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 30 mL). The organic extracts were combined, washed with sat. NaHCO3(aq)
(60 mL) and brine (60 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by
flash column chromatography (EtOAc:hexanes, 1:19) to afford 4 (2.6 g, 94%) as a white solid. Data for
4: Mp 144–146 °C; IR (film) 3417, 2923, 1633, 1576, 1461, 1255 cm-1; 1H NMR (400 MHz, CDCl3):
δ 7.04 (t, J = 8.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.60 (dd, J = 8.0 Hz, J = 0.8 Hz, 1H), 4.70 (s, 1H),
2.85 (dd, J = 17.0 Hz, J = 6.6 Hz, 1H), 2.67–2.58 (m, 1H), 2.32–2.24 (m, 1H), 2.22–1.93 (m, 1H),
1.82–1.57 (m, 3H), 1.53–1.45 (m, 1H), 1.44–1.30 (m, 1H), 1.28–1.17 (m, 1H), 1.20 (s, 3H), 0.97 (s,
13
3H), 0.94 (s, 3H); C NMR (100 MHz, CDCl3): δ 153.1, 152.1, 126.3, 121.6, 116.8, 111.4, 49.7,
41.6, 38.9, 37.8, 33.4, 33.3, 24.8, 24.0, 21.6, 19.3, 18.3; HRMS (EI) calcd for C17H24O [M]+:
244.1827, found: 244.1820. (Table 1, entry 2): A mixture of RuCl3·xH2O (2.1 mg, 0.01 mmol) and
AgOTf (5.1 mg, 0.02 mmol) in ClCH2CH2Cl (2 mL) was stirred vigorously for 1 h. Then the
cyclization precursor 2 (258 mg, 1.0 mmol) in ClCH2CH2Cl (3 mL) was added at room temperature.
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The resulting solution was heated to 60 °C and stirred for 3h. TLC analysis indicated that the reaction
was completed, and the crude was filtered through a short pad of silica gel with the aid of CH2Cl2. The
filtrate was concentrated in vacuo and under high vacuum for 20 minutes. The resulting residue was
dissolved in CH2Cl2 (2.5 mL) and was added BBr3 (115 μL, 1.2 mmol) dropwise at 0 °C. The stirring
was continued for 2h, and the reaction was quenched by H2O (2.5 mL) and allowed to warm to room
temperature gradually. The phases were separated, and the aqueous layer was extracted with DCM (3 ×
5 mL). The organic extracts were combined, washed with sat. NaHCO3(aq) (5 mL) and brine (5 mL),
dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column
chromatography (EtOAc:hexanes, 1:19) and then recrystallized from hexanes/CH2Cl2 (1:1) to afford 4
as a white solid (185 mg, 76 %). (Table 1, entry 3): To a solution of 2 (400 mg, 1.55 mmol) in CH2Cl2
(15.5 mL) was added BBr3 (0.36 mL, 3.72 mmol) dropwise at -15 oC, and stirring was continued for 1h.
The reaction was warmed to 0 °C and stirred for another 4h. The reaction was quenched by H2O (15
mL), and then sat. NaHCO3(aq) (15 mL) was added. The reaction was allowed to warm to room
temperature gradually. The phases were separated, and the aqueous layer was extracted with CH2Cl2 (3
× 10 mL). The organic extracts were combined, washed with brine (15 mL), dried over Na2SO4, and
concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc:hexanes,
1:19) to afford 4 (61%) as a white solid.
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General Procedure for the Enantioselective Cyclization of 3 in Table 2. To a solution of (R)-
binaphthalene ligand (0.21 mmol) in toluene (2.1 mL) was added a 1.0 M solution of SnCl4 in heptane
(0.19 mL, 0.19 mmol) at room temperature, and the solution was stirred for 5 min. After the solution of
complex prepared in situ as above was cooled to -78 °C and stirred for another 30 min, 2-
(homogeranyl)anisole 2 (50 mg, 0.19 mmol) in toluene (0.38 mL) was added dropwise. The reaction
mixture was stirred at -78 °C for 24h, quenched with saturated NaHCO3(aq), and extracted with ether (3
× 8 mL). The combined organic phases were washed with brine (8 mL), dried over Na2SO4 and
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concentrated. The residue was coated on silica gel and purified by flash column chromatography (3:97
CH2Cl2:hexanes) to give a mixture of 3, 3a, and 3b. The mixture of 3, 3a and 3b was used for the
subsequent cyclization without further separation.
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Diastereoselective Cyclization of 3, 3a and 3b (Scheme 3). To a solution of trifluoroacetic acid
(0.13 mL, 1.7 mmol) in EtNO2 (1.7 mL) at -78 °C was added a 1.0 M solution of SnCl4 in heptane (0.34
mL, 0.34 mmol), and the solution was stirred for 20 min. The mixture of 3, 3a and 3b (45.5 mg, 0.17
mmol, from Table 2, entry 3) in EtNO2 (1.7 mL) was then added dropwise. The reaction mixture was
stirred at -78 °C for 4h, quenched with saturated NaHCO3(aq) (10 mL), and extracted with ether (3 × 10
mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4 and concentrated.
