Synthesis of guaia-4(5)-en-11-ol, guaia-5(6)-en-11-ol, aciphyllene, 1- epi -melicodenones C and E, and other guaiane-type sesquiterpenoids via the diastereoselective epoxidation of guaiol

DOI: 10.1021/np500611z

Source and publish data:

Journal of Natural Products p. 2522 - 2536 (2014)

Update date:2022-08-04

Topics: Synthesis

Authors:

Huang, An-Cheng

Sumby, Christopher J.

Tiekink, Edward R.T.

Taylor, Dennis K.

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Article abstract of DOI:10.1021/np500611z

The diastereomeric ratio of epoxidation of the internally bridged carbon-carbon double bond of guaiol (1a) is strongly influenced by the combined effects of the types of remote protecting groups on the hydroxyisopropyl side chain, choice of solvent, and e

Full text of DOI:10.1021/np500611z

Article

pubs.acs.org/jnp

Synthesis of Guaia-4(5)-en-11-ol, Guaia-5(6)-en-11-ol, Aciphyllene, 1-

epi-Melicodenones C and E, and Other Guaiane-Type

Sesquiterpenoids via the Diastereoselective Epoxidation of Guaiol

An-Cheng Huang,^†Christopher J. Sumby,^§Edward R. T. Tiekink,^‡and Dennis K. Taylor*^,†

^†School of Agriculture, Food and Wine, The University of Adelaide, Waite Campus, Glen Osmond 5064, Adelaide, South Australia,

Australia

^§School of Chemistry and Physics, The University of Adelaide, North Terrace 5000, Adelaide, South Australia, Australia

^‡Department of Chemistry, University of Malaya, Kuala Lumpur 50603, Malaysia

* Supporting Information

ABSTRACT: The diastereomeric ratio of epoxidation of the internally bridged carbon−carbon double bond of guaiol (1a) is

strongly inﬂuenced by the combined eﬀects of the types of remote protecting groups on the hydroxyisopropyl side chain, choice

of solvent, and epoxidizing reagent. This observation has allowed us to devise concise stereoselective syntheses of a range of

guaiane-type sesquiterpenoids via an epoxidation, ring-opening/elimination, and functionality manipulation sequence. Natural

products guaia-4(5)-en-11-ol (2a), guaia-5(6)-en-11-ol (3), and aciphyllene (4a) and epimers of the recently isolated natural

products, 1-epi-guaia-4(5)-en-11-ol (2b), 1-epi-aciphyllene (4b), and 1-epi-melicodenones C (5a) and E (6a), were synthesized

in good yields in relatively few steps.

wood essential oil²¹and which already has the bicyclic [5.3.0]-

uaiane-type sesquiterpenoids occur widely in nature and

G_{have been isolated and identiﬁed in many diﬀerent hosts}core installed with three deﬁned stereogenic centers near the

bridged CC bond.

including plants, fungi, and marine life with dozens reported on

an annual basis.^1,2The continual discovery of these structurally

Indeed others have utilized guaiol (1a) to prepare several

sesquiterpenes including (+)-hedycaryol and (+)-γ-eudesmol²¹

intriguing organics and their well-documented important

bioactivities coupled with their often low natural abundance

and cadalane,²²by either beginning with the oxidative cleavage

of the bridged CC bond or direct acid-catalyzed dehydration

in nature have rendered them exciting targets for numerous

organic synthesis groups.^2,3Key synthesis strategies to

of the hydroxyisopropyl side-chain. We speculated that

epoxidation of 1a would allow for diastereoselective installation

of a centrally positioned epoxy moiety, based on its sterically

biased structure and choice of epoxidizing agent, which should

be able to be further ﬁne-tuned based on the inﬂuence of

varying steric eﬀects imposed by protecting groups on the

remote hydroxyisopropyl moiety of guaiol (1a). Ring-opening

reactions of the resultant epoxide(s) would then allow for the

regio- and stereoselective installation of hydroxy moieties,

which upon dehydration should realize the migration of the

bridged double bond and allow for rapid access to a range of

recently isolated sesquiterpenes. The epoxidation of 1a has

construct the guaiane skeleton are annulation, ring-expan-

sion/contraction, or direct cyclization through acid/base-

mediated and free radical routes.³⁻⁸Total syntheses of

guaiane-type sesquiterpenoids including guaiol (1a),^9,10aci-

phyllene (4a),¹¹indicanone,¹²pesudolaric acid A,¹³and

englerin A and its analogues^7,14−20have been accomplished.

However, the overall yields are often low, and challenges have

been experienced in installing the proper stereochemistry and

functionalities when constructing the fused [5.3.0]-bicyclic ring

cores. Alternative approaches to enable rapid access to diﬀerent

guaiene sesquiterpenoids are thus warranted. A plausible

solution noted by us hinged on developing synthesis routes

starting with cheap guaiane natural products such as guaiol

(1a), which can be easily isolated in large quantities from guaiac

Received: August 1, 2014

Published: October 20, 2014

American Society of Pharmacognosy

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Figure 1. Aciphyllene, melicodenones (C and E), and their C-1 epimers along with several isomeric guaiols.

