Total syntheses of marrubiin and related labdane diterpene lactones

Article abstract of DOI:10.3390/molecules25071610

Total syntheses of the labdane diterpene lactones marrubiin, marrulibacetal, desertine, marrulibacetal A, marrubasch F, cyllenine C, marrulanic acid, and marrulactone are described. The trans-decalin moiety of these molecules was constructed in a stereoselective manner by a Pauson-Khand reaction, and the resultant cyclopentenone was oxidatively cleaved for formation of the lactone ring. Elongation of the side chain at C9 was achieved by an epoxide-opening reaction with a variety of nucleophiles, and the functional group manipulations completed the syntheses of these natural products. Stereochemistries of desertine could be established by the transformations.

Full text of DOI:10.3390/molecules25071610

molecules
Article
Total Syntheses of Marrubiin and Related Labdane
Diterpene Lactones
Yukari Sakagami, Naoki Kondo, Yuki Sawayama, Hiroyuki Yamakoshi and
Seiichi Nakamura *
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya
467-8603, Japan; yukarinnuu@gmail.com (Y.S.); c202709@ed.nagoya-cu.ac.jp (N.K.); ys020205@gmail.com (Y.S.);
yamakoshi@phar.nagoya-cu.ac.jp (H.Y.)
* Correspondence: nakamura@phar.nagoya-cu.ac.jp; Tel.: +81-52-836-3439
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Marc C. Kimber
Received: 6 March 2020; Accepted: 30 March 2020; Published: 1 April 2020
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: Total syntheses of the labdane diterpene lactones marrubiin, marrulibacetal, desertine,
marrulibacetal A, marrubasch F, cyllenine C, marrulanic acid, and marrulactone are described.
The trans-decalin moiety of these molecules was constructed in a stereoselective manner by a
Pauson-Khand reaction, and the resultant cyclopentenone was oxidatively cleaved for formation of
the lactone ring. Elongation of the side chain at C9 was achieved by an epoxide-opening reaction
with a variety of nucleophiles, and the functional group manipulations completed the syntheses of
these natural products. Stereochemistries of desertine could be established by the transformations.
Keywords: marrubiin; total synthesis; labdane; terpenoid; chiral building block; Pauson-Khand
reaction
1. Introduction
Flowering plants of the genus Marrubium (Lamiaceae) are distributed in the Mediterranean
and temperate regions of the Eurasian zone, and most of the plants are used in folk medicine [
The therapeutic properties of these herbs, including anti-inflammatory, hypoglycemic, analgesic,
antispasmodic, vasorelaxant, and anti-diabetic effects, are attributed in part to marrubiin ( ), which
was first isolated in 1842 from Marrubium vulgare and is a prominent member of the labdane diterpene
lactones [ ] (Figure 1). This furanoid natural product, formed from premarrubiin ( ), was also reported to
inhibit KCl-induced contraction of the rat aorta in a concentration-dependent manner [ ]. The important
pharmacological action of this family of mints prompted phytochemical analysis, leading to the isolation
and characterization of a number of labdane diterpene lactones [ ]: peregrinine ( ) [ ], marrubinones A
) and B (polyodonine, ) [ ], velutines A ( ), B ( ) and C ( ) [ ], marrulibanoside ( ) [ ], marrulanic
1].
1
2
2
3
4
3 5
(4
5
6,
7
6
7
8
8
9 9
acid (10) [10], cyllenines A (11) and C (12) [11], marrulibacetal (13), marrulactone (14) [12], marrusidins
A (15) and B (16) [13], marrulibacetal A (17), desertine (18) [14], and marrubasch F (19) [15] have
been reported to date [16]. These natural products are biosynthesized from (E,E,E)-geranylgeranyl
diphosphate (GGPP) through peregrinol diphosphate synthase (CPS1)-catalyzed bicyclization, followed
by 9,13-epoxylabd-14-ene synthase (ELS)-catalyzed formation of tetrahydropyran and regiospecific
oxygenations with P450s [17
of marrubiin ( ) in a racemic form [19] and semi-syntheses of premarrubiin (
marrubasch F (19) and (13R)-9 ,13 -epoxylabda-6 (19),16 (15)-diol dilactone from marrubiin (
been reported by Mangoni and co-workers [20].
,
18]. Despite their remarkable biological activities, only a total synthesis
), marrulibanoside ( ),
) have
1
2
9
α
α
β
1
Recently, we have developed a method for stereocontrolled preparation of enyne 20 (Figure 2,
TMS = trimethylsilyl) by exploiting a ring-contractive coupling between an α-bromo-δ-valerolactone
and a secondary alcohol, and subsequent Ireland Claisen rearrangement [21,22]. Since compound 20
−
Molecules 2020, 25, 1610; doi:10.3390/molecules25071610
www.mdpi.com/journal/molecules

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embodies the C8
−
C10 stereotriad of C9-oxygenated labdane diterpenoids, compound 20 can serve as
a useful chiral building block for the synthesis of pharmacologically interesting, marrubiin-related
natural products. In this article, we describe the total syntheses of members of the marrubiin family
including marrubiin (1), marrulanic acid (10), cyllenine C (12), marrulibacetal (13), marrulactone (14),
marrulibacetal A (17), desertine (18), and marrubasch F (19) [23].
Figure 1. Structures of marrubiin and related natural products.
Figure 2. Structure of building block 20.
2. Results and Discussion
2.1. Retrosynthetic Analysis
Our retrosynthetic analysis of marrubiin-related natural products is depicted in Scheme 1. Since the
difference between the target molecules lies in the variation in the side chain at C9, we planned to install
the full C9 side chain late in the synthesis by a nucleophilic ring-opening reaction of advanced epoxide
intermediate 22, which could be derived from ester 23 through a chemoselective reduction of the ester
functionality in the presence of the lactone moiety. While the methyl group at C4 would be introduced
from the less-hindered diastereoface by an enolate alkylation, C5
C4, and oxidative cleavage of the C C bond at C6 were required for the conversion of enyne 20 to
lactone 23. In light of these requirements, we chose to use the intramolecular Pauson Khand reaction
(PKR) [24 25] to fashion the six-membered ring and introduce the carbonyl group at C4. Although
−
C6 bond formation, carboxylation at
−
−
,

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some concern arose over the formation of cis-fused isomer cis-24 from enyne 20 considering that
[RhCl(CO)2]2-catalyzed PKRs of substituted 5-(pent-4-ynyl)cyclohexa-1,3-dienes are precedented to
afford cis-decalin derivatives stereoselectively [26], we expected that the stereocenter at C5 would be
epimerized after oxidative cleavage of the double bond at C6.
Scheme 1. Retrosynthetic analysis.
2.2. Synthesis of Advanced Intermediate 22
The synthesis of advanced intermediate 22 commenced with the key PKR of enyne 20 (Scheme 2).
Initial attempts to cyclize dicobalt complex 25, prepared by treatment of enyne 20 with Co2(CO)8 in
CH2Cl2 (97% yield), upon heating in refluxing acetonitrile failed to produce any of the PKR products,
leading to decomplexation. After considerable experimentation, we found that the desired tricyclic
compound 24 could be produced with the aid of a promoter, with CyNH2 (Cy = cyclohexyl) [27] being
optimal for this purpose. Gratifyingly, the product, obtained in (CH2Cl)2 at a substrate concentration
of 10 mM under optimized conditions in 97% yield, proved to be the desired stereoisomer trans-24 as
confirmed by the absence of a cross-peak between C10-CH3 and C5-H in the nuclear Overhauser effect
spectroscopy (NOESY) spectrum. It has been suggested on the basis of quantum mechanical studies
that the stereochemistry of PKR is determined by the irreversible olefin insertion step [28]. Since the
chair
−
chairlike transition state (TS)
A
suffers from steric repulsion between C8-CH3 and C1-Hax, the
reaction proceeded through chair
trans-24.
−
boatlike TS , leading to the exclusive formation of trans-decalin
B
Scheme 2. Construction of the tricyclic lactone. KHMDS = potassium bis(trimethylsilyl)amide, THF
= tetrahydrofuran.

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To enhance the synthetic utility of PKR, a number of catalytic methods have been reported, and
a variety of metal complexes have been employed for this purpose [29]. However, our attempts
to carry out the catalytic reaction with enyne 20 met with failure: the use of Krafft conditions [30
]
resulted in recovery of enyne 20 in 49% yield, whereas a complicated mixture was obtained when
using 2-naphthaldehyde as a CO donor in the [RhCl(cod)]2-catalyzed reaction [31]. In contrast to these
unsuccessful results, the transformation of enyne 20 to enone trans-24 could be refined to a one-pot
procedure, wherein the cobalt complex was formed in (CH2Cl)2 and heated under reflux after addition
of CyNH2 and 10-fold dilution with (CH2Cl)2. As anticipated, alkylation of the potassium enolate
generated from trans-24 with MeI in THF took place exclusively from the less-hindered
provide enone 26 in 89% yield.
α-face to
With tricyclic compound 26 in hand, efforts were next focused on the transformation of the
cyclopentenone moiety to the corresponding -butyrolactone. With regard to the oxidative cleavage of
the cyclopentenone ring, it was found that desired -ketocarboxylic acid 27 could be obtained upon
exposure of enone 26 to ozone in CH2Cl2 at
78 ◦C followed by either reductive (Me2S) or oxidative
(H2O2, NaOH) workup [32], but the reaction suffered from low yield (33%) and reproducibility issues.
While -ketocarboxylic acid 28, detected as a byproduct, could be converged to -ketocarboxylic
acid 27 upon treatment with H2O2 in aqueous NaOH/THF, no improvement in overall yield was
observed. We then investigated a stepwise approach via -ketocarboxylic acid 28. After an extensive
screening of oxidants, the KMnO4/NaIO4 system proved to be effective for the conversion of enone 26
to 28. To our surprise, submission of crude -ketocarboxylic acid 28 to activated carbon for removal
of the residual Mn salt to avoid decomposition of H2O2 effected desired decarbonylation. As a
consequence, -ketocarboxylic acid 27 could be obtained in 53% yield over two steps. The reason for
the decarbonylation is unclear at present, but the possibility of involvement of contaminated Mn salt
was excluded due to the fact that the reaction occurred from -ketocarboxylic acid 28 produced by
ozonolysis [33]. To the best of our knowledge, this is the first example of activated carbon-mediated
decarbonylation of -ketocarboxylic acid. Lactone formation from -ketocarboxylic acid 27 was
γ
γ
−
α
γ
α
α
γ
α
α
γ
achieved following the precedents of Wheeler [34] and Mangoni [19]: selective reduction of the
carbonyl group at C6 with NaBH4 in EtOH at 0 ◦C was followed by lactonization through a mixed
anhydride upon treatment with ClCO2Et in the presence of Et3N in CH2Cl2 at 0 ◦C to give lactone 23
in 88% yield over two steps [35].
The remaining operation necessary for the synthesis of advanced intermediate 22 involved
chemoselective reduction of the ester functionality in the presence of the lactone moiety (Scheme 3). As
a prelude to the conversion, TMS ether 23 was converted to α-hydroxyester 29 by exposure to Bu4NF
in THF at 0 ◦C (98% yield). With regard to the reduction, the use of NaBH4 or LiBH4 resulted in no
reaction even at the reflux temperature, whereas the lactone moiety in 29 was selectively reduced with
diisobutylaluminum hydride (DIBALH) in CH2Cl2 at
78 ◦C. We were gratified to find that the desired
−
chemoselective reduction could be achieved by the use of sodium bis(2-methoxyethoxy)aluminum
hydride (Red-Al®) as a reducing agent. It should be noted that the hydroxyl-directed reduction
was accompanied by some lactone reduction when performed using Et2O or THF as a solvent or
◦
when performed at temperatures above
−
20 C. The use of CH2Cl2 proved optimal in terms of
chemoselectivity and solubility of substrate 29, but the collapse of the five-membered aluminate
intermediate was retarded under the optimal conditions, resulting in the formation of a mixture of
aldehyde 30 and 1,2-diol 31 after aqueous workup. Thus, the mixture needed to be subjected again
◦
to Red-Al® in CH2Cl2 at
−
23 C for the full reduction to 1,2-diol 31. The synthesis of advanced
intermediate 22 was completed upon treatment of 1,2-diol 31 with p-toluenesulfonylimidazole and
NaH in THF at 0 ◦C (84% yield over three steps).