The residue was coated on silica gel and purified by flash column chromatography (3:97 CH2Cl2:hexanes)
to give (+)-3 (42.8 mg, 94%). Enantioselectivity was determined by HPLC analysis (Daicel OD-H column,
0.3 mL/min, hexane/i-PrOH 99.7/0.3, 220 nm); tR= 15.5 min ((-)-enantiomer) and 16.7 min ((+)-
enantiomer). []30 = 29.5 (c 1.0, CHCl3) for 57% ee.
D
(4bS)-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octah-ydroph-enanthren-1-ol (4). Demethylation of (+)-3
afforded (+)-4 in 94% yield (the same procedure as the second step in Table 1, entry 1). []30 = 30.0 (c
D
1.0, CHCl3).
(1S,4aS,4bR,10aS)-4b,8,8-trimethyltetradecahy-drophe-n-anthren-1-ol
(5)
&
(1R,
4aS,4bR,10aS)-4b,8,8-trimeth-ylte-tradecahydrophenanthren-1-ol (6).14 A suspension of 4 (2 g, 8.19
mmol) and Raney Nickel (52% slurry in EtOH, 2.36g, 1.23 mmol) in EtOH (20.5 mL) was in a teflon-
made container. The reaction contents in the container were put into an autoclave and hydrogenated at
180 °C and 550 psi pressure of hydrogen. After 2d, the reaction was cooled to room temperature
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gradually. The catalyst was removed by filtration through celite and washed through repeatedly with
ethanol. The solvent was removed in vacuo. The crude was dissolved in EtOAc (30 mL), washed with
brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column
chromatography (gradient from 1:19 → 1:9 EtOAc:hexanes) to afford 5 (0.29 g, 14%) and 6 (1.33 g,
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65%). Both 5 and 6 are white solids. Data for 5: []31 = 4.5 (c 1.0, CHCl3); Mp 97–99 °C; IR (film)
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3397, 2935, 2865, 1442, 1380 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.74–3.73 (m, 1H), 1.82–1.74 (m,
1H), 1.72–1.57 (m, 4H), 1.57–1.49 (m, 3H), 1.49–1.41 (m, 3H), 1.41–1.33 (m, 3H), 1.33–1.23 (m,
1H), 1.18–1.05 (m, 2H), 0.98–0.85 (m, 3H), 0.84 (s, 3H), 0.82 (s, 6H); 13C NMR (100 MHz, CDCl3):
δ 70.9, 54.8, 48.1, 42.1, 40.6, 39.2, 36.7, 33.6, 33.5, 33.2, 30.5, 24.7, 22.0, 21.4, 20.0, 18.9, 14.1;
HRMS (EI) calcd for C17H30O [M]+: 250.2297, found: 250.2298. Data for 6: []31 = -22.4 (c 1.0,
D
CHCl3); Mp 116–118 °C; IR (film) 3297, 2927, 2865, 1446, 1385, 1362, 1056, 1039, 1007, 971 cm-1;
1H NMR (400 MHz, CDCl3): δ 3.15–3.08 (m, 1H), 2.26–2.20 (m, 1H), 1.92–1.85 (m, 1H), 1.79–1.71
(m, 1H), 1.71–1.57 (m, 4H), 1.57–1.47 (m, 1H), 1.45–1.33 (m, 2H), 1.33–1.13 (m, 4H), 1.13–1.07
(m, 1H), 1.03–0.78 (m, 4H), 0.84 (s, 3H), 0.82 (s, 3H), 0.81 (s, 3H), 0.73 (td, J = 11.5 Hz, J = 3.0 Hz,
1H); 13C NMR (100 MHz, CDCl3): δ 76.8, 55.0, 53.8, 44.1, 42.1, 39.3, 36.7, 35.3, 33.6, 33.2, 30.9,
24.4, 24.0, 21.9, 21.1, 18.9, 14.2; HRMS (EI) calcd for C17H30O [M]+: 250.2297, found: 250.2301.
(4aS,4bR,10aS)-4b,8,8-trimethyldodecahydrop-henanth-ren-1(4bH)-one (7).25 To a solution of 5
(0.29 g, 1.19 mmol) and 6 (1.33 g, 5.44 mmol) in CH2Cl2 (33 mL) was added PCC (2.86 g, 13.26
mmol) at room temperature, and the stirring was continued for 5h. Dry ether (165 mL) was added and
stirred for another 30 minutes. The supernatant solution decanted from the black gum. The insoluble
residue was washed thoroughly with dry ether whereupon it became a black granular solid. The
combined organic solvents were passed through a short pad of celite and the solvent was removed in
vacuo. The resulting brown oil was dissolved in dry ether (100 mL) and followed the above procedure
once again. The crude was directly coated on silica gel and purified by flash column chromatography
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(gradient from 1:49 → 1:19 EtOAc:hexanes) to afford 7 (1.38 g, 86%) as a white solid. Data for 7:
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[]31 = -11.9 (c 1.0, CHCl3); Mp 69–71 °C; H NMR (400 MHz, CDCl3) δ 2.37–2.30 (m, 1H), 2.28–
D
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2.17 (m, 2H), 2.11–2.02 (m, 1H), 2.00–1.92 (m, 1H), 1.89–1.81 (m, 1H), 1.77–1.61 (m, 2H), 1.61–
1.50 (m, 2H), 1.50–1.29 (m, 4H), 1.28–1.09 (m, 3H), 0.97–0.86 (m, 1H), 0.93 (s, 3H), 0.85 (s, 3H),
0.83 (s, 3H), 0.82–0.77 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 213.4, 57.0, 54.3, 49.4, 41.8, 41.6,
39.2, 37.3, 33.3, 33.0, 26.2, 26.1, 24.1, 21.7, 20.4, 18.8, 13.7.
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(5aS,11aS,11bR)-8,8,11a-trimethyldodecahydrona-phtho-[2,1-b]oxepin-4(5aH)-one (8). To a
suspension of 7 (638 mg, 2.41 mmol) and NaHCO3 (810 mg, 9.64 mmol) in CH2Cl2 (24 mL) at room
temperature was added mCPBA (70–75 % balance 3-chlorobenzoic acid and water, 1.2 g, 4.82 mmol),
and stirring was continued overnight. The reaction was quenched by 1M Na2SO3(aq) (24 mL) and stirred
for another 30 minutes. The phases were separated, and the aqueous layer was extracted with CH2Cl2 (3
× 10 mL). The organic extracts were combined, washed with brine (30 mL), dried over Na2SO4, and
concentrated in vacuo. The residue was purified by flash chromatography (1:9 EtOAc:hexanes) to
afford 8 (625 mg, 86%). Data for 8: []30 = 34.7 (c 1.0, CHCl3); Mp 100–102 °C; IR (film): 2945,
D
1
2865, 1731, 1448, 1388, 1335, 1274, 1211, 1183, 1124, 1013 cm-1; H NMR (500 MHz, CDCl3) δ
4.34–4.28 (m, 1H), 2.65–2.58 (m, 1H), 2.54–2.46 (m, 1H), 2.23–2.16 (m, 1H), 2.03–1.95 (m, 1H),
1.94–1.86 (m, 1H), 1.79–1.73 (m, 1H), 1.70–1.63 (m, 1H), 1.63–1.52 (m, 2H), 1.52–1.34 (m, 4H),
1.34–1.24 (m, 2H), 1.13 (td, J = 13.0 Hz, J = 4.0 Hz, 1H), 0.98–0.89 (m, 2H), 0.88 (s, 3H), 0.87 (s,
3H), 0.82 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 175.6, 80.0, 53.7, 53.7, 41.4, 39.6, 38.6, 34.9, 33.9,
33.7, 33.1, 28.0, 22.1, 22.1, 20.4, 18.5, 15.2; HRMS (EI) calcd for C17H28O2 [M]+: 264.2089, found:
264.2083.
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4-((1R,2R,8aS)-2-hydroxy-5,5,8a-trimethyldeca-hydrona-phthalen-1-yl)butan-emide (9). To dry
1,1,2-trichloroethane (5.7 mL) in a double-necked round-bottom flask, fitted with a reflux condenser
topped with a rubber serum cap and connected to an oil tube, was bubbled anhydrous NH3 at 0 °C for
25 min. After this time, AlMe3 (2.0 M in toluene, 1.4 mL, 2.84 mmol) was added. The mixture was
then heated to 80 °C and stirred at 80 °C for 1h to bubble off excess NH3. Then lactone 8 (300 mg,
1.14 mmol) in dry 1,1,2-trichloroethane (5.7 mL) was added and stirred at 80 °C for another 1h. The
mixture was cooled to 0 °C, 1N HCl (20 mL) was added and stirred for 30min. The organic phase was
separated, and the aqueous phase was extracted with CH2Cl2 (3 × 20 mL). The organic extracts were
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combined, washed with brine (60 mL), dried over Na2SO4, and concentrated in vacuo. The residue was
coated on silica gel and purified by flash column chromatography (EtOAc:hexanes, 1:4 →
CH2Cl2:MeOH, 9:1) to give 9 (286 mg, 90%) as a white solid. Data for 9: []29 = -2.5 (c 1.0, MeOH);
D
Mp 154–156 °C; IR (film) 3445, 3415, 3330, 3179, 2935, 2915, 2863, 2848, 1680, 1657, 1619,
1
1441, 1411, 1384, 1363, 1303, 1097, 1032, 966, 880, 694, 592, 558 cm-1; H NMR (500 MHz,
CDCl3) δ 5.97 (s, 1H), 5.63 (s, 1H), 3.52–3.46 (m, 1H), 2.35–2.28 (m, 1H), 2.23–2.16 (m, 1H), 2.06–
2.03 (m, 2H), 1.86–1.75 (m, 1H), 1.75–1.69 (m, 1H), 1.69–1.62 (m, 1H), 1.62–1.57 (m, 1H), 1.57–
1.52 (m, 1H), 1.52–1.37 (m, 3H), 1.37–1.31 (m, 1H), 1.31–1.20 (m, 3H), 1.13 (td, J = 14.0 Hz, J =
4.0 Hz, 1H), 0.91–0.86 (m, 2H), 0.86 (s, 3H), 0.78 (s, 3H), 0.75 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 176.2, 73.3, 58.3, 54.7, 42.0, 38.7, 38.6, 36.6, 35.6, 33.4, 33.2, 27.3, 27.0, 21.7, 20.8, 18.4, 14.4;
HRMS (ESI) calcd for C17H31NO2Na [M+Na]+: 304.2252, found: 304.2245.