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Scheme 3. Completion of the synthesis of advanced intermediate 22. Ts = p-toluenesulfonyl.
2.3. Total Syntheses of Marrubiin and Related Labdane Diterpene Lactones
Having established a route to epoxide 22, the stage was now set for elongation of the side chain
for total syntheses. In this regard, Welch and co-workers reported the synthesis of isomarrubiin
(C9-epi-marrubiin) by a CuI-catalyzed epoxide ring-opening reaction of the C9-epimer of epoxide
22 in Et2O at room temperature (40% yield) [36]. With this reaction serving as a reference, we first
examined Cu(I)-catalyzed epoxide-opening reaction with Grignard reagent 32
some experimentation, we found that the use of a stoichiometric amount of CuBr
effective, providing marrubiin (
), [α]2D1 +34.4 (c 1.04, CHCl3) [lit. [38], [α]D20 +35.8 (c 3.1, CHCl3)] in
[
37] (Scheme 4). After
·
SMe2 was more
1
65% yield. However, Grignard reagent 32 is prone to isomerization due to the high acidity of the furan
2-position, resulting in the formation of isomer 33 in 9% yield [39]. This problem was circumvented by
the use of Grignard reagent 34
[40], the TMS group of which was uneventfully removed with Bu4NF in
THF [41] after the epoxide-opening reaction.
Scheme 4. Total syntheses of marrubiin (
F (19) from epoxide 22.
1), marrulibacetal (13), marrulibacetal A (17), and marrubasch

Molecules 2020, 25, 1610
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An inspection of the structures of marrulibacetal (13) and marrulibacetal A (17) revealed that the
highly oxidized tetrahydrofuran ring of these molecules could be formed by oxidation of the furan
moiety in marrubiin (1) followed by internal acetalization. While unprecedented in the transformation
of the marrubiin class labdane diterpenoids, successive oxidations of a furan ring have been documented
in semi-synthesis of the neoclerodane diterpene natural products salvinicins A and B by Prisinzano
and co-workers [42]. Furthermore, Frontana-Uribe and co-workers reported construction of the
[6,6,5,5]-tetracyclic framework, in which 4,5,6,7a-tetrahydro-2H-furo[2,3-b]pyran is spirolinked to a
trans-decalin ring system, by an electrochemical oxidation of hispanolone [43]. When marrubiin (1)
was exposed to pyridine tribromide in EtOH/CH2Cl2 at 0 ◦C, oxidative acetalization occurred to give
bisacetal 36 in 79% yield with a cis/trans ratio of 2:1, albeit with no sign of internal acetalization in
contrast to Frontana-Uribe’s work. This result is attributed to the conformational constraint imposed by
the lactone ring. The chemical yield was improved to 84% in the presence of K2CO3 as an acid scavenger.
As expected from the precedent [44], the reaction rate of bisacetal 36 with OsO4/4-methylmorpholine
N-oxide (NMO) in aqueous THF was influenced by the substrate structure: the reaction of a 1:1 mixture
of diastereomers with the cis relative configuration at room temperature proceeded to completion within
1 h to give diols 38 and 39 in a stereoselective manner, whereas the trans-isomers were almost recovered
unchanged under these conditions. Although the remaining trans-isomers could be consumed at an
elevated temperature after prolonged reaction times, the lower π-facial selectivity (desired:undesired
= 1:1.2), together with the fact that recovered trans-isomers could be isomerized to cis-isomers upon
exposure to pyridinium p-toluenesulfonate (PPTS) in EtOH for 1 h, prompted us to perform the reaction
at room temperature. Submission of an inseparable mixture of diols 38 and 39 to TsOH in benzene
effected internal transacetalization, affording marrulibacetal (13), [α]2D7−21.7 (c 1.16, CHCl3) [lit. [12],
[
α]2D5−13.1 (c 0.29, CHCl3)], in 36% yield along with isomer 41 (38% yield) and other diastereomers
(1:1, 18% combined yield). It is noteworthy that the dehydration of commercially available benzene
with 3 Å molecular sieves prior to use affected the transacetalization, leading to the decomposition of
substrates, although the reason is unclear at present.
Following the same reaction sequence using MeOH instead of EtOH, marrulibacetal A (17),
[
α]D21−14.0 (c 1.69, CHCl3) [lit. [14], [α]2D5−10.77 (the solvent and concentration were not reported)],
could be synthesized from marrubiin (1). It should be mentioned that one of two diastereomers,
obtained as an inseparable mixture in a ratio of 1:1 by dihydroxylation of bisacetal 37, matched by
1H-NMR with desertine (18), although the chemical correlation to establish the stereochemistry will
be presented later (vide infra). The low chemical yield (16%) of 17 was due to the formation of two
isomers with the trans H15/H16 stereochemistry in 38% yield.
Kuwajima and Urabe reported that 2-(trimethylsilyl)furans could be oxidized regioselectively
with peracetic acid [45], and the method was successfully applied for the synthesis of substituted
∆
2-butenolides by Goldsmith, Liotta, and co-workers [46]. On the basis of these precedents, we next
examined the oxidation of 2-(trimethylsilyl)furan 35 for the conversion to marrubasch F (19). Screening
of peracids revealed that the use of m-chloroperoxybenzoic acid (m-CPBA) (57% yield) and peracetic
acid (52% yield) afforded 19, mp 195
−
196 ◦C, [α]D21 + 41.1 (c 0.53, CHCl3) [lit. [20], mp 191 193 ◦C,
−
[α]D +41.5 (c 1.00, CHCl3)], with m-CPBA being the optimal oxidizing agent, whereas only desilylation
occurred to give marrubiin (
1
) with either performic acid or magnesium monoperoxyphthalate (MMPP).
) and natural products possessing the same carbon framework
Having synthesized marrubiin (
1
in a higher oxidation state, we next addressed the conversion of epoxide 22 to natural products 12
and 14, which required two- and three-carbon nucleophiles, respectively (Scheme 5). Fortunately,
epoxide 22 underwent nucleophilic ring-opening reaction with commercially available lithium acetylide
ethylenediamine complex, affording alcohol 43 in 95% yield. Oxidative lactonization of homopropargyl
alcohol 43 could be attained by the gold(I)-catalyzed cycloisomerization/oxidation sequence under
Ye conditions [47], completing the synthesis of cyllenine C (12). On the other hand, the use of
Grignard reagent 44
[48] as a three-carbon nucleophile under conditions identical to those with 32 gave
alcohol 45 (48% yield), which was desilylated with Bu4NF in THF to furnish 1,5-diol 46 in 82% yield.

Molecules 2020, 25, 1610
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δ
-Lactone could be formed upon oxidation of 1,5-diol 46 with 2,2,6,6-tetramethylpiperidin-1-oxyl
(TEMPO)/PhI(OAc)2 in CH2Cl2 according to the Forsyth protocol [49] to give marrulactone (14) in
91% yield. Since the -lactone in 14 proved more reluctant to hydrolyze, regioselective saponification
γ
could be realized with LiOH in THF, providing marrulanic acid (10) in 84% yield. Although synthetic
1
compounds 12
,
14, and 10 would be identical to natural products as judged by H and 13C-NMR
analysis (see Supplementary Materials), their specific rotations [[α]2D4 + 22.1 (c 0.69, CH2Cl2), [α]2D1
11.6 (c 0.61, CHCl3), and [α]2D7 + 25.4 (c 0.53, CHCl3), respectively] were inconsistent with those
observed for natural cyllenine C (12), marrulactone (14), and marrulanic acid (10) [[α]2D0 + 11.82 (c
0.33, CH2Cl2) [11], [α]D25 23.80 (c 0.22, CHCl3) [12], and [α]2D5
10.8 (c 1.2, CHCl3) [12], respectively].
−
−
−
This result is attributed to contamination of the impurity in these natural products, as detected by
NMR spectroscopy.
Scheme 5. Total syntheses of cyllenine C (12), marrulactone (14), and marrulanic acid (10) from
epoxide 22. DMSO = dimethyl sulfoxide, Tf = trifluoromethanesulfonyl, Ms = methanesulfonyl, TBS =
tert-butyldimethylsilyl.
Of the eight natural products synthesized, desertine (18) could not be purified due to the difficulty
of separation from its diastereomer 40. With regard to this natural product, stereochemistries were
determined by an NOESY experiment by Dijoux-Franca and co-workers, who indicated two structures
differing in the configuration at C15 [14]. Furthermore, evidence that supports the stereochemical
relationship between the decalin and tetrahydrofuran moieties, separated by the C11 C12 two-carbon
−
bridge, was not provided in their report. Therefore, we felt compelled to perform experiments to
determine the stereochemistries of 18, and we found that exposure of marrulibacetal A (17) and its
diastereomer 42 to TsOH in refluxing MeOH to effect transacetalization resulted in the formation of
triol 40 and desertine (18), respectively, albeit in low yields (Scheme 6). These results suggest that the
stereocenters at C13 and C14 of 18 have configurations opposite to those of 17. Together with our
previous observation that desertine was produced from cis-37, the stereochemistries of this natural
product can be established as shown for 18.

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Scheme 6. Conversion of marrulibacetal A (17) and its isomer 42 to triol 40 and desertine (18).
3. Materials and Methods
Chemistry
3.0.1. General Information
Optical rotations were recorded on a digital polarimeter with a sodium lamp (589 nm). Infrared
(IR) spectra were recorded on an FT-IR spectrophotometer and absorbance bands are reported in
wavenumber (cm−1). Proton nuclear magnetic resonance (1H-NMR) spectra were recorded with
tetramethylsilane (δH 0.00), CHCl3 (δH 7.26), or CH2Cl2 (δH 5.32) as an internal standard. Coupling
constants (J) are reported in hertz (Hz). Abbreviations of multiplicity are as follows: s, singlet;
d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Data are presented as follows: chemical
shift, multiplicity, coupling constants, integration, and assignment. Marrulibacatal numbering is
used for proton assignments of all intermediates. Carbon nuclear magnetic resonance (13C-NMR)
spectra were recorded with CDCl3 (δC 77.0), CD2Cl2 (δC 53.84), or acetone-d6 (δC 29.84) as an
internal standard. High-resolution mass spectra (HRMS) were recorded either by electrospray
ionization (ESI) using a time-of-flight (TOF) analyzer, or by electron impact (EI) using a magnetic
sector analyzer. Column chromatography was carried out on silica gel 60 N (63
−
210 µm or
40 50 m). Analytical thin layer chromatography (TLC) was carried out with 0.25 mm silica
−
µ
gel plates. Visualization was accomplished with ultraviolet light and anisaldehyde stain, followed
by heating. Reagents and solvents were purified by standard means or used as received unless
otherwise noted. Dehydrated dichloromethane (CH2Cl2) and tetrahydrofuran (THF, stabilizer free)
were purchased. Cyclohexylamine was distilled from calcium hydride. 4 Å molecular sieves was
◦
finely ground in mortar and heated in vacuo at 180 C for 4 h. p-Toluenesulfonylimidazole [50],
(3-furylmethyl)magnesium bromide [37], CuBr SMe2 [51], [2-(trimethylsilyl)furan-3-yl]methanol [52],
·
and 3-(tert-butyldimethylsilyl)oxypropylmagnesium bromide (44) [48] were prepared according to
literature procedures. All reactions were conducted under an argon atmosphere unless otherwise noted.
3.0.2. Experimental Procedures and Compound Data
Methyl [2R,2(1S),3R]-3-methyl-2-(1-methylcyclohex-2-en-1-yl)-2-(trimethylsilyl)oxyhex-5-ynoate dicobalt
hexacarbonyl complex (25). Co2(CO)8 (663 mg, 1.94 mmol) was added to an ice-cooled (0 ◦C) solution
of enyne 20 (522 mg, 1.62 mmol) in CH2Cl2 (16 mL). After 1.5 h of stirring at room temperature, the
reaction mixture was concentrated in vacuo, and the reddish brown residue was chromatographed
twice (silica gel 38 g, 20:1 n-hexane/AcOEt) to give dicobalt complex 25 (958 mg, 97%) as a dark red
oil. Rf 0.51 (20:1 n-hexane/AcOEt); IR (neat) 2951, 2091, 2048, 2016, 1748, 1250, 1175, 1138, 841 cm−1
1H-NMR (500 MHz, CDCl3)
0.19 (s, 9H, Si(CH3)3), 0.87 (d, J = 6.6 Hz, 3H, C8-CH3), 1.00 (s, 3H,
C10-CH3), 1.42 (br d, J = 13.8 Hz, 1H, one of C1-H2), 1.63 (m, 1H, one of C2-H2), 1.71 (m, 1H, one of
C2-H2), 1.89 2.03 (m, 3H, one of C1-H2, C3-H2), 2.28 (ddq, J = 2.7, 11.4, 6.6 Hz, 1H, C8-H), 2.60 (ddd, J
;
δ
−
= 1.0, 11.4, 14.7 Hz, 1H, one of C7-H2), 3.49 (br d, J = 14.7 Hz, 1H, one of C7-H2), 3.71 (s, 3H, CO2CH3),
5.71 (ddd, J = 1.7, 5.2, 10.2 Hz, 1H, C4-H), 5.82 (br d, J = 10.2 Hz, 1H, C5-H), 6.01 (br t, J = 1.0 Hz, 1H,

Molecules 2020, 25, 1610
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C6-CH); 13C-NMR (125.7 MHz, CDCl3)
δ
2.8 (CH3), 16.1 (CH3), 20.0 (CH2), 24.4 (CH2), 25.1 (CH3), 31.5
(CH2), 36.9 (CH2), 41.3 (CH), 42.4 (C), 51.5 (CH3), 74.2 (C), 88.5 (C), 95.8 (CH), 126.8 (CH), 132.8 (CH),
175.1 (C), 200.0 (C).
Methyl (1S,6R,7R,8S,12R)-6,8-dimethyl-2-oxo-7-(trimethylsilyl)oxytricyclo[6.3.1.04,12]dodec-3-ene-7-carboxylate
(trans-24). A solution of dicobalt complex 25 (150 mg, 0.247 mmol) in 1,2-dichloroethane (5 mL plus
2
×
2.5 mL rinse) was added to a refluxing solution of cyclohexylamine (0.17 mL, 1.49 mmol) in
1,2-dichloroethane (15 mL), and the resulting mixture was refluxed for 1.5 h. After cooling, the mixture
was filtered through a Celite pad, and the filtrate was concentrated in vacuo. Purification of the
residue (503 mg) by column chromatography (silica gel 30 g, 3:1 n-hexane/AcOEt) gave enone trans-24
(84.0 mg, 97%) as a white solid. Rf 0.42 (3:1 n-hexane/AcOEt); mp 75
n-hexane); [α]2D5 + 62.1 (c 1.34, CHCl3); IR (KBr) 2945, 1736, 1694, 1620, 1458, 1260, 1184, 1096, 1034, 982,
843 cm−1; 1H-NMR (500 MHz, CD2Cl2)
0.20 (s, 9H, Si(CH3)3), 0.62 (s, 3H, C10-CH3), 0.91 (d, J = 6.2
Hz, 3H, C8-CH3), 1.01 (dt, J = 13.4, 7.4 Hz, 1H, one of C1-H2), 1.51 1.63 (m, 2H, one of C2-H2, one of
C3-H2), 1.69 (m, 1H, one of C2-H2), 1.80 (m, 1H, one of C3-H2), 1.89 (ddd, J = 4.5, 8.9, 13.4 Hz, 1H, one
of C1-H2), 2.16 (t, J = 13.9 Hz, 1H, one of C7-H2), 2.47 (ddd, J = 7.3, 8.5, 9.5 Hz, 1H, C4-H), 2.56 2.61 (m,
2H, one of C7-H2, C8-H), 3.16 (d, J = 7.3 Hz, 1H, C5-H), 3.70 (s, 3H, CO2CH3), 5.80 (s, 1H, =CHCO);
13C-NMR (125.7 MHz, CD2Cl2)
2.6 (CH3), 18.3 (CH3), 19.7 (CH2), 19.9 (CH2), 21.1 (CH3), 28.8 (CH2),
−
76 ◦C (colorless plates from
δ
−
−
δ
34.9 (CH2), 37.0 (CH), 43.7 (CH), 45.0 (CH), 45.8 (C), 51.8 (CH3), 86.1 (C), 126.0 (CH), 172.9 (CH), 179.4
(C), 211.9 (C); HRMS (ESI) m/z [M + Na]+ calcd for C19H30O4SiNa 373.1806; found 373.1823.
◦
One-pot reaction. Co2(CO)8 (4.08 g, 11.9 mmol) was added to an ice-cooled (0 C) solution of
enyne 20 (3.20 g, 9.93 mmol) in 1,2-dichloroethane (100 mL), and the mixture was stirred at room
temperature for 3 h. The resulting dark red suspension was diluted with 1,2-dichloroethane (900
mL), and cyclohexylamine (8.0 mL, 70.7 mmol) was added. After 5 h of heating at reflux, the reaction
mixture was cooled to room temperature, and the volatile elements were removed in vacuo. The
residue was suspended in 4:1 n-hexane/AcOEt and filtered through a Celite pad. Evaporation of the
filtrate in vacuo furnished the crude product (5.75 g), which was purified by column chromatography
(silica gel 200 g, 25:1
white solid.
→
10:1
→
4:1
→
1:1 n-hexane/AcOEt) to give enone trans-24 (3.26 g, 94%) as a
Methyl (1S,6R,7R,8S,12R)-1,6,8-trimethyl-2-oxo-7-(trimethylsilyl)oxytricyclo[6.3.1.04,12]dodec-3-ene-7-
carboxylate (26). KHMDS in toluene (0.5 M, 6.2 mL, 3.10 mmol) was added to a cooled (
78 ◦C) solution
−
of enone trans-24 (988 mg, 2.82 mmol) in THF (30 mL). After 40 min of stirring, iodomethane (0.23 mL,
3.69 mmol) was added, and the resulting mixture was stirred at 0 ◦C for 40 min. The reaction was
quenched with saturated aqueous NH4Cl (30 mL), and the mixture was extracted with AcOEt (3
×
60
mL). The combined organic extracts were washed with brine (2 30 mL), and dried over anhydrous
×
Na2SO4. Filtration and evaporation in vacuo furnished the crude product (1.16 g), which was purified
by column chromatography (silica gel 30 g, 6:1 n-hexane/AcOEt) to give methylated product 26 (915
mg, 89%) as a yellow oil. Rf 0.40 (4:1 n-hexane/AcOEt); [α]2D2 +72.2 (c 0.95, CHCl3); IR (neat) 3433, 2953,
1
1738, 1703, 1624, 1458, 1252, 1186, 1103, 1042, 841 cm−1; H-NMR (500 MHz, CDCl3)
δ 0.20 (s, 9H,
Si(CH3)3), 0.71 (s, 3H, C10-CH3), 0.91 (d, J = 6.3 Hz, 3H, C8-CH3), 1.02 (ddd, J = 7.4, 9.2, 13.5 Hz, 1H,
one of C1-H2), 1.11 (s, 3H, C4-CH3), 1.43 (m, 1H, one of (CH2)2), 1.60 (m, 1H, one of (CH2)2), 1.64 1.75
(m, 2H, two of (CH2)2), 1.92 (ddd, J = 2.8, 10.2, 13.5 Hz, 1H, one of C1-H2), 2.12 (m, 1H, one of C7-H2),
2.54 2.62 (m, 2H, one of C7-H2, C8-H), 2.67 (br s, 1H, C5-H), 3.73 (s, 3H, CO2CH3), 5.78 (t, J = 1.4
−
−
Hz, 1H, =CHCO); 13C-NMR (125.7 MHz, CDCl3) δ 2.5 (CH3), 17.7 (CH2), 18.0 (CH3), 21.1 (CH3), 26.6
(CH2), 27.3 (CH3), 28.0 (CH2), 34.8 (CH2), 36.4 (CH), 45.80 (C), 45.84 (C), 51.5 (CH3), 52.3 (CH), 85.7 (C),
123.8 (CH), 172.6 (C), 178.5 (C), 215.8 (C); HRMS (ESI) m/z [M + Na]+ calcd for C20H32O4SiNa 387.1962;
found 387.1950.
(1S,4aS,5R,6R,8aR)-5-(Methoxycarbonyl)-1,4a,6-trimethyl-8-oxo-5-(trimethylsilyl)oxydecahydronaphthalene-
1-carboxylic acid (27). KMnO4 (4.6 mg, 29.1
µmol) was added to a solution of NaIO4 (270 mg, 1.26
mmol) in H2O (7.0 mL), and the mixture was stirred for 30 min. To the mixture was added K2CO3 (23.0

Molecules 2020, 25, 1610
10 of 22
mg, 0.166 mmol), followed by a solution of enone 26 (50.3 mg, 0.138 mmol) in t-BuOH (1.4 mL plus 2
1 mL rinse). After 24 h of stirring, the reaction was quenched with NaHSO3 (507 mg, 4.87 mmol), and
the resulting mixture was extracted with AcOEt (3 20 mL). The combined organic extracts were
washed with brine (2 15 mL), and dried over anhydrous Na2SO4. Filtration and evaporation in
vacuo furnished the crude product (70.9 mg), which was used without further purification.
Activated carbon (708 mg) was added to an ice-cooled (0 ◦C) solution of the crude
-ketocarboxylic
×
×
×
α
acid 28 (70.9 mg) in AcOEt (14 mL). After 63 h of stirring at room temperature, the resulting suspension
was filtered through a Celite pad, and the filtrate was evaporated in vacuo. Purification of the
crude product (74.7 mg) by column chromatography (silica gel 5.2 g, 7:1 n-hexane/AcOEt) gave
γ
-ketocarboxylic acid 27 (28.3 mg, 53%) as an amorphous solid. Rf 0.60 (1:1 n-hexane/AcOEt); [α]D21
+
62.5 (c 1.01, CHCl3); IR (neat) 2953, 1732, 1717, 1674, 1456, 1252, 1182, 1153, 1090, 843 cm−1; 1H-NMR
(500 MHz, CDCl3) δ 0.24 (s, 9H, Si(CH3)3), 0.82 (dt, J = 3.5, 13.4 Hz, 1H, one of C3-H2), 0.88 (d, J = 6.4
Hz, 3H, C8-CH3), 0.97 (s, 3H, C10-CH3), 1.04 (d, J = 13.2 Hz, 1H, one of C1-H2), 1.29 (s, 3H, C4-CH3),
1.51 (m, 1H, one of C2-H2), 1.85 (m, 1H, one of C2-H2), 1.92 (dt, J = 4.3, 13.2 Hz, 1H, one of C1-H2), 2.26
(d, J = 13.4 Hz, 1H, one of C3-H2), 2.30 (dd, J = 4.3, 13.0 Hz, 1H, one of C7-H2), 2.51 (t, J = 13.0 Hz, 1H,
one of C7-H2), 2.72 (ddq, J = 4.3, 13.0, 6.4 Hz, 1H, C8-H), 3.13 (s, 1H, C5-H), 3.75 (s, 3H, CO2CH3), 12.62
(br s, 1H, CO2H); 13C-NMR (125.7 MHz, CDCl3)
δ 2.8 (CH3), 17.3 (CH3), 17.5 (CH3), 18.4 (CH2), 28.0
(CH3), 32.7 (CH2), 37.0 (CH), 38.7 (CH2), 43.6 (C), 46.4 (CH2), 49.6 (C), 52.0 (CH3), 60.3 (CH), 86.1 (C),
171.9 (C), 176.0 (C), 218.8 (C); HRMS (ESI) m/z [M + Na]+ calcd for C19H32O6SiNa 407.1860; found
407.1847.
Methyl (1S,4R,6R,7R,8S,12R)-1,6,8-trimethyl-2-oxo-7-(trimethylsilyl)oxy-3-oxatricyclo[6.3.1.04,12]dodecane
-7-carboxylate (23). A solution of γ-ketocarboxylic acid 27 (38.6 mg, 0.10 mmol) in EtOH (0.25 mL plus 2
×
0.25 mL rinse) was added to an ice-cooled (0 ◦C) solution of NaBH4 (4.3 mg, 0.11 mmol) in EtOH (0.5
mL). After 30 min of stirring at 0 ◦C, NaBH4 (3.7 mg, 0.098 mmol) was added, and the mixture was
stirred at 0 ◦C for another 30 min. The reaction was quenched with saturated aqueous NH4Cl (5 mL),
and the resulting mixture was partitioned between AcOEt (10 mL) and H2O (3 mL). The aqueous layer
was extracted with AcOEt (5
(10 mL), and dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude
×
10 mL), and the combined organic extracts were washed with brine
product (42.7 mg), which was used without further purification.
◦
Ethyl chloroformate (50
µL, 0.523 mmol) was added to an ice-cooled (0 C) mixture of crude
γ
-hydroxycarboxylic acid (42.7 mg) and Et3N (0.10 mL, 0.717 mmol) in CH2Cl2 (1.7 mL), and the
mixture was stirred for 30 min. The reaction was quenched with saturated aqueous NaHCO3 (5 mL),
and the mixture was partitioned between n-hexane/AcOEt (10:1, 22 mL) and H2O (5 mL). The aqueous
layer was extracted with n-hexane/AcOEt (10:1, 22 mL), and the combined organic extracts were
washed with brine (20 mL) and dried over anhydrous Na2SO4. Filtration and evaporation in vacuo
followed by column chromatography (silica gel 2.5 g, 9:1 n-hexane/AcOEt) afforded lactone 23 (32.6
mg, 88% for two steps) as a colorless oil. Rf 0.44 (4:1 n-hexane/AcOEt); [α]2D2 + 24.6 (c 1.07, CHCl3); IR
(neat) 2953, 1771, 1732, 1456, 1250, 1180, 1142, 1105, 1053, 841 cm−1; 1H-NMR (500 MHz, CDCl3)
(s, 9H, Si(CH3)3), 0.79 (d, J = 6.4 Hz, 3H, C8-CH3), 0.85 (dt, J = 13.0, 8.5 Hz, 1H, one of C1-H2), 1.10 (s,
3H, C10-CH3), 1.30 (s, 3H, C4-CH3), 1.42 1.56 (m, 3H, one of C2-H2, one of C3-H2, one of C7-H2), 1.69
(m, 1H, one of C2-H2), 1.77 (dd, J = 11.5, 13.0 Hz, 1H, one of C1-H2), 2.10 2.16 (m, 2H, one of C3-H2,
C5-H), 2.22 (dd, J = 6.0, 16.2 Hz, 1H, one of C7-H2), 2.56 (m, 1H, C8-H), 3.73 (s, 3H, CO2CH3), 4.68
(br t, J = 5.3 Hz, 1H, C6-H); 13C-NMR (125.7 MHz, acetone-d6)
2.6 (CH3), 18.38 (CH3), 18.40 (CH2),
δ 0.15
−
−
δ
22.3 (CH3), 23.4 (CH3), 29.0 (CH2), 29.4 (CH2), 30.6 (CH), 31.9 (CH2), 40.4 (C), 44.1 (C), 45.6 (CH), 52.0
(CH3), 76.0 (CH), 86.1 (C), 173.6 (C), 183.2 (C); HRMS (ESI) m/z [M + Na]+ calcd for C19H32O5SiNa
391.1911; found 391.1917.
Methyl
(1S,4R,6R,7R,8S,12R)-7-hydroxy-1,6,8-trimethyl-2-oxo-3-oxatricyclo[6.3.1.04,12]dodecane-7-
carboxylate (29). Bu4NF in THF (1.0 M, 2.0 mL, 2.0 mmol) was added to an ice-cooled (0 ◦C) solution
of TMS ether 23 (488 mg, 1.32 mmol) in THF (14 mL). After 1 h of stirring at 0 ◦C, the mixture was