4-((1R,8aS)-5,5,8a-trimethyl-2-oxodecahydrona-phthale-n-1-yl)butanenitrile (10). A solution of
dimethyl sulfoxide (0.92 mL, 12.90 mmol) in CH2Cl2 (2.8 mL) was added to a stirred solution of oxalyl
chloride (0.55 mL, 6.45 mmol) in CH2Cl2 (2.9 mL) at -78 °C. After 15 minutes, a solution of 9 (605
mg, 2.15 mmol) was added to the reaction mixture. Stirring was continued for 20 minutes at -78 oC, and
then Et3N was added. After 30 minutes at -78 °C, the reaction mixture was warmed to room
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temperature and the reaction was quenched with sat. NH4Cl(aq) (20 mL) and CH2Cl2 (20 mL). The
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residue was purified by flash column chromatography (gradient from 1:19 → 1:4 EtOAc:hexanes) to
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give 10 (410 mg, 73%) as yellow oil. Data for 10: []29 = -26.8 (c 1.0, CHCl3); IR (film) 2947, 2868,
D
2845, 2245, 1709, 1460, 1429, 1389, 1365, 1185, 1122, 1105, 968 cm-1; 1H NMR (400 MHz, CDCl3)
δ 2.45–2.39 (m, 1H), 2.39–2.23 (m, 3H), 2.09–2.01 (m, 2H), 1.82–1.67 (m, 3H), 1.67–1.61 (m, 1H),
1.61–1.48 (m, 3H), 1.48–1.33 (m, 3H), 1.28–1.12 (m, 2H), 0.96 (s, 3H), 0.84 (s, 3H), 0.71 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 211.6, 119.7, 63.6, 54.2, 42.7, 42.4, 41.8, 39.3, 33.7, 33.5, 25.0, 23.9,
21.6, 21.2, 18.9, 17.4, 14.6; HRMS (EI) calcd for C17H27NO [M]+: 261.2093, found: 261.2093.
4-((1R,2S,8aS)-5,5,8a-trimethyloctahydro-1H-spiro[nap-hthalene-2,2'-oxirane]-1-
yl)butanenitrile (11). NaH (60%, 140 mg, 3.48 mmol) was dissolved in DMSO (3.5 mL) and heated
for 20 minutes to 75 °C (until the formation of hydrogen has ended). After cooling to room temperature,
THF (1.75 mL) was added and the mixture was cooled to 0 °C. To this solution, (CH3)3SI (738 mg,
3.61 mmol) was added. After 5 minutes, 10 (183 mg, 0.70 mmol) in THF (1.75 mL) was added and the
reaction was allowed to warm to room temperature gradually. After 3h, the reaction was quenched by
sat. NaHCO3(aq) (5 mL) and H2O (5 mL). The phases were separated, and aqueous layer was extracted
with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4, and concentrated in
vacuo. The residue was purified by flash column chromatography (gradient from 1:9 → 1:4
EtOAc:hexanes) to give 11 (173 mg, 90%) as a white solid. Data for 11: []30 = 28.7 (c 1.0, CHCl3);
D
Mp 100–102 °C; IR (film) 2930, 2859, 2843, 2245, 1470, 1457, 1443, 1433, 1386, 1366, 1205, 972,
939 cm-1; 1H NMR (500 MHz, CDCl3) δ 2.48 (d, J = 4.0 Hz, 1H), 2.33 (d, J= 4.0 Hz, 1H), 2.31–2.22
(m, 2H), 1.88 (td, J = 13.5 Hz, J = 5.5 Hz, 1H), 1.78 (d, J = 12.5 Hz, 1H), 1.70–1.48 (m, 6H), 1.48–
1.38 (m, 2H), 1.38–1.31 (m, 1H), 1.31–1.21 (m, 2H), 1.16 (td, J = 13.5 Hz, J = 4.0 Hz, 1H), 0.98 (dd,
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J = 12.0 Hz, J = 2.5 Hz, 1H), 0.95–0.90 (m, 1H), 0.89 (s, 3H), 0.87 (s, 3H), 0.85 (s, 3H); C NMR
(125 MHz, CDCl3) δ 119.5, 57.0, 55.1, 52.1, 48.7, 42.0, 39.8, 38.8, 35.8, 33.4, 27.3, 21.6, 20.7, 20.0,
18.4, 17.2, 14.3, 14.3; HRMS (EI) calcd for C18H29NO [M]+: 275.2249, found: 275.2246.