Molecules 2020, 25, 1610
11 of 22
partitioned between AcOEt (40 mL) and H2O (15 mL), and the aqueous layer was extracted with
AcOEt (40 mL). The combined organic extracts were washed with brine (2 20 mL) and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude product (634 mg),
×
which was purified by column chromatography (silica gel 10 g, 10:1
→
3:1 n-hexane/AcOEt) to gi◦ve
α
-hydroxyester 29 (383 mg, 98%) as a white solid. Rf 0.45 (2:1 n-hexane/AcOEt); mp 142 143 C
−
(colorless needles from n-hexane); [α]2D1 + 25.0 (c 1.04, CHCl3); IR (KBr) 3455, 2959, 1761, 1732, 1466,
1375, 1236, 1144, 1098, 1045, 932 cm−1; 1H-NMR (500 MHz, CDCl3)
0.78 (d, J = 6.4 Hz, 3H, C8-CH3),
0.87 (dt, J = 13.0, 8.5 Hz, 1H, one of C1-H2), 1.22 (s, 3H, C10-CH3), 1.30 (s, 3H, C4-CH3), 1.44 1.71 (m,
δ
−
5H, one of C1-H2, C2-H2, one of C3-H2, one of C7-H2), 2.15 (dt, J = 4.5, 13.4 Hz, 1H, one of C3-H2), 2.28
(dd, J = 6.3, 16.4 Hz, 1H, one of C7-H2), 2.32 (d, J = 4.6 Hz, 1H, C5-H), 2.53 (ddq, J = 6.3, 11.7, 6.4 Hz,
1H, C8-H), 3.33 (s, 1H, C9-OH), 3.82 (s, 3H, CO2CH3), 4.74 (dd, J = 4.6, 6.8 Hz, 1H, C6-H); 13C-NMR
(125.7 MHz, CDCl3)
δ 16.4 (CH3), 17.6 (CH2), 21.6 (CH3), 23.0 (CH3), 27.9 (CH2), 28.1 (CH2), 29.0 (CH),
30.7 (CH2), 38.9 (C), 43.4 (C), 44.7 (CH), 52.8 (CH3), 75.9 (CH), 80.8 (C), 175.9 (C), 183.6 (C); HRMS (ESI)
m/z [M + Na]+ calcd for C16H24O5Na 319.1516; found 319.1519; Anal. Calcd for C16H24O5: C, 64.84; H,
8.16. Found: C, 64.82; H, 8.06.
(20R,2aS,5aS,6R,7R,8aR)-2a,5a,7-Trimethyloctahydrospiro[6H-naphtho[1,8-bc]furan-6,20-oxiran]-2(2aH)-one
(
22). Sodium bis(2-methoxyethoxy)aluminum hydride in toluene (3.3 M, 1.1 mL, 3.6 mmol) was
diluted with CH2Cl2 (5.6 mL), and the solution was cooled to -hydroxyester 29
78 ◦C. A solution of
(255 mg, 0.86 mmol) in CH2Cl2 (2 mL plus 2 0.5 mL rinse) was added, and the mixture was stirred at
23 ◦C for 22 h. The reaction was quenched by addition of MeOH (3 mL) followed by 10% aqueous
potassium sodium tartrate (12 mL). After 3 h of stirring, the resulting mixture was extracted with
AcOEt (2 40 mL), and the combined organic extracts were washed with brine (2 20 mL) and dried
−
α
×
−
×
×
over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude product (235 mg),
which was used without further purification.
This sequence was repeated employing bis(2-methoxyethoxy)aluminum hydride in toluene (3.3 M,
0.16 mL, 0.53 mmol) and CH2Cl2 (4 mL) with the reaction time of 16 h at
(216 mg) was used without further purification.
−
23 ◦C. The crude product
A solution of crude diol 31 (216 mg) in THF (2 mL plus 1 mL and 2
×
0.5 mL rinse) was added
dropwise to an ice-cooled (0 ◦C) suspension of NaH (60% in oil, 240 mg, 6.01 mmol) in THF (4.6 mL).
After 30 min of stirring at 0 ◦C, p-toluenesulfonyl imidazole (577 mg, 2.59 mmol) was added, and the
mixture was stirred at 0 ◦C for 11 h. The reaction was quenched with saturated aqueous NH4Cl (10
mL), and the resulting mixture was extracted with AcOEt (2
were washed with brine (2 20 mL), and dried over anhydrous Na2SO4. Filtration and evaporation in
vacuo furnished the crude product (563 mg), which was purified by column chromatography (silica
gel 15 g, 40:1 10:1 n-hexane/AcOEt) to give epoxide 22 (182 mg, 84% for three steps) as a white solid.
Rf 0.53 (2:1 n-hexane/AcOEt); mp 83
84 ◦C (colorless needles from 8:1 n-hexane/Et2O); [α]2D1 +13.7 (c
1.21, CHCl3); IR (KBr) 2941, 1761, 1464, 1393, 1354, 1209, 1105, 997 cm−1; 1H-NMR (500 MHz, CDCl3)
0.76 (d, J = 6.6 Hz, 3H, C8-CH3), 0.97 (dt, J = 12.4, 8.5 Hz, 1H, one of C1-H2), 1.24 (s, 3H, C10-CH3), 1.30
(s, 3H, C4-CH3), 1.35 (dd, J = 10.1, 12.4 Hz, 1H, one of C1-H2), 1.45 1.51 (m, 2H, one of C2-H2, one of
×
40 mL). The combined organic extracts
×
→
−
δ
−
C3-H2), 1.66 (ddd, J = 4.7, 11.8, 16.0 Hz, 1H, one of C7-H2), 1.72 (m, 1H, one of C2-H2), 1.90 (d, J = 4.7
Hz, 1H, C5-H), 2.14 (dt, J = 5.4, 15.5 Hz, 1H, one of C3-H2), 2.37 (dd, J = 6.1, 16.0 Hz, 1H, one of C7-H2),
2.55 (ddq, J = 6.1, 11.8, 6.6 Hz, 1H, C8-H), 2.63 (d, J = 3.9 Hz, 1H, one of C11-H2), 2.71 (d, J = 3.9 Hz,
1H, one of C11-H2), 4.79 (br t, J = 4.7 Hz, 1H, C6-H); 13C-NMR (125.7 MHz, CDCl3) δ 15.0 (CH3), 17.3
(CH2), 22.4 (CH3), 24.9 (CH), 25.0 (CH3), 26.8 (CH2), 28.1 (C), 32.5 (CH2), 34.6 (C), 44.1 (C), 45.9 (CH2),
47.5 (CH), 63.7 (C), 76.0 (CH), 183.3 (C); HRMS (ESI) m/z [M + Na]+ calcd for C15H22O3Na 273.1461;
found 273.1469.
Marrubiin (
1
). To a cooled (
−
10 ◦C) suspension of CuBr
SMe2 (65.1 mg, 0.316 mmol) in Et2O (1.5 mL)
·
was added a 0.14 M solution of (3-furylmethyl)magnesium bromide (32) in Et2O (3.35 mL, 0.69 mmol)
[prepared from 3-(bromomethyl)furan (563 mg, 3.37 mmol) and magnesium (103 mg, 4.22 mmol) in

Molecules 2020, 25, 1610
12 of 22
Et2O (4 mL) at 0 ◦C], followed by addition of a solution of epoxide 22 (40.2 mg, 0.161 mmol) in Et2O
(0.5 mL plus 2 0.5 mL rinse). After 2 h, the reaction was quenched with saturated aqueous NH4Cl (5
mL), and the resulting mixture was extracted with AcOEt (3 10 mL). The combined organic extracts
were washed with brine (20 mL), and dried over anhydrous Na2SO4. Filtration and evaporation in
vacuo furnished the crude product (200 mg), which was chromatographed twice (silica gel 5 g, 20:1
10:1 n-hexane/AcOEt) to give marrubiin ( , 34.7 mg, 65%) and isomer 33 (4.7 mg, 9%) as white solids.
Rf 0.59 (1:1 n-hexane/AcOEt); mp 160
161 ◦C (colorless needles from 4:1 n-hexane/AcOEt) (lit. [38], mp
160 ◦C); [α]2D1 +34.4 (c 1.04, CHCl3) [lit. [38], [α]D20 +35.8 (c 3.1, CHCl3)]; IR (KBr) 3466, 2940, 2870, 1740,
1468, 1395, 1356, 1304, 1269, 1200, 1153, 1101, 1024, 984 cm−1; 1H-NMR (500 MHz, CDCl3)
0.97 (d, J =
6.4 Hz, 3H, C8-CH3), 1.07 (s, 3H, C10-CH3), 1.26 (s, 1H, C9-OH), 1.29 (s, 3H, C4-CH3), 1.32 (dt, J = 12.8,
8.5 Hz, 1H, one of C1-H2), 1.43 1.55 (m, 2H, one of C2-H2, one of C3-H2), 1.66 1.79 (m, 4H, one of
C1-H2, one of C2-H2, one of C7-H2, one of C11-H2), 1.90 (ddd, J = 7.2, 10.1, 14.4 Hz, 1H, one of C11-H2),
2.09 2.18 (m, 3H, one of C3-H2, one of C7-H2, C8-H), 2.23 (d, J = 4.6 Hz, 1H, C5-H), 2.48 2.58 (m, 2H,
C12-H2), 4.74 (br dd, J = 4.6, 6.5 Hz, 1H, C6-H), 6.27 (s, 1H, C14-H), 7.24 (s, 1H, C16-H), 7.37 (s, 1H,
C15-H); 13C-NMR (125.7 MHz, CDCl3)
16.6 (CH3), 18.2 (CH2), 21.0 (CH2), 22.3 (CH3), 22.9 (CH3),
×
×
→
1
−
δ
−
−
−
−
δ
28.3 (CH2), 28.6 (CH2), 31.5 (CH2), 32.4 (CH), 35.1 (CH2), 39.7 (C), 43.8 (C), 44.8 (CH), 75.8 (C), 76.2
(CH), 110.7 (CH), 125.0 (C), 138.6 (CH), 143.1 (CH), 183.8 (C); HRMS (ESI) m/z [M + Na]+ calcd for
C20H28O4Na 355.1880; found 355.1867.
Data for (1S,4R,6R,7R,8S,12R)-7-[(3-methylfuran-2-yl)methyl]-7-hydroxy-1,6,8-trimethyl-2-oxo-3-
oxatricyclo[6.3.1.04,12]dodecane (33): Rf 0.27 (3:1 n-hexane/AcOEt); mp 173 174 ◦C (colorless needles
−
from 3:1 n-hexane/AcOEt); [α]2D2 +12.0 (c 0.38, CHCl3); IR (KBr) 3453, 2955, 2928, 2874, 1738, 1456, 1393,
1352, 1300, 1279, 1198, 1152, 1138, 999, 982 cm−1; 1H-NMR (500 MHz, CDCl3)
0.85 (d, J = 6.4 Hz, 3H,
C8-CH3), 1.07 (s, 3H, C10-CH3), 1.15 (m, 1H, one of C1-H2), 1.28 (s, 3H, C4-CH3), 1.41 1.52 (m, 2H,
one of C1-H2, one of C2-H2), 1.66 1.74 (m, 3H, one of C2-H2, one of C3-H2, one of C7-H2), 1.98 (s, 3H,
C13-CH3), 2.06 2.21 (m, 3H, one of C3-H2, one of C7-H2, C8-H), 2.28 (d, J = 4.7 Hz, 1H, C5-H), 2.33 (s,
δ
−
−
−
1H, C9-OH), 2.78 (d, J = 15.5 Hz, 1H, one of C11-H2), 2.88 (d, J = 15.5 Hz, 1H, one of C11-H2), 4.73 (ddd,
J = 1.4, 4.7, 6.1 Hz, 1H, C6-H), 6.19 (d, J = 1.8 Hz, 1H, C14-H), 7.28 (d, J = 1.8 Hz, 1H, C15-H); 13C-NMR
(125.7 MHz, CDCl3)
δ 10.3 (CH3), 16.3 (CH3), 18.3 (CH2), 22.2 (CH3), 22.9 (CH3), 28.23 (CH2), 28.24
(CH2), 30.6 (CH2), 31.93 (CH), 31.94 (CH2), 39.6 (C), 43.8 (C), 44.6 (CH), 76.2 (CH), 76.9 (C), 113.3 (CH),
116.4 (C), 140.5 (CH), 148.0 (C), 183.9 (C); HRMS (ESI) m/z [M + Na]+ calcd for C20H28O4Na 355.1880;
found 355.1871.
(1S,4R,6R,7R,8S,12R)-7-[2-[2-(Trimethylsilyl)furan-3-yl]ethyl]]-7-hydroxy-1,6,8-trimethyl-2-oxo-3-oxatricyclo
[6.3.1.04,12]dodecane (35). Phosphorus tribromide (0.28 mL, 2.98 mmol) was added to an ice-cooled
(0 ◦C) solution of [2-(trimethylsilyl)furan-3-yl]methanol (998 mg, 5.86 mmol) in Et2O (30 mL). After
30 min of stirring, the reaction was quenched with brine (30 mL), and the resulting mixture was
extracted with Et2O (30 mL). The organic extract was dried over anhydrous Na2SO4. Filtration
and evaporation in vacuo furnished the pale brown oil, which was purified by distillation to give
3-(bromomethyl)-2-(trimethylsilyl)furan (618 mg, 45%) as a pale brown oil.
A solution of 3-(bromomethyl)-2-(trimethylsilyl)furan (584 mg, 2.50 mmol) in Et2O (1
mL) was added to a cooled (
10 ◦C) suspension of magnesium tuning (102 mg, 4.20 mmol)
−
in Et2O (1 mL), and the reaction mixture was stirred for 1.5 h. The 0.23 M solution of
[2-(trimethylsilyl)furan-3-yl]methylmagnesium bromide (34) in Et2O (1.5 mL, 0.345 mmol) thus
obtained was added to a cooled (
mL), followed by addition of a solution of epoxide 22 (42.6 mg, 0.170 mmol) in Et2O (1.0 mL). After 4 h
−
10 ◦C) suspension of CuBr
SMe2 (69.6 mg, 0.339 mmol) in Et2O (0.6
·
of stirring, the reaction was quenched with saturated aqueous NH4Cl (3 mL), and the resulting mixture
was extracted with AcOEt (3
mL), and dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the pale brown
oil (206 mg), which was purified by flash column chromatography (silica gel 4 g, n-hexane 40:1
20:1 5:1 n-hexane/AcOEt) to give silylated marrubiin 35 (52.0 mg, 76%) as a colorless solid. Rf 0.32
(3:1 n-hexane/AcOEt); [α]2D4 +29.3 (c 2.05, acetone); IR (neat) 3479, 3417, 2954, 2870, 1749, 1633, 1568,
×
10 mL). The combined organic extracts were washed with brine (10
→
→
→

Molecules 2020, 25, 1610
13 of 22
1464, 1387, 1248, 1197, 1149, 1089, 1045, 1020, 991, 914, 840 cm−1; 1H-NMR (500 MHz, CDCl3)
δ
0.29 (s,
9H, Si(CH3)3), 0.99 (d, J = 6.5 Hz, 3H, C8-CH3), 1.06 (s, 3H, C10-CH3), 1.29 (s, 3H, C4-CH3), 1.30 (m,
1H, one of C1-H2), 1.45 (m, 1H, one of C3-H2), 1.52 (m, 1H, one of C2-H2), 1.68 1.75 (m, 4H, one of
C1-H2, one of C2-H2, one of C7-H2, one of C11-H2), 1.87 (ddd, J = 7.1, 10.3, 14.5 Hz, 1H, one of C11-H2),
2.09 2.19 (m, 3H, one of C3-H2, one of C7-H2, C8-H), 2.23 (d, J = 4.6 Hz, 1H, C5-H), 2.56 2.75 (m, 2H,
−
−
−
C12-H2), 4.74 (dd, J = 4.6, 6.3 Hz, 1H, C6-H), 6.27 (d, J = 1.2 Hz, 1H, C14-H), 7.55 (d, J = 1.2 Hz, 1H,
C15-H); 13C-NMR (125.7 MHz, CDCl3) δ −0.9 (CH3), 16.6 (CH3), 18.2 (CH2), 21.7 (CH2), 22.3 (CH3),
22.9 (CH3), 28.3 (CH2), 28.7 (CH2), 31.5 (CH2), 32.4 (CH), 36.2 (CH2), 39.7 (C), 43.8 (C), 44.9 (CH), 75.8
(C), 76.2 (CH), 110.7 (CH), 135.0 (C), 146.4 (CH), 154.3 (C), 183.9 (C); HRMS (ESI) m/z [M + Na]+ calcd
for C23H36O4SiNa 427.2275; found 427.2259.
Marrubiin (
1). Bu4NF in THF (1.0 M, 20
µL, 20 µmol) was added to a solution of silylated marrubiin 35
(0.7 mg, 1.7
µmol) in THF (0.2 mL). After 4 h of stirring, the mixture was partitioned between AcOEt (8
mL) and H2O (8 mL), and the aqueous layer was extracted with AcOEt (8 mL). The combined organic
extracts were washed with brine (8 mL) and dried over anhydrous Na2SO4. Filtration and evaporation
in vacuo furnished the colorless oil (0.5 mg), which was purified by column chromatography (silica gel
1 g, 4:1 → 1:1 n-hexane/AcOEt) to give marrubiin (1, 0.4 mg, 70%) as a white solid.
(1S,4R,6R,7R,8S,12R)-7-[2-(2,5-Diethoxy-2,5-dihydrofuran-3-yl)ethyl]-7-hydroxy-1,6,8-trimethyl-2-oxo-3-oxa
tricyclo[6.3.1.04,12]dodecane (36). Pyridinium tribromide (11.0 mg, 34
µ
mol) was added to an ice-cooled
◦
(0 C) solution of marrubiin (
1
, 10.4 mg, 31
µmol) in CH2Cl2/EtOH (1:1, 0.6 mL). After 10 min of
stirring, the reaction was quenched with a mixture of saturated aqueous NaHCO3 (3 mL) and 1 M
aqueous Na2S2O3 (2 mL), and the resulting mixture was extracted with AcOEt (2 20 mL). The
×
combined organic extracts were washed with brine (30 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the crude product (14.7 mg), which was purified by
column chromatography (silica gel 2.5 g, 3:1
→
1:1 n-hexane/AcOEt) to give bisacetals 36 (10.4 mg,
79%, dr = 2:2:1:1) as a colorless oil. Rf 0.58 (2:3 n-hexane/AcOEt); [α]2D3 +33.9 (c 1.19, CHCl3); IR (neat)
3516, 2972, 2930, 1767, 1755, 1458, 1373, 1346, 1198, 1101, 1045, 1018, 984 cm−1; 1H-NMR (500 MHz,
CDCl3)
1.66 1.77 (m, 4H), 1.86 (m, 1H, one of CH2), 2.05
(m, 1H, C6-H), 5.48 (s, 0.65H, C15-H), 5.60 (s, 0.65H, C16-H), 5.67 (s, 1H, C14-H), 5.75 (br d, J = 3.6
Hz, 0.35H, C16-H), 5.85 (br d, J = 3.6 Hz, 0.35H, C15-H); 13C-NMR (125.7 MHz, CDCl3)
15.3 (CH3),
δ
0.92 (d, J = 6.3 Hz, 3H, C8-CH3), 1.05 (s, 3H, C10-CH3), 1.21
−
1.34 (m, 11H), 1.43
−
1.56 (m, 2H),
−
−
2.32 (m, 6H), 3.53
−
3.82 (m, 4H, 2 OCH2CH3), 4.74
×
δ
15.4 (CH3), 16.50 (CH3), 16.51 (CH3), 16.54 (CH3), 18.09 (CH2), 18.12 (CH2), 22.22 (CH3), 22.23 (CH3),
22.26 (CH3), 22.28 (CH3), 22.31 (CH2), 22.4 (CH2), 22.49 (CH2), 22.52 (CH2), 22.87 (CH3), 22.89 (CH3),
22.96 (CH3), 22.97 (CH3), 28.27 (CH2), 28.28 (CH2), 28.59 (CH2), 28.61 (CH2), 28.63 (CH2), 31.4 (CH2),
31.46 (CH2), 31.47 (CH2), 32.0 (CH2), 32.11 (CH2), 32.15 (CH), 32.22 (CH), 32.29 (CH2), 32.33 (CH2),
32.5 (CH), 39.69 (C), 39.70 (C), 39.71 (C), 39.73 (C), 43.71 (C), 43.72 (C), 43.76 (C), 44.7 (CH), 44.8 (CH),
62.3 (CH2), 62.61 (CH2), 62.62 (CH2), 62.8 (CH2), 63.1 (CH2), 63.41 (CH2), 63.42 (CH2), 63.5 (CH2),
75.37 (C), 75.388 (C), 75.394 (C), 76.06 (CH), 76.12 (CH), 76.13 (CH), 105.95 (CH), 105.97 (CH), 106.937
(CH), 106.943 (CH), 107.5 (CH), 107.6 (CH), 108.2 (CH), 108.3 (CH), 123.8 (CH), 124.0 (CH), 124.1 (CH),
124.3 (CH), 145.3 (C), 145.78 (C), 145.81 (C), 183.7 (C), 183.8 (C); HRMS (ESI) m/z [M + Na]+ calcd for
C24H38O6Na 445.2561; found 445.2550.
[1S,4R,6R,7R,7(2S,3S,4R,5R),8S,12R]-7-[2-(2,5-Diethoxy-3,4-dihydroxytetrahydrofuran-3-yl)ethyl]-7-hydroxy
-1,6,8-trimethyl-2-oxo-3-oxatricyclo[6.3.1.04,12]dodecane
(
38
12R]-7-[2-(2,5-diethoxy-3,4-dihydroxytetrahydrofuran-3-yl)ethyl]-7-hydroxy-1,6,8-trimethyl-2-oxo-3-oxatri
cyclo[6.3.1.04,12]dodecane (39). A 0.157 M solution of OsO4 in t-BuOH (0.06 mL, 9.4
mol) was added to a
solution of bisacetals 36 (21.7 mg, 51 mol) and NMO (4.8 M in H2O, 0.04 mL, 0.19 mmol) in THF/H2O
(10:1, 0.55 mL). After 1 h of stirring, the reaction was quenched with 1 M aqueous Na2S2O3 (5 mL), and
the resulting mixture was extracted with AcOEt (2 15 mL). The combined organic extracts were
)
and [1S,4R,6R,7R,7(2R,3R,4S,5S),8S,
µ
µ
×
washed with brine (15 mL), and dried over anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product (29.1 mg), which was purified by flash column chromatography (silica gel

Molecules 2020, 25, 1610
14 of 22
2.3 g, 1:1 n-hexane/AcOEt) to give a 1:1 mixture of triols 38 and 39 (14.3 mg, 61%) as a colorless oil,
along with recovered bisacetals 36 (8.2 mg, 38%) as a colorless oil. Rf 0.49 (1:4 n-hexane/AcOEt); [α]D21
+29.1 (c 0.56, CHCl3); IR (neat) 3462, 2930, 1751, 1458, 1389, 1375, 1101, 978 cm−1; 1H-NMR (500 MHz,
CDCl3)
1.207 (t, J = 7.1 Hz, 1.5H, OCH2CH3), 1.214 (t, J = 7.1 Hz, 1.5H, OCH2CH3), 1.23 (t, J = 7.1 Hz, 3H,
OCH2CH3), 1.29 (s, 3H, C4-CH3), 1.42 1.52 (m, 2H, CH2), 1.60 1.97 (m, 8H, 4 CH2), 2.03 2.15 (m,
3.5H, CH2, C8-H, OH), 2.24 (d, J = 4.7 Hz, 1H, C5-H), 2.33 (br s, 0.5H, OH), 2.99 (d, J = 6.9 Hz, 0.5H,
OH), 3.05 (m, 1H, OH), 3.44 3.57 (m, 2.5H, OCH2CH3, OH), 3.76 3.84 (m, 2H, OCH2CH3), 3.96 (m, 1H,
C14-H), 4.73 (br s, 1H, C6-H), 4.85 (s, 0.5H, C16-H), 4.86 (s, 0.5H, C16-H), 4.97 (d, J = 4.3 Hz, 0.5H,
C15-H), 4.98 (d, J = 4.3 Hz, 0.5H, C15-H); 13C-NMR (125.7 MHz, CDCl3)
14.88 (CH3), 14.93 (CH3),
δ 0.91 (d, J = 6.5 Hz, 1.5H, C8-CH3), 0.92 (d, J = 6.4 Hz, 1.5H, C8-CH3), 1.04 (s, 3H, C10-CH3),
−
−
×
−
−
−
δ
15.2 (CH3), 16.5 (CH3), 16.8 (CH3), 18.1 (CH2), 22.2 (CH3), 22.3 (CH3), 22.85 (CH3), 22.93 (CH3), 27.4
(CH2), 28.1 (CH2), 28.27 (CH2), 28.28 (CH2), 28.31 (CH2), 28.4 (CH2), 28.5 (CH2), 28.6 (CH2), 31.5 (CH2),
31.6 (CH2), 32.47 (CH), 32.49 (CH), 39.97 (C), 40.03 (C), 43.88 (C), 43.91 (C), 44.90 (CH), 44.93 (CH),
63.07 (CH2), 63.10 (CH2), 64.55 (CH2), 64.57 (CH2), 75.30 (C), 75.33 (C), 76.3 (CH), 76.4 (CH), 80.3 (CH),
80.4 (CH), 81.2 (C), 81.3 (C), 106.5 (CH), 106.7 (CH), 109.17 (CH), 109.19 (CH), 184.10 (C), 184.12 (C);
HRMS (ESI) m/z [M + Na]+ calcd for C24H40O8Na 479.2615; found 479.2631.
Marrulibacetal (13). TsOH (2.9 mg, 17
mol) in benzene (1 mL), and the mixture was stirred for 1.5 h. The reaction was quenched with
saturated aqueous NaHCO3 (5 mL), and the resulting mixture was extracted with AcOEt (2 15 mL).
µmol) was added to a mixture of triols 38 and 39 (12.5 mg, 27
µ
×
The combined organic extracts were washed with brine (15 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the crude product (19.2 mg), which was purified by flash
column chromatography (silica gel 2 g, 2:1 n-hexane/AcOEt) to give a mixture of marrulibacetal (13
)
and its diastereomers. The mixture was flash chromatographed (silica gel 4.5 g, 30:1 CHCl3/ acetone)
to provide a mixture of marrulibacetal (13) and C13,14,15,16-epimer 41, along with a 1:1 mixture of
C15-epimer and C13,14,16-epimer (2.0 mg, 18%). Separation of marrulibacetal (13) and 41 by flash
column chromatography (silica gel 4.5 g, 50:1 CHCl3/acetone) yielded marrulibacetal (13, 4.1 mg, 36%)
and C13,14,15,16-epimer 41 (4.3 mg, 38%) as white solids. Rf 0.44 (4:1 CH2Cl2/acetone); mp 177
◦C (colorless needles from n-hexane/benzene); [α]2D7 21.7 (c 1.16, CHCl3) [lit. [12], [α]2D5
13.1 (c 0.29,
CHCl3)]; IR (neat) 3435, 2961, 2928, 1773, 1740, 1458, 1389, 1244, 1200, 1111, 1053, 935 cm−1; 1H-NMR
(500 MHz, CDCl3) 1.03 (s, 3H, C10-CH3), 1.11 (d, J = 6.8 Hz, 3H, C8-CH3), 1.19 (m, 1H, one of C1-H2),
1.22 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.28 (s, 3H, C4-CH3), 1.42 (m, 1H, one of C3-H2), 1.49 (m, 1H, one of
C2-H2), 1.71 1.78 (m, 2H, one of C2-H2, one of C11-H2), 1.80 1.90 (m, 3H, one of C7-H2, one of C11-H2,
one of C12-H2), 1.98 (m, 1H, one of C1-H2), 2.05 2.20 (m, 4H, one of C3-H2, one of C7-H2, C8-H, one of
−
179
−
−
δ
−
−
−
C12-H2), 2.36 (d, J = 4.7 Hz, 1H, C5-H), 2.60 (s, 1H, C13-OH), 2.61 (d, J = 6.2 Hz, 1H, C14-OH), 3.51 (dq,
J = 9.5, 7.1 Hz, 1H, one of OCH2CH3), 3.82 (dq, J = 9.5, 7.1 Hz, 1H, one of OCH2CH3), 3.95 (dd, J = 2.0,
6.2 Hz, 1H, C14-H), 4.77 (br dd, J = 4.7, 5.9 Hz, 1H, C6-H), 5.04 (d, J = 2.0 Hz, 1H, C15-H), 5.46 (s, 1H,
C16-H); 13C-NMR (125.7 MHz, CDCl3)
δ 15.0 (CH3), 17.9 (CH2), 19.5 (CH3), 21.1 (CH2), 22.1 (CH3),
23.1 (CH3), 27.8 (CH2), 28.2 (CH2), 29.6 (CH2), 32.3 (CH2), 33.6 (CH), 40.9 (C), 43.9 (C), 44.6 (CH), 63.9
(CH2), 75.6 (C), 76.5 (CH), 78.5 (CH), 80.4 (C), 105.3 (CH), 108.7 (CH), 184.0 (C); HRMS (EI) m/z [M+]
calcd for C22H34O7 410.2305; found 410.2300.
Data for (2S,20aS,3S,3aR,50aS,6R,70R,7aR,80aR,80bR)-2-ethoxy-3,3a-dihydroxy-20a,50a,70-trimethylt
etradecahydrospiro[6H-furo[2,3-b]pyran-6,60-[6H]naphtho[1,8-bc]furan]-20(20aH)-one (41). Rf 0.56 (4:1
CH2Cl2/acetone); [α]2D8 +57.2 (c 1.26, CHCl3); IR (KBr) 3458, 2930, 1771, 1749, 1466, 1389, 1260, 1198,
1153, 1094, 1063, 1040, 989, 941 cm−1; 1H-NMR (500 MHz, CDCl3)
δ
0.96 (d, J = 6.1 Hz, 3H, C8-CH3),
1.01 (s, 3H, C10-CH3), 1.21 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.30 (s, 3H, C4-CH3), 1.39 1.54 (m, 4H, one of
C1-H2, one of C2-H2, one of C3-H2, one of C11-H2), 1.70 1.83 (m, 4H, one of C1-H2, one of C2-H2, one
of C7-H2, one of C12-H2), 1.95 2.11 (m, 4H, one of C3-H2, one of C7-H2, C8-H, one of C11-H2), 2.20
−
−
−
(m, 1H, one of C12-H2), 2.34 (d, J = 4.5 Hz, 1H, C5-H), 2.75 (d, J = 4.8 Hz, 1H, C14-OH), 2.79 (s, 1H,
C13-OH), 3.46 (dq, J = 9.5, 7.1 Hz, 1H, one of OCH2CH3), 3.74 (d, J = 4.8 Hz, 1H, C14-H), 3.86 (dq, J =
9.5, 7.1 Hz, 1H, one of OCH2CH3), 4.78 (br dd, J = 4.5, 7.7 Hz, 1H, C6-H), 5.01 (s, 1H, C15-H), 5.50 (s,