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(4aR,4bS,10aR)-10a-(hydroxymethyl)-4b,8,8-trimethyl-dodecahydrophenant-hren-1(4bH)-one
(12). A mixture of Cp2TiCl2 (667 mg, 2.68 mmol) and Zn powders (526 mg, 8.05 mmol) in strictly
deoxygenated THF (12 mL) was stirred at room temperature until the red solution turned green (around
20 min). Then 11 (335 mg, 1.22 mmol) in strictly deoxygenated THF (12 mL) was added to the
mixture. After 3 h, the reaction was quenched by sat. NaH2PO4(aq) (24 mL), and zinc powder and
titanocene reagent were removed by filtration through celite. The phases were separated, and the
aqueous layer was extracted with ether (3 × 20 mL). The combined organic layers were washed with sat.
NaHCO3(aq) (40 mL) and brine (40 mL), dried over Na2SO4, and concentrated in vacuo. The residue
was purified by flash column chromatography (gradient from 1:19 → 1:4 EtOAc:hexanes) to give 12
(270 mg, 80%) as a white solid. Data for 12: []27 = 20.0 (c 1.0, CHCl3); Mp 165–167 °C; IR (film)
D
3448, 2938, 2865, 2837, 1701, 1458, 1440, 1385, 1363, 1121, 1103, 1039, 1016, 969 cm-1;1H NMR
(500 MHz, CDCl3) δ 4.11 (d, J = 11.0 Hz, 1H), 3.94 (d, J = 11.0 Hz, 1H), 2.62 (td, J = 13.8 Hz, J =
6.5 Hz, 1H), 2.31–2.24 (m, 1H), 2.16–2.07 (m, 1H), 1.94–1.87 (m, 1H), 1.77–1.47 (m, 9H), 1.45–
1.22 (m, 3H), 1.17 (dd, J = 12.0 Hz, J = 3.5 Hz, 1H), 1.11 (td, J = 13.5 Hz, J = 4.0 Hz, 1H), 0.85 (s,
13
3H), 0.82 (s, 3H), 0.80 (s, 3H); C NMR (100 MHz, CDCl3) δ 214.0, 62.5, 59.0, 56.0, 41.8, 39.7,
39.0, 38.4, 33.3, 33.2, 29.1, 26.7, 21.4, 19.7, 18.7, 17.8, 17.8, 16.4; HRMS (EI) calcd for C18H30O2
[M]+: 278.2246, found: 278.2251.
(4aR,4bS,10aR)-methyl
10a-((methoxycarbony-loxy)m-ethyl)-4b,8,8-trimethyl-1-
oxotetradecahydrop-henanthrene-2-carboxylate (13). To a solution of 12 (144 mg, 0.52 mmol) in
THF (10.4 mL) was added LiHMDS (0.5M in THF, 4.1 mL, 2.07 mmol) at -78 °C. The mixture was
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allowed to warm slowly to -20 °C over the course of 2h. Then, cooled down to -78 °C, and NCCOOMe
(0.25 mL, 3.11 mmol) and TMEDA (0.42 mL, 3.11 mmol) were added dropwise to the reaction
mixture. Let it slowly warmed to room temperature over the course of 4h, and then was stirred at room
temperature for another 8h. The reaction contents were quenched with 1N HCl(aq) (10 mL) under ice-
bath and let it gradually warmed to rt. The reaction crude was extracted with ether (3 × 10 mL). The
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organic extracts were combined, washed with brine (30 mL), dried over Na2SO4, and concentrated in
vacuo. The residue was coated on silica gel and purified by flash column chromatography (gradient
from 1:19 → 1:4 EtOAc:hexanes) to give 13 (133 mg, 65%) as a white foam. Data for 13: []31 = -5.5
D
(c 1.0, CHCl3); IR (film) 2951, 2870, 2843, 1748, 1716, 1651, 1613, 1441, 1367, 1316, 1262, 956
cm-1; 1H NMR (400 MHz, CDCl3; keto and enol tautomers, ca. 2:1) δ 12.32 (s, 0.3H, enol), 4.56 (d, J =
8.8 Hz, 0.7H, keto), 4.52 (d, J = 8.8 Hz, 0.7H, keto), 4.45 (d, J = 8.8 Hz, 0.3H, enol), 4.39 (d, J = 8.8
Hz, 0.3H, enol), 3.72 (s, 2H, keto), 3.71 (s, 1H, enol), 3.70 (s, 1H, enol), 3.69 (s, 2H, keto), 3.64–3.59
(m, 0.7H), 2.42–2.07 (m, 2H, keto/enol), 1.96–1.77 (m, 3H, keto/enol), 1.77–1.48 (m, 5H, keto/enol),
1.45–1.19 (m, 5H, keto/enol), 1.15–1.04 (m, 1H, keto/enol), 0.87 (s, 1H, enol), 0.85 (s, 2H, keto), 0.82
(s, 3H, keto/enol), 0.78 (s, 3H, keto/enol); 13C NMR (100 MHz, CDCl3) δ 206.0, 175.1, 173.4, 170.5,
155.6, 97.0, 70.2, 67.1, 59.1, 56.3, 55.7, 54.9, 54.6, 54.1, 53.5, 51.9, 51.3, 42.9, 41.8, 41.5, 39.4,
38.3, 37.3, 33.1, 33.1, 32.1, 29.2, 22.8, 21.3, 21.1, 18.7, 18.5, 18.4; HRMS (ESI) calcd for
C22H34O6Na [M+Na]+: 417.2253, found: 417.2258.