Molecules 2020, 25, 1610
15 of 22
1H, C16-H); 13C-NMR (125.7 MHz, CDCl3)
δ
14.8 (CH3), 16.1 (CH3), 18.1 (CH2), 21.5 (CH2), 23.2 (CH3),
23.9 (CH3), 28.3 (CH2), 30.4 (CH2), 30.9 (CH2), 31.3 (CH2), 35.0 (CH), 40.8 (C), 43.9 (C), 45.5 (CH), 63.7
(CH2), 75.9 (C), 76.7 (CH), 80.0 (CH), 80.5 (C), 106.1 (CH), 108.2 (CH), 183.9 (C); HRMS (EI) m/z [M+]
calcd for C22H34O7 410.2305; found 410.2297.
[1S,4R,6R,7R,7(2S,3S,4R,5R),8S,12R]-7-[2-(3,4-Dihydroxy-2,5-dimethoxytetrahydrofuran-3-yl)ethyl]-7-hydro
xy-1,6,8-trimethyl-2-oxo-3-oxatricyclo[6.3.1.04,12]dodecane (40) and desertine (18). Pyridinium tribromide
(32.9 mg, 0.102 mmol) was added to an ice-cooled (0 ◦C) solution of marrubiin (
1
, 30.5 mg, 91.7
in CH2Cl2/MeOH (1:1, 1.8 mL). After 20 min of stirring, the reaction was quenched with saturated
aqueous NaHCO3 (5 mL), and the resulting mixture was extracted with AcOEt (2 15 mL). The
combined organic extracts were washed with brine (2 10 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the yellow oil (53.1 mg), which was purified by column
µmol)
×
×
chromatography (silica gel 3 g, 4:1
= 2:2:1:1) as a yellow oil.
→
2:1
→
1:1 n-hexane/AcOEt) to give bisacetals 37 (33.1 mg, 91%, dr
A 0.157 M solution of OsO4 in t-BuOH (0.08 mL, 12.5
37 (28.3 mg, 71.7 mol) and NMO (4.8 M in H2O, 0.06 mL, 0.29 mmol) in THF/H2O (1:1, 0.8 mL). After
1 h of stirring, the reaction was quenched with 1 M aqueous Na2S2O3 (5 mL), and the resulting mixture
was extracted with AcOEt (2 15 mL). The combined organic extracts were washed with brine (2 10
mL), and dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the brown oil
(40.7 mg), which was purified by column chromatography (silica gel 3.1 g, 2:1 1:1 n-hexane/AcOEt)
µmol) was added to a solution of bisacetals
µ
×
×
→
to give a 1:1 mixture of desertine (18) and its diastereomer 40 (20.2 mg, 66%) as a brown oil, along with
recovered bisacetals 37 (8.8 mg, 29%) as a colorless oil. Rf 0.30 (1:1 n-hexane/AcOEt); [α]2D0 +12.9 (c 1.02,
CHCl3); IR (neat) 3464, 2951, 1748, 1454, 1391, 1258, 1198, 1148, 1101, 1043, 989 cm−1; 1H-NMR (500
MHz, CDCl3)
(m, 1H, one of C1-H2), 1.29 (s, 3H, C4-CH3), 1.45 (m, 1H, one of C3-H2), 1.51 (m, 1H, one of C2-H2),
1.65 (m, 1H, one of C7-H2), 1.60 1.98 (m, 6H, one of C1-H2, one of C2-H2, C11-H2, C12-H2), 2.07 (m,
δ 0.91 (d, J = 6.5 Hz, 3H, C8-CH3), 1.04 (s, 1.5H, C10-CH3), 1.05 (s, 1.5H, C10-CH3), 1.28
−
1H, C8-H), 2.11 (m, 1H, one of C3-H2), 2.14 (m, 1H, one of C7-H2), 2.22 (d, J = 4.2 Hz, 0.5H, C5-H), 2.23
(d, J = 4.2 Hz, 0.5H, C5-H), 3.40 (s, 3H, C16-OCH3), 3.47 (s, 3H, C15-OCH3), 3.92 (d, J = 3.5 Hz, 0.5H,
C14-H), 3.95 (d, J = 3.5 Hz, 0.5H, C14-H), 4.73 (m, 1H, C6-H), 4.76 (s, 0.5H, C16-H), 4.77 (s, 0.5H, C16-H),
4.89 (d, J = 3.5 Hz, 0.5H, C15-H), 4.90 (d, J = 3.5 Hz, 0.5H, C15-H); 13C-NMR (125.7 MHz, CDCl3)
δ 16.4
(CH3), 16.8 (CH3), 18.1 (CH2), 22.2 (CH3), 22.3 (CH3), 22.86 (CH3), 22.94 (CH3), 27.4 (CH2), 28.0 (CH2),
28.2 (CH2), 28.26 (CH2), 28.28 (CH2), 28.41 (CH2), 28.43 (CH2), 28.5 (CH2), 31.5 (CH2), 31.6 (CH2), 32.5
(CH), 32.6 (CH), 40.0 (C), 40.1 (C), 43.87 (C), 43.91 (C), 44.9 (CH), 45.0 (CH), 55.08 (CH3), 55.11 (CH3),
56.40 (CH3), 56.42 (CH3), 75.3 (C), 75.4 (C), 76.2 (CH), 76.3 (CH), 80.2 (CH), 80.3 (CH), 81.2 (C), 81.4 (C),
108.3 (CH), 108.6 (CH), 110.7 (CH), 110.8 (CH), 183.95 (C), 183.99 (C); HRMS (ESI) m/z [M + Na]+ calcd
for C22H36O8Na 451.2302; found 451.2308.
Marrulibacetal A (17). TsOH (8.6 mg, 50
diastereomer 40 (29.6 mg, 69.0 mol) in benzene (1.4 mL). After 5 h of stirring, an additional portion
of TsOH (1.6 mg, 9.3 mol) was added, and the reaction mixture was stirred for 3.5 h. The reaction
was quenched with saturated aqueous NaHCO3 (2 mL), and the resulting mixture was extracted with
AcOEt (3 5 mL). The combined organic extracts were washed with brine (5 mL), and dried over
µmol) was added to a mixture of desertine (18) and its
µ
µ
×
anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the brown oil (68.1 mg), which was
purified by flash column chromatography (silica gel 5 g, 1:1 n-hexane/AcOEt) to give marrulibacetal
A (17, 4.3 mg, 16%) and C13,14,15,16-isomer 42 (6.2 mg, 23%) as colorless amorphous solids. Rf 0.73
(AcOEt); [α]2D1
1198, 1117, 1053, 1015, 989, 935 cm−1; 1H-NMR (500 MHz, CDCl3)
= 7.0 Hz, 3H, C8-CH3), 1.19 (m, 1H, one of C1-H2), 1.28 (s, 3H, C4-CH3), 1.42 (m, 1H, one of C3-H2),
1.49 (m, 1H, one of C2-H2), 1.71 1.92 (m, 5H, one of C2-H2, one of C7-H2, C11-H2, one of C12-H2),
1.96 (t, J = 10.6 Hz, 1H, one of C1-H2), 2.05 2.15 (m, 3H, one of C3-H2, C8-H, one of C12-H2), 2.20
(dd, J = 5.5, 16.0 Hz, 1H, one of C7-H2), 2.38 (d, J = 4.5 Hz, 1H, C5-H), 3.42 (s, 3H, OCH3), 3.89 (d, J =
−
14.0 (c 1.69, CHCl3) (lit. [14], [α]D25
−
10.77); IR (neat) 2953, 2928, 1769, 1748, 1456, 1259,
1.03 (s, 3H, C10-CH3), 1.11 (d, J
δ
−
−

Molecules 2020, 25, 1610
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1.2 Hz, 1H, C14-H), 4.79 (dd, J = 4.5, 6.3 Hz, 1H, C6-H), 4.93 (d, J = 1.2 Hz, 1H, C15-H), 5.48 (s, 1H,
C16-H); 13C-NMR (125.7 MHz, CDCl3)
17.9 (CH2), 19.4 (CH3), 20.7 (CH2), 22.0 (CH3), 23.1 (CH3),
δ
27.8 (CH2), 28.2 (CH2), 30.0 (CH2), 32.2 (CH2), 33.5 (CH), 40.9 (C), 43.9 (C), 44.6 (CH), 55.5 (CH3), 75.8
(C), 76.5 (CH), 78.6 (CH), 80.3 (C), 105.7 (CH), 109.8 (CH), 184.1 (C); HRMS (ESI) m/z [M + Na]+ calcd
for C21H32O7Na 419.2045; found 419.2037.
Data for (2S,20aS,3S,3aR,50aS,6R,70R,7aR,80aR,80bR)-3,3a-dihydroxy-2-methoxy-20a,50a,70-trimethyl
tetradecahydrospiro[6H-furo[2,3-b]pyran-6,60-[6H]naphtho[1,8-bc]furan]-20(20aH)-one (42): Rf 0.78
(AcOEt); [α]2D2 +49.1 (c 0.75, CHCl3); IR (neat) 2955, 2928, 1749, 1541, 1506, 1456, 1265 cm−1; 1H-NMR
(500 MHz, CDCl3)
1.42 1.56 (m, 4H, one of C1-H2, one of C2-H2, one of C3-H2, one of C11-H2), 1.70
of C1-H2, one of C2-H2, one of C7-H2, one of C12-H2), 1.98 (dt, J = 3.8, 14.2 Hz, 1H, one of C11-H2),
1.99 2.12 (m, 3H, one of C3-H2, one of C7-H2, C8-H), 2.17 (dt, J = 4.4, 14.2 Hz, 1H, one of C12-H2), 2.35
(d, J = 4.5 Hz, 1H, C5-H), 2.87 (br s, 1H, OH), 3.41 (s, 3H, OCH3), 3.73 (s, 1H, C14-H), 4.79 (dd, J = 4.5,
6.2 Hz, 1H, C6-H), 4.91 (s, 1H, C15-H), 5.52 (s, 1H, C16-H); 13C-NMR (125.7 MHz, CDCl3)
16.0 (CH3),
δ
0.94 (d, J = 6.1 Hz, 3H, C8-CH3), 1.01 (s, 3H, C10-CH3), 1.31 (s, 3H, C4-CH3),
−
−
1.83 (m, 4H, one
−
δ
18.1 (CH2), 21.4 (CH2), 23.1 (CH3), 24.0 (CH3), 28.3 (CH2), 30.6 (CH2), 30.9 (CH2), 31.3 (CH2), 35.0 (CH),
40.8 (C), 43.9 (C), 45.5 (CH), 55.2 (CH3), 76.1 (C), 76.7 (CH), 79.8 (CH), 80.5 (C), 106.3 (CH), 109.4 (CH),
184.1 (C); HRMS (ESI) m/z [M + Na]+ calcd for C21H32O7Na 419.2045; found 419.2059.
Marrubasch F (19). m-CPBA (ca. 70%, 10.7 mg, 43.4
dissolved in CH2Cl2 (0.2 mL). The m-CPBA solution was added to an ice-cooled (0 ◦C) solution of
silylated marrubiin 35 (8.1 mg, 20.0 mol) in CH2Cl2 (0.8 mL). After 1.5 h of stirring, the reaction was
µmol) was azeotropically dried with benzene, and
µ
quenched with a mixture of 1 M aqueous Na2S2O3 (2 mL) and saturated aqueous NaHCO3 (2 mL), and
the resulting mixture was extracted with AcOEt (10 mL). The organic extract was washed with brine (4
mL), and dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the colorless
oil (28.4 mg), which was purified by preparative thin layer chromatography (200 mm
mm preparative silica gel plate and elution with 1:1 n-hexane/AcOEt) to give marrubasch F (19, 3.9
mg, 56%) as a white solid. Rf 0.32 (1:1 n-hexane/AcOEt); mp 195
196 ◦C (pale yellow plates from 1:2
n-hexane/AcOEt) (lit. [20], mp 191 ]D + 41.5 (c 1.00,
193 ◦C); [α]D21 +41.1 (c 0.534, CHCl3) [lit. [20], [
CHCl3)]; IR (neat) 3536, 2926, 2873, 1747, 1456, 1199, 1139, 1095, 1076, 1041, 983 cm−1; 1H-NMR (500
MHz, CDCl3) 0.96 (d, J = 6.4 Hz, 3H, C8-CH3), 1.04 (s, 3H, C10-CH3), 1.25 (dt, J = 12.8, 8.5 Hz, 1H, one
of C1-H2), 1.30 (s, 3H, C4-CH3), 1.45 (dt, J = 14.4, 4.8 Hz, 1H, one of C3-H2), 1.53 (m, 1H, one of C2-H2),
1.69 1.84 (m, 5H, one of C1-H2, one of C2-H2, one of C7-H2, C11-H2), 2.05 2.17 (m, 3H, one of C3-H2,
one of C7-H2, C8-H), 2.28 (d, J = 4.5 Hz, 1H, C5-H), 2.41 2.52 (m, 2H, C12-H2), 4.75 (dd, J = 4.5, 6.5 Hz,
1H, C6-H), 4.80 (br d, J = 1.4 Hz, 2H, C15-H2), 7.14 (t, J = 1.4 Hz, 1H, C14-H); 13C-NMR (125.7 MHz,
CDCl3) 16.7 (CH3), 18.1 (CH2), 21.2 (CH2), 22.3 (CH3), 22.9 (CH3), 28.3 (CH2), 28.6 (CH2), 31.6 (CH2),
×
100 mm
×
0.25
−
−
α
δ
−
−
−
δ
32.4 (CH2), 32.6 (CH2), 39.9 (C), 43.8 (C), 44.9 (CH), 70.4 (CH2), 75.2 (C), 76.2 (CH), 134.7 (C), 144.3
(CH), 174.9 (C), 183.9 (C); HRMS (ESI) m/z [M + Na]+ calcd for C20H28O5Na 371.1830; found 371.1834.
(1S,4R,6R,7R,8S,12R)-7-Hydroxy-1,6,8-trimethyl-2-oxo-7-propargyl-3-oxatricyclo[6.3.1.04,12]dodecane (43).
Lithium acetylide ethylene diamine complex (36.5 mg, 0.397 mmol) was added to a solution of epoxide
22 (10.7 mg, 42.7
(1 mL), and the resulting mixture was extracted with AcOEt (3
were washed with brine (2 5 mL), and dried over anhydrous Na2SO4. Filtration and evaporation
µmol) in DMSO (0.2 mL). After 30 min of stirring, the reaction was quenched with H2O
×
5 mL). The combined organic extracts
×
in vacuo furnished the pale yellow solid (13.1 mg), which was purified by column chromatography
(silica gel 3 g, 2:1 n-hexane/AcOEt) to give alcohol 43 (11.2 mg, 95%) as a pale yellow solid. Rf 0.57 (1:1
n-hexane/AcOEt); mp 195
IR (neat) 3306, 3019, 2955, 2934, 2872, 1757, 1458, 1427, 1393, 1136, 1096, 1045, 1003 cm−1; 1H-NMR (500
MHz, CDCl3) 0.99 (d, J = 6.3 Hz, 3H, C8-CH3), 1.05 (s, 3H, C10-CH3), 1.25 (dt, J = 13.0, 9.0 Hz, 1H,
−
196 ◦C (colorless plates from n-hexane/Et2O); [α]D25 +29.9 (c 0.249, CHCl3);
δ
one of C1-H2), 1.30 (s, 3H, C4-CH3), 1.46 (dt, J = 14.7, 4.2 Hz, 1H, one of C3-H2), 1.53 (m, 1H, one of
C2-H2), 1.69 (ddd, J = 6.3, 13.3, 17.7 Hz, 1H, one of C7-H2), 1.76 (m, 1H, one of C2-H2), 1.85 (dd, J = 9.6,
11.6 Hz, 1H, one of C1-H2), 2.09 2.18 (m, 3H, one of C3-H2, one of C7-H2, C8-H), 2.19 (t, J = 2.7 Hz, 1H,
−

Molecules 2020, 25, 1610
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C13-H), 2.26 (d, J = 4.5 Hz, 1H, C5-H), 2.36 (dd, J = 2.7, 17.1 Hz, 1H, one of C11-H2), 2.59 (dd, J = 2.7,
17.1 Hz, 1H, one of C11-H2), 4.73 (dd, J = 4.5, 6.3 Hz, 1H, C6-H); 13C-NMR (125.7 MHz, CDCl3)
16.3
δ
(CH3), 18.1 (CH2), 22.3 (CH3), 22.6 (CH3), 25.3 (CH2), 28.21 (CH2), 28.22 (CH2), 31.5 (CH2), 32.3 (CH),
39.2 (C), 43.9 (C), 44.8 (CH), 73.77 (C), 73.79 (CH), 76.1 (CH), 80.7 (C), 183.8 (C); HRMS (ESI) m/z [M +
Na]+ calcd for C17H24O3Na 299.1618; found 299.1623.
Cyllenine C (12). To an ice-cooled (0 ◦C) mixture of alcohol 43 (6.8 mg, 24.6
65%, 9.8 mg, 36.9 mol) in CH2Cl2 (0.3 mL) was added a 0.123 M solution of methanesulfonic acid in
CH2Cl2 (0.20 mL, 24.6 mol) followed by Ph3PAuNTf2 (1.0 mg, 1.3 mol). After 1 h of stirring at room
temperature, the reaction was quenched with saturated aqueous NaHCO3 (1 mL), and the resulting
mixture was extracted with AcOEt (2 5 mL). The combined organic extracts were washed with brine
µmol) and m-CPBA (ca.
µ
µ
µ
×
(5 mL), and dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the colorless
oil (13.7 mg), which was purified by column chromatography (silica gel 2 g, 2:1 n-hexane/AcOEt)
to give cyllenine C (12, 6.9 mg, 96%) as a white solid. Rf 0.32 (1:2 n-hexane/AcOEt); mp 164
◦C (colorless needles from n-hexane/Et2O); [α]D24 +22.1 (c 0.69, CH2Cl2) [lit. [11], [α]2D0 +11.82 (c 0.33,
CH2Cl2)]; IR (neat) 3019, 2934, 2870, 1763, 1474, 1458, 1420, 1391, 1273, 1120, 1067, 1042, 993 cm−1
1H-NMR (500 MHz, CDCl3)
0.93 (d, J = 6.5 Hz, 3H, C8-CH3), 1.09 (s, 3H, C10-CH3), 1.30 (dt, J =
−
165
;
δ
12.2, 9.8 Hz, 1H, one of C1-H2), 1.31 (s, 3H, C4-CH3), 1.46 (m, 1H, one of C1-H2), 1.49 (m, 1H, one of
C3-H2), 1.52 (m, 1H, one of C2-H2), 1.72 (ddd, J = 6.3, 11.9, 16.4 Hz, 1H, one of C7-H2), 1.78 (m, 1H,
one of C2-H2), 1.95 (ddd, J = 4.4, 11.4, 13.8 Hz, 1H, one of C11-H2), 2.12 (m, 1H, one of C3-H2), 2.18
(ddq, J = 6.3, 11.9, 6.5 Hz, 1H, C8-H), 2.19 (d, J = 4.5 Hz, 1H, C5-H), 2.22 (ddd, J = 8.9, 11.5, 13.8 Hz, 1H,
one of C11-H2), 2.28 (dd, J = 6.3, 16.4 Hz, 1H, one of C7-H2), 2.54 (ddd, J = 4.4, 11.5, 18.8 Hz, 1H, one
of C12-H2), 2.62 (ddd, J = 8.9, 11.4, 18.8 Hz, 1H, one of C12-H2), 4.75 (dd, J = 4.5, 6.3 Hz, 1H, C6-H);
13C-NMR (125.7 MHz, CDCl3)
δ 15.4 (CH3), 17.7 (CH2), 22.2 (CH3), 22.4 (CH3), 24.5 (CH2), 27.7 (CH2),
28.2 (CH2), 29.3 (CH2), 31.2 (CH2), 32.3 (CH), 38.6 (C), 44.0 (C), 45.3 (CH), 75.6 (CH), 91.2 (C), 176.9 (C),
183.3 (C); HRMS (ESI) m/z [M + Na]+ calcd for C17H24O4Na 315.1567; found 315.1566.
(1S,4R,6R,7R,8S,12R)-7-[4-(tert-Butyldimethylsily◦l)oxybutyl]-7-hydroxy-1,6,8-trimethyl-2-oxo-3-oxatricyclo
[6.3.1.04,12]dodecane (45). To an ice-cooled (0 C) solution of 3-(tert-butyldimethylsilyl)oxypropyl
magnesium bromide (44) [prepared from (3-bromopropoxy)(tert-butyl)dimethylsilane (2.00 g, 7.90
mmol) and magnesium tuning (241 mg, 9.93 mmol)] in THF (14 mL) was added CuBr
0.627 mmol), followed by addition of a solution of epoxide 22 (39.1 mg, 0.156 mmol) in THF (0.20 mL
plus 2 0.20 mL rinse). After 5 h of stirring at room temperature, the reaction was quenched with
saturated aqueous NH4Cl (15 mL), and the resulting mixture was extracted with AcOEt (3 20 mL).
·SMe2 (129 mg,
×
×
The combined organic extracts were washed with brine (20 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the pale yellow oil (869 mg), which was purified by
column chromatography (silica gel 20 g, 10:1 → 6:1 → 3:1 n-hexane/AcOEt) to give TBS ether 45 (42.1
mg, 48%) as a pale yellow amorphous. Rf 0.46 (3:1 n-hexane/AcOEt); [α]2D2 +23.2 (c 1.00, CHCl3); IR
(neat) 3534, 2953, 2927, 2859, 1755, 1471, 1462, 1336, 1253, 1197, 1149, 1099, 994 cm−1; 1H-NMR (500
MHz, C6D6)
1H, one of C1-H2), 0.97 (s, 6H, C4-CH3, C10-CH3), 1.00 (s, 9H, SiC(CH3)3), 1.14
C2-H2, one of C3-H2, C11-H2, C12-H2), 1.35 1.45 (m, 4H, one of C2-H2, one of C7-H2, C13-H2), 1.47
δ
0.08 (s, 6H, Si(CH3)2), 0.65 (d, J = 6.6 Hz, 3H, C8-CH3), 0.78 (br s, 1H, OH), 0.96 (m,
−
1.30 (m, 6H, one of
−
(m, 1H, one of C1-H2), 1.77 (ddq, J = 6.2, 11.2, 6.6 Hz, 1H, C8-H), 1.92 (dd, J = 6.2, 15.8 Hz, 1H, one
of C7-H2), 2.00 (d, J = 4.6 Hz, 1H, C5-H), 2.18 (dt, J = 4.3, 13.7 Hz, 1H, one of C3-H2), 3.52 (t, J = 6.1
Hz, 2H, C14-H2), 4.36 (dd, J = 4.6, 6.4 Hz, 1H, C6-H); 13C-NMR (125.7 MHz, C6D6) δ −5.1 (CH3), 16.6
(CH3), 18.51 (C), 18.55 (CH2), 21.9 (CH2), 22.6 (CH3), 22.9 (CH3), 26.1 (CH3), 28.8 (CH2), 28.9 (CH2),
32.0 (CH2), 32.3 (CH), 34.0 (CH2), 34.8 (CH2), 39.8 (C), 43.7 (C), 44.9 (CH), 62.8 (CH2), 75.48 (C), 75.52
(C), 182.6 (C); HRMS (ESI) m/z [M + Na]+ calcd for C24H44O4SiNa 447.2907; found 447.2891.
(1S,4R,6R,7R,8S,12R)-7-Hydroxy-7-(4-hydroxybutyl)-1,6,8-trimethyl-2-oxo-3-oxatricyclo[6.3.1.04,12]dodecane
(
46). Bu4NF in THF (1.0 M, 0.38 mL, 0.38 mmol) was added to an ice-cooled (0 ◦C) solution of TBS
ether 45 (32.1 mg, 0.76 mmol) in THF (1.0 mL). After 1 h of stirring at room temperature, the mixture