(6aR,11aR,11bS)-methyl
6a-((methoxycarbonyl-oxy)met-hyl)-4,4,11b-trimetyl-7-
oxotetradecahydro-1H-cyclohepta-[a]naphthalene-9-carboxylate (14). To a solution of 13 (23 mg,
0.058 mmol) in ClCH2CH2Cl (0.6 mL) was added Et2Zn (1.0 M in hexane, 93 μL, 0.093 mmol) at 0
°C. After 10 minutes, CH2I2 (8μL, 0.093 mmol) was added and the mixture was stirred at 0 °C for 2h.
Then the reaction mixture was allowed to warm to room temperature and stirred for another 14h. The
reaction contents were quenched with sat. NH4Cl(aq) (2 mL) at 0 °C and allowed to warm to room
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temperature. The phases were separated, and the aqueous layer was extracted with ether (3 × 2 mL).
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The organic extracts were combined, washed with sat. NaHCO3(aq) (10 mL) and brine (10 mL), dried
over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography
(gradient from 0:1 → 1:1 EtOAc:DCM) to afford 14 (16 mg, 61%) as colorless liquid. Data for 14:
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[]31 = 9.1 (c 1.0, CHCl3); IR (film) 2951, 2868, 2843, 1750, 1704, 1441, 1389, 1367, 1264, 1201,
D
1175, 1158, 1116, 961, 791 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.72 (d, J = 11.2 Hz, 1H), 4.55 (d, J
= 11.2 Hz, 1H), 3.76 (s, 3H), 3.69 (s, 3H), 2.99 (dd, J = 11.6 Hz, J = 6.8 Hz, 1H), 2.87–2.73 (m, 2H),
2.14–2.04 (m, 1H), 1.84–1.72 (m, 3H), 1.72–1.61 (m, 5H), 1.61–1.57 (m, 1H), 1.52–1.42 (m, 1H),
1.42–1.28 (m, 2H), 1.28–1.21 (m, 1H), 1.15 (td, J = 13.4 Hz, J = 4.0 Hz, 1H), 0.94–0.89 (m, 1H),
0.87 (s, 3H), 0.87 (s, 3H), 0.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 211.2, 175.5, 155.6, 68.5, 56.4,
56.2, 54.8, 54.6, 52.1, 41.7, 39.6, 38.7, 38.5, 38.5, 33.4, 33.2, 31.5, 29.4, 21.4, 21.3, 18.6, 18.1, 16.0;
HRMS (MALDI) calcd for C23H36O6Na [M+Na]+: 431.2410, found: 431.2422.
(6aR,11aR,11bS)-methyl
6a-((methoxycarbonyl-oxy)me-thyl)-4,4,11b-trimeth-yl-7-oxo-
2,3,4,4a,5,6,6a,7,10,11,11a,11b-dodecahydro-1H-cyclohepta[a]naphthalen-e-9-carboxylate (15).
To a solution of 14 (8.0 mg, 0.020 mmol) in THF (0.2 mL) was added LiHMDS (0.5M in THF, 59 μL,
0.029 mmol) at -78 °C. The mixture was allowed to warm slowly to -20 °C over the course of 2h. Then,
cooled down to -78 °C, a solution of PhSeCl (5.6 mg, 0.029 mmol) in THF (0.05 mL) was added at -78
°C. After 3h, the reaction was quenched by sat. NaHCO3(aq) (2 mL), and the aqueous layer was
extracted with ether (3 × 2 mL). The organic extracts were combined, washed with brine (6 mL), dried
over Na2SO4, and concentrated in vacuo. To a solution of the residue mentioned above in THF (0.4 mL)
was added H2O2(aq) (4 μL, 0.050 mmol) and pyrine (4 μL, 0.050 mmol) at room temperature. After 2h,
the reaction was quenched by sat. NaHCO3(aq) (2 mL), and the aqueous layer was extracted with ether
(3 × 2 mL). The organic extracts were combined, washed with brine (6 mL), dried over Na2SO4, and
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concentrated in vacuo. The residue was purified by flash column chromatography (gradient from 1:49
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→ 1:9 EtOAc:hexanes) to give 15 (5.0 mg, 63%) as colorless oil. Data for 15: []26 = -30.5 (c 1.0,
D
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8
CHCl3); IR (film) 2952, 2865, 2845, 1752, 1721, 1693, 1440, 1389, 1363, 1264, 1210, 1134, 965,
948 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.94 (d, J = 2.0 Hz, 1H), 4.70 (d, J = 11.0 Hz, 1H), 4.59 (d, J
= 11.0 Hz, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 2.88–2.79 (m, 1H), 2.32–2.21 (m, 1H), 1.96–1.85 (m, 1H),
1.85–1.77 (m, 2H), 1.72–1.65 (m, 1H), 1.65–1.42 (m, 4H), 1.42–1.23 (m, 3H), 1.14 (td, J = 13.4 Hz,
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J = 4.0 Hz, 1H), 0.97–0.87 (m, 2H), 0.92 (s, 3H), 0.86 (s, 3H), 0.81 (s, 3H); C NMR (100 MHz,
CDCl3) δ 207.2, 167.5, 155.5, 138.1, 137.0, 69.0, 56.2, 55.5, 54.9, 54.9, 52.5, 41.7, 39.3, 38.9, 33.4,
33.2, 32.4, 29.5, 21.8, 21.4, 18.5, 18.2, 16.2; HRMS (ESI) calcd for C23H34O6Na [M+Na]+: 429.2253,
found: 429.2254.
(6aR,11aR)-methyl
6a-((methoxycarbonylox-y)methyl)-4,4,11b-trimethyl-7-oxo-
2,3,4,4a,5,6,6a,7,8,11,11a,11b-dodeca-hydro-1H-cyclohepta[a]naphthalene-9-carboxylate (16). A
solution of 15 (25 mg, 0.062 mmol) and DBU (19 μL, 0.124 mmol) in benzene (1.24 mL) was
refluxed for 3 h. The reaction was cooled down to room temperature and then quenched by sat.
NH4Cl(aq) (2 mL). The phases were separated, and the aqueous layer was extracted with EtOAc (3 × 2
mL). The combined organic layers were washed with sat. NaHCO3(aq) (5 mL) and brine (5 mL), dried
over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography
(gradient from 1:49 → 1:9 EtOAc:hexanes) to give 16 (20 mg, 80%) as colorless oil. Data for 16:
[]26 = -0.7 (c 1.0, CHCl3); IR (film) 2950, 2868, 2843, 1751, 1711, 1645, 1440, 1388, 1367, 1260,
D
1116, 1069, 963, 790 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.13–7.09 (m, 1H), 4.75 (d, J = 11.2 Hz,
1H), 4.63 (d, J = 11.2 Hz, 1H), 3.81 (dd, J = 13.8 Hz, J = 2.2 Hz, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.58
(d, J = 14.0 Hz, 1H), 2.78–2.66 (m, 1H), 2.60–2.50 (m, 1H), 2.08–2.01 (m, 1H), 1.86–1.78 (m, 1H),
1.73–1.54 (m, 3H), 1.54–1.44 (m, 1H), 1.44–1.23 (m, 3H), 1.16 (td, J = 13.4 Hz, J = 4.0 Hz, 1H),
13
0.95 (s, 3H), 0.94–0.88 (m, 2H), 0.87 (s, 3H), 0.82 (s, 3H); C NMR (100 MHz, CDCl3) δ 207.2,
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167.0, 155.4, 144.0, 124.4, 69.3, 56.3, 55.8, 54.8, 52.2, 52.1, 41.6, 39.8, 38.3, 37.5, 33.7, 33.4, 33.1,
26.6, 21.3, 18.5, 18.5, 15.6; HRMS (EI) calcd for C23H34O6Na [M+Na]+: 429.2253, found: 429.2260.
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((6aR,7S,11bS)-7-hydroxy-4,4,11b-trimethyl-2,3, 4,4a,5,6, 6a,7,8,11,11a,11b-dodecahydro-1H-
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cyclohepta-[a]naphthalene-6a,9-diyl)dimethanol (17)
&
((6aR,7R,11bS)-7-hydroxy-4,4,11b-
trimethyl-2,3,4,4a,5,6,6a,7,8,11,11a,11b-dodecahydro-1H-cyclohepta[a]naphtha-lene-6a,9-
diyl)dimethanol (17). To a solution of 16 (20 mg, 0.05 mmol) in DCM (0.5 mL) at -78 °C was added
DIBAL solution (1.0 M in toluene, 0.41 mL, 0.50 mmol), and the reaction was allowed to warm to
room temperature gradually. After 12h, the reaction was quenched by 1N HCl(aq) (2 mL) and stirred for
1h at room temperature. The phases were separated, and the aqueous layer was extracted with DCM (3
× 2 mL). The organic extracts were combined, washed with brine (5 mL), dried over Na2SO4, and
concentrated in vacuo. The residue was purified by flash chromatography (gradient from 1:1 → 1:0
EtOAc:hexanes) to afford 17 and 17 (12 mg, 75%, 1:3.5 ratio) as white solids.