Molecules 2020, 25, 1610
18 of 22
was partitioned between AcOEt (2 mL) and H2O (2 mL), and the aqueous layer was extracted with
AcOEt (3 2 mL). The combined organic extracts were washed with brine (5 mL), and dried over
×
anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the pale yellow oil (144 mg), which
was purified by column chromatography (silica gel 2 g, 1:4 n-hexane/AcOEt) to give diol 46 (19.3 mg,
82%) as a colorless amorphous. Rf 0.33 (1:2 n-hexane/AcOEt); [α]2D2 +24.4 (c 0.90, CHCl3); IR (neat)
3478, 2951, 2930, 2870, 1747, 1462, 1454, 1350, 1263, 1199, 1149, 1099, 1072, 1041, 991 cm−1; 1H-NMR
(500 MHz, C6D6)
of C1-H2), 0.95 (s, 3H, C10-CH3), 0.97 (s, 3H, C4-CH3), 1.07
C11-H2, C12-H2, C13-H2), 1.36 1.48 (m, 3H, one of C2-H2, one of C3-H2, one of C7-H2), 1.73 (ddq, J =
δ
0.54 (s, 1H, OH), 0.61 (d, J = 6.7 Hz, 3H, C8-CH3), 0.86 (s, 1H, OH), 0.91 (m, 1H, one
−
1.30 (m, 8H, one of C1-H2, one of C2-H2,
−
6.2, 11.3, 6.7 Hz, 1H, C8-H), 1.91 (ddd, J = 1.3, 6.2, 15.9 Hz, 1H, one of C7-H2), 2.00 (d, J = 4.8 Hz, 1H,
C5-H), 2.18 (dt, J = 4.2, 13.8 Hz, 1H, one of C3-H2), 3.30 (t, J = 6.1 Hz, 2H, C14-H2), 4.35 (ddd, J = 1.3,
4.8, 6.2 Hz, 1H, C6-H); 13C-NMR (125.7 MHz, C6D6)
δ 16.6 (CH3), 18.6 (CH2), 21.8 (CH2), 22.5 (CH3),
22.9 (CH3), 28.7 (CH2), 28.9 (CH2), 32.0 (CH2), 32.3 (CH), 33.7 (CH2), 34.7 (CH2), 39.8 (C), 43.7 (C), 44.9
(CH), 62.2 (CH2), 75.4 (C), 75.6 (CH), 182.7 (C); HRMS (ESI) m/z [M + Na]+ calcd for C18H30O4Na
333.2042; found 333.2052.
Marrulactone (14). TEMPO (2.3 mg, 14.7
(13.1 mg, 42.2 mol) and PhI(OAc)2 (40.5 mg, 0.125 mmol) in CH2Cl2 (0.3 mL). After 4 h of stirring at
room temperature, the reaction was quenched with 1 M aqueous Na2S2O3 (1 mL), and the resulting
mixture was extracted with AcOEt (3 1 mL). The combined organic extracts were washed with brine
µ
mol) was added to an ice-cooled (0 ◦C) mixture of diol 46
µ
×
(3 mL), and dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the colorless
oil (64.0 mg), which was purified by column chromatography (silica gel 1 g, 1:1 n-hexane/AcOEt) to
give marrulactone (14, 11.8 mg, 91%) as a colorless amorphous. Rf 0.60 (1:2 n-hexane/AcOEt); [α]D22
−
11.6 (c 0.61, CHCl3) [lit. [12], [α]D25
−
23.80 (c 0.22, CHCl3)]; IR (neat) 3017, 2961, 2928, 2872, 1769, 1719,
1458, 1391, 1329, 1261, 1244, 1215, 1188, 1117, 1070, 1030, 1003 cm−1; 1H-NMR (500 MHz, CDCl3)
0.98
(d, J = 6.3 Hz, 3H, C8-CH3), 1.11 (s, 3H, C10-CH3), 1.31 (s, 3H, C4-CH3), 1.34 1.42 (m, 2H, C1-H2), 1.48
(m, 1H, one of C3-H2), 1.55 (m, 1H, one of C2-H2), 1.74 1.80 (m, 2H, one of C2-H2, one of C11-H2),
1.80 1.94 (m, 4H, one of C7-H2, one of C11-H2, C12-H2), 2.09 2.20 (m, 3H, one of C3-H2, one of C7-H2,
δ
−
−
−
−
C8-H), 2.25 (ddd, J = 6.2, 11.2, 17.3 Hz, 1H, one of C13-H2), 2.32 (d, J = 4.4 Hz, 1H, C5-H), 2.57 (ddt, J =
2.0, 17.3, 4.1 Hz, 1H, one of C13-H2), 4.78 (ddd, J = 0.7, 4.4, 5.5 Hz, 1H, C6-H); 13C-NMR (125.7 MHz,
CDCl3)
δ 16.5 (CH3), 17.8 (CH2), 18.9 (CH2), 22.0 (CH3), 22.8 (CH3), 26.1 (CH2), 28.1 (CH2), 28.6 (CH2),
30.4 (CH2), 30.9 (CH2), 34.3 (CH), 40.8 (C), 44.0 (C), 44.3 (CH), 75.8 (CH), 88.3 (C), 172.2 (C), 183.5 (C);
HRMS (ESI) m/z [M + Na]+ calcd for C18H26O4Na 329.1723; found 329.1711.
Marrulanic acid (10). LiOH (18.7 mg, 0.78 mmol) was added to a solution of marrulactone (14, 11.8 mg,
38.5
µmol) in THF/H2O (2:1, 1.2 mL). After 31 h of stirring, the mixture was acidified with 1 M aqueous
HCl (3 mL), and the resulting mixture was extracted with AcOEt (3
extracts were washed with brine (5 mL), and dried over anhydrous Na2SO4. Filtration and evaporation
in vacuo furnished the colorless oil (11.7 mg), which was purified by column chromatography (silica
×
3 mL). The combined organic
gel 1 g, 1:1 n-hexane/AcOEt
as a colorless amorphous. Rf 0.19 (1:2 n-hexane/AcOEt); [α]2D7 +25.4 (c 0.53, CHCl3) [lit. [12], [α]2D5
(c 1.2, CHCl3)]; IR (neat) 3536, 3196, 2949, 2928, 2868, 1761, 1732, 1464, 1412, 1391, 1287, 1260, 1196,
1179, 1159, 1126, 1094, 1078, 1042, 1018 cm−1; 1H-NMR (500 MHz, CDCl3)
0.92 (d, J = 6.5 Hz, 3H,
C8-CH3), 1.04 (s, 3H, C10-CH3), 1.26 (m, 1H, one of C1-H2), 1.29 (s, 3H, C4-CH3), 1.44 1.80 (m, 9H, one
of C1-H2, C2-H2, one of C3-H2, one of C7-H2, C11-H2, C12-H2), 2.04 2.17 (m, 3H, one of C3-H2, one of
C7-H2, C8-H), 2.24 (d, J = 4.6 Hz, 1H, C5-H), 2.38 (dt, J = 1.8, 7.0 Hz, 2H, C13-H2), 4.74 (ddd, J = 1.2,
4.6, 5.8 Hz, 1H, C6-H); 13C-NMR (125.0 MHz, CDCl3)
16.5 (CH3), 18.2 (CH2), 20.3 (CH2), 22.3 (CH3),
→
AcOEt
→
20:1 AcOEt/MeOH) to give marrulanic acid (10, 10.5 mg, 84%)
−
10.8
δ
−
−
δ
22.9 (CH3), 28.3 (CH2), 28.6 (CH2), 31.5 (CH2), 32.2 (CH), 34.29 (CH2), 34.31 (CH2), 39.7 (C), 43.8 (C),
44.8 (CH), 75.6 (C), 76.2 (CH), 178.5 (C), 183.9 (C); HRMS (ESI) m/z [M + Na]+ calcd for C18H28O5Na
347.1834; found 347.1813.

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[1S,4R,6R,7R,7(2S,3S,4R,5R),8S,12R]-7-[2-(3,4-Dihydroxy-2,5-dimethoxytetrahydrofuran-3-yl)ethyl]-7-hydro
xy-1,6,8-trimethyl-2-oxo-3-oxatricyclo[6.3.1.04,12]dodecane (40). TsOH (0.4 mg, 2.3
mol) was added to a
solution of marrulibacetal A (17, 0.90 mg, 2.3 mol) in MeOH (1.0 mL), and the mixture was heated at
reflux for 5 h. After cooling to 0 ◦C, the reaction was quenched with half saturated aqueous NaHCO3
(4 mL), and the resulting mixture was extracted with AcOEt (2 5 mL). The combined organic extracts
µ
µ
×
were washed with brine (5 mL), and dried over anhydrous Na2SO4. Filtration and evaporation in
vacuo furnished the colorless oil (1.4 mg), which was purified by flash column chromatography (silica
gel 0.8 g, 1:1 n-hexane/AcOEt
n-hexane/AcOEt); [α]D23 +16.5 (c 0.46, benzene); IR (neat) 3447, 2930, 1744, 1466, 1449, 1389, 1288, 1198,
1130, 1094, 1042, 991 cm−1; 1H-NMR (500 MHz, CDCl3)
0.91 (d, J = 6.4 Hz, 3H, C8-CH3), 1.05 (s, 3H,
C10-CH3), 1.28 (m, 1H, one of C1-H2), 1.29 (s, 3H, C4-CH3), 1.45 (m, 1H, one of C3-H2), 1.51 (m, 1H,
one of C2-H2), 1.65 (m, 1H, one of C7-H2), 1.74 (m, 1H, one of C2-H2), 1.60 1.98 (m, 5H, one of C1-H2,
→
AcOEt) to give triol 40 (0.24 mg, 25%) as a colorless oil. Rf 0.30 (1:1
δ
−
C11-H2, C12-H2), 2.07 (m, 1H, C8-H), 2.11 (m, 1H, one of C3-H2), 2.14 (m, 1H, one of C7-H2), 2.22 (d, J
= 4.5 Hz, 1H, C5-H), 3.40 (s, 3H, C16-OCH3), 3.48 (s, 3H, C15-OCH3), 3.92 (d, J = 3.7 Hz, 1H, C14-H),
4.73 (dd, J = 4.5, 6.5 Hz, 1H, C6-H), 4.77 (s, 1H, C16-H), 4.89 (d, J = 3.7 Hz, 1H, C15-H); 13C-NMR
(125.7 MHz, CDCl3)
δ 16.4 (CH3), 18.1 (CH2), 22.3 (CH3), 22.9 (CH3), 28.0 (CH2), 28.26 (CH2), 28.28
(CH2), 28.4 (CH2), 31.5 (CH2), 32.6 (CH), 40.0 (C), 43.9 (C), 44.9 (CH), 55.1 (CH3), 56.4 (CH3), 75.4 (C),
76.2 (CH), 80.3 (CH), 81.4 (C), 108.3 (CH), 110.7 (CH), 184.0 (C); HRMS (ESI) m/z [M + Na]+ calcd for
C22H36O8Na 451.2302; found 451.2308.
Desertine (18). TsOH (1.6 mg, 9.3 µmol) was added to a solution of bisacetal 42 (2.0 mg, 4.7 µmol) in
MeOH (0.5 mL), and the mixture was heated at reflux for 3.5 h. After cooling to 0 ◦C, the reaction
was quenched with saturated aqueous NaHCO3 (2 mL), and the resulting mixture was extracted
with AcOEt (2
×
5 mL). The combined organic extracts were washed with brine (10 mL), and dried
over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the pale yellow oil (3.6 mg),
which was purified by flash column chromatography (silica gel 0.8 g, 1:1 n-hexane/AcOEt) to give
desertine (18, 0.34 mg, 16%) as a colorless oil. Rf 0.30 (1:1 n-hexane/AcOEt); [α]2D3 +22.8 (c 0.50, benzene)
(lit. [14], [α]2D5
1H-NMR (500 MHz, CDCl3)
of C1-H2), 1.29 (s, 3H, C4-CH3), 1.45 (m, 1H, one of C3-H2), 1.51 (m, 1H, one of C2-H2), 1.65 (m, 1H,
one of C7-H2), 1.74 (m, 1H, one of C2-H2), 1.60 1.98 (m, 5H, one of C1-H2, C11-H2, C12-H2), 2.07 (m,
−
56.6); IR (neat) 3464, 2930, 1748, 1463, 1450, 1391, 1256, 1198, 1152, 1099, 1043, 989 cm−1
;
δ
0.91 (d, J = 6.2 Hz, 3H, C8-CH3), 1.04 (s, 3H, C10-CH3), 1.28 (m, 1H, one
−
1H, C8-H), 2.11 (m, 1H, one of C3-H2), 2.14 (m, 1H, one of C7-H2), 2.23 (d, J = 4.0 Hz, 1H, C5-H), 3.41 (s,
3H, C16-OCH3), 3.47 (s, 3H, C15-OCH3), 3.95 (d, J = 3.5 Hz, 1H, C14-H), 4.73 (dd, J = 4.0, 6.9 Hz, 1H,
C6-H), 4.76 (s, 1H, C16-H), 4.90 (d, J = 3.5 Hz, 1H, C15-H); 13C-NMR (125.7 MHz, CDCl3)
δ 16.8 (CH3),
18.2 (CH2), 22.2 (CH3), 23.0 (CH3), 27.4 (CH2), 28.3 (CH2), 28.4 (CH2), 28.5 (CH2), 31.6 (CH2), 32.5 (CH),
40.1 (C), 43.9 (C), 45.0 (CH), 55.1 (CH3), 56.4 (CH3), 75.3 (C), 76.2 (CH), 80.2 (CH), 81.2 (C), 108.6 (CH),
110.8 (CH), 183.8 (C); HRMS (ESI) m/z [M + Na]+ calcd for C22H36O8Na 451.2302; found 451.2313.
4. Conclusions
Total syntheses of eight labdane diterpene lactones, marrubiin (1), marrulanic acid (10),
cyllenine C (12), marrulibacetal (13), marrulactone (14), marrulibacetal A (17), desertine (18), and
marrubasch F (19), have been accomplished. Since chiral building block 20 could be prepared from
(4R,6S)-6-[(tert-butyldimethylsilyl)oxymethyl]-4-methyltetrahydro-2H-pyran-2-one [53] in 37% yield
over eight steps, the syntheses proceeded in 19 22 steps involving a stereoselective intramolecular
−
PKR, and these natural products were obtained in yields ranging from 1.1% (marrulibacetal A) to
10.9% (cyllenin C). Stereochemistries of desertine were established by the facts that the compound
could be obtained by both osmylation of bisacetal 37 and transacetalization of the diastereomer of
marrulibacetal A with MeOH. The syntheses illustrate the synthetic utility of chiral building block
20 for the synthesis of this class of diterpenoids. The synthetic strategy also features elongation of
the C9 side chain through an epoxide-opening reaction as well as high convergency and flexibility.

Molecules 2020, 25, 1610
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The syntheses of other natural products and non-natural analogues for biological and pharmaceutical
investigations are in progress in our laboratory and will be reported in due course.
Supplementary Materials: The following are available online. Comparison data for natural products and
synthetic materials, and copies of 1H and 13C-NMR spectra for all new compounds.
Author Contributions: Y.S. (Yukari Sakagami), N.K., Y.S. (Yuki Sawayama), and H.Y. performed the experiments.
S.N. conceived and designed the project. H.Y. and S.N. directed the investigations and prepared this manuscript.
All authors discussed the experimental results. All authors have read and agreed to the published version of
the manuscript.
Funding: This research was supported in part by the Platform Project for Supporting in Drug Discovery and Life
Science Research from Japan Agency for Medical Research and Development (AMED), and Shionogi Award in
Synthetic Organic Chemistry, Japan.
Acknowledgments: The authors acknowledge the assistance of the Research Equipment Sharing Center at Nagoya
City University. We are grateful to Mr. Kota Suzuki of the Faculty of Pharmaceutical Sciences, Nagoya City
University, for experimental assistance.
Conflicts of Interest: The authors declare no conflict of interest.
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2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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