Galanal A & galanal B. A solution of 17 and 17 (12.0 mg, 0.037 mmol), TEMPO (1.2 mg,
0.0074 mmol), and TBACl (2.1 mg, 0.0074 mmol) in CH2Cl2 (0.37 mL) and aqueous solution of
NaHCO3 (0.5M, 0.19 mL) and K2CO3 (0.05M, 0.19 mL) were vigorously stirred at room temperature.
NCS (20 mg, 0.148 mmol) was then added. Stirring was maintained and the reaction monitored by TLC.
After 12 h, the reaction was quenched with sat. NH4Cl (2 mL), the organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 3 mL). The CH2Cl2 extracts were washed with brine (10
mL), dried over Na2SO4, and concentrated in vacuo. The residue was coated on silica gel and purified
by flash column chromatography (gradient from 1:19 → 1:4 EtOAc:hexanes) to give galanal A (1.8 mg,
15%) and galanal B (5.9 mg, 49%). Both glanal A and galanal B are white solids. Data for galanal A:
[]25 = -34.6 (c 0.8, CHCl3); Mp 167–169 °C;1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 9.39 (s,
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1H), 6.88 (d, J = 7.3 Hz, 1H), 4.06 (d, J = 8.1 Hz, 1H), 2.85–2.74 (m, 1H), 2.73–2.59 (m, 2H), 2.49
(dd, J = 18.6 Hz, J = 8.4 Hz, 1H), 2.30–2.26 (m, 1H), 2.05 (s, 1H), 1.83–1.75 (m, 2H), 1.63–1.59 (m,
1H), 1.61 (d, J = 10.4 Hz, 1H), 1.46–1.36 (m, 4H), 1.16 (td J = 13.4 Hz, J = 4.0 Hz, 1H), 0.95–0.90
(m, 1H), 0.89 (s, 3H), 0.84–0.81 (m, 1H), 0.80 (s, 3H), 0.78 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
206.4, 193.2, 155.9, 142.2, 71.2, 55.7, 55.5, 53.5, 41.6, 38.6, 38.4, 33.4, 33.2, 28.4, 27.6, 23.5, 21.2,
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18.6, 18.4, 16.5; HRMS (ESI) calcd for C20H30O3Na [M+Na]+: 341.2093, found: 341.2097. Data for
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galanal B: []25 = -39.1 (c 1.0, CHCl3); Mp 142–144 °C; H NMR (500 MHz, CDCl3) δ 10.21 (s, 1H),
D
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(dd, J = 16.3 Hz, J = 9.0 Hz, 1H), 2.68 (d, J = 16.3 Hz, 1H), 2.61–2.52 (m, 2H), 1.87 (d, J = 12.6 Hz,
1H), 1.80–1.70 (m, 1H), 1.70–1.62 (m, 1H), 1.60–1.44 (m, 2H), 1.47 (d, J = 10.2 Hz, 1H), 1.43–1.36
(m, 1H), 1.36–1.27 (m, 1H), 1.20–1.08 (m, 2H), 0.90 (dd, J = 13.2 Hz, J = 4.0 Hz, 1H), 0.86 (s, 3H),
13
0.83 (d, J = 2.2 Hz, 1H), 0.78 (s, 3H), 0.77 (s, 3H); C NMR (125 MHz, CDCl3) δ 208.1, 193.3,
157.5, 140.8, 78.7, 55.6, 55.5, 55.4, 41.7, 38.9, 38.9, 34.5, 33.4, 33.3, 28.7, 24.1, 21.3, 19.0, 18.6,
15.9; HRMS (ESI) calcd for C20H30O3Na [M+Na]+: 341.2093, found: 341.2087. The NMR spectral
data of galanal A and galanal B were in accord with literature values.7
■ ASSOCIATED CONTENT
*S Supporting Information
Calculated structure coordinates for 15 and 16, X-ray crystallographic data for 11 and 12, copies of
13
1H and C NMR spectra, and HPLC data for 3. This material is available free of charge on the ACS
Publications website.
■ AUTHER INFORMATION
Corresponding Author
*E-mail: rjchein@chem.sinica.edu.tw.
Notes
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The authors declare no competing financial interest.
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■ ACKNOWLEDGEMENTS
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We thank Academia Sinica and Ministry of Science and Technology (Taiwan) for financial support
and the MS laboratory and the X-ray laboratory of the Institute of Chemistry, Academia Sinica, for data
analysis.
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