been visited previously with the focus placed mainly on the

characterization of the epoxidation products.²³

chloroperbenzoic acid (m-CPBA) and dimethyl dioxirane

(DMDO) were utilized as potential epoxidizing agents, while

other common epoxidizing reagents such as peracetic acid in

acetic acid were not pursued due to the sensitivity of most

epoxides of guaiol (1a) and its derivatives to acid-induced

fragmentation.³²

To evaluate the feasibility of this strategy, a range of natural

sesquiterepenes with structures related to guaiol (1a) including

guaia-4(5)-en-11-ol (2a), guaia-5(6)-en-11-ol (3), aciphyllene

(4a), and melicodenones C (5b) and E (6b) were chosen as

targets. Guaia-4(5)-en-11-ol (2a) and guaia-5(6)-en-11-ol (3)

are natural sesquiterpenes with anti-inﬂammatory activity and

were recently isolated from the methanol extracts of the fruit of

the highly invasive weed Pittosporum undulatum.²⁴Aciphyllene

(4a) was ﬁrst isolated from the essential oils of Lindera glauca

in 1983²⁵and later isolated and identiﬁed from Dumotiera

hirsuta²⁶and numerous other natural sources.²⁷⁻³⁰Melicode-

nones C and E (5b and 6b) are novel guaiane-type

sesquiterpenoids isolated from the roots of Melicope denhamii,

one of ca. 230 species of Melicope (Rutaceae) distributed from

Madagascar east to the Hawaiian Islands and south to New

Zealand.³¹We report herein that by controlling the initial

diastereoselective epoxidation of guaiol (1a), subsequent ring-

opening and elimination allow for the ready migration and

installation of the requisite CC bonds at the cores of these

structures along with tight control of the C-1 stereochemistry

and consequently, with further simple functional group

manipulation, allow for rapid access to the natural products

(2a, 3, and 4a) and the ready synthesis of the C-1 epimers of

targeted natural products (2b, 4b, 5a, and 6a) and their

derivatives in moderate to good yields.

Epoxidation of guaiol (1a) with m-CPBA in CH₂Cl₂revealed

little π facial selectivity with a preference for formation of the β-

epoxide (8a) of 1.3:1 (entry 1). In contrast, epoxidation with

DMDO aﬀorded the α-epoxide (8b) as the major stereoisomer

(19:1) in 65% yield (entry 7). Changing the solvent system

(entries 13−22) had only a minor beneﬁcial eﬀect on the

observed π facial selectivity of epoxidation of 1a when

employing m-CPBA, with DMF returning the best π facial

selectivity in favor of β-epoxide (8a) of 2.1:1. In order to

improve the preference for β π facial selectivity, we next

explored the eﬀects that the remote hydroxy protecting groups

would have on epoxidation, entries 1−12. The benzoate (1e)

yielded the highest π facial selectivity with 80% β-orientation

(12a) followed by acetate (11a, 75%), TMS ether (9a, 71%),

and benzyl (10a, 59%) when m-CPBA was employed as oxidant

in CH₂Cl₂at RT. When using DMDO as oxidant, the α-

epoxide (8b−12b) was the dominant stereoisomer in all cases,

although minor diﬀerences were observed due to the nature of

the protecting group, Table 1.

In sharp contrast to the observed preference for β facial

epoxidation of 1a−1e, regioselective epoxidation of guaiene

(7a) with m-CPBA in CH₂Cl₂at −78 °C yielded the α-mono-

epoxide (13b) as the major epoxide (65%, entry 6) similar to

the predominant α-epoxy orientation observed in the

regioselective epoxidation of β-himachalene.³³Performing the

epoxidation of 7a but with 1 equiv of m-CPBA at ambient

temperature yielded the same mixture of mono-epoxides (13a

and 13b) in a 35:65 ratio, along with the bis-epoxides (14a−

14d) (Scheme 1). Addition of excess oxidant furnished the two

pairs of bis-epoxides (14a/14b and 14c/14d) in a ratio of

36:64, consistent with that found for mono-epoxide formation

RESULTS AND DISCUSSION

■

Diastereoselective Epoxidation of Guaiol (1a). The ﬁrst

step in the synthesis of the guaiane-type natural products

depicted above was to eﬃciently control the π facial selectivity

of the epoxidation of the centrally bridged double bond of

guaiol (1a) or its hydroxy-protected derivatives, namely, the

trimethylsilyl ether (1b), benzyl ether (1c), acetate (1d), and

benzoate (1e). These latter derivatives were prepared in good

to excellent yields as depicted in Table 1. Both m-

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Table 1. Eﬀects of Remote Substituents, Reagents, and Choice of Solvent on Diastereoselective Epoxidation of Guaiol

Derivatives 1a−1e and α-Guaiene 7a

entry

solvent

substrate

reagent

β:α

yield (%)

CH₂Cl₂

acetone

toluene

1,4-dioxane

Et₂O

m-CPBA

56:44

71:29

59:41

75:25

80:20

35:65

5:95

DMDO

11:89

6:94

DMDO

30:70

13:87

2:98

DMDO

m-CPBA

60:40

65:35

57:43

62:38

67:33

61:39

71:29

68:32

84:16

83:17

78:22

CHCl₃

(CH₂Cl)₂

acetone

EtOAc

MeCN

DMF

100

MeOH

Et₂O

100

EtOAc

DMF

MeOH

Substrate (0.1 mmol) and m-CPBA (0.2 mmol) in CH₂Cl₂(1 mL) at RT for 10 min. Substrate (0.50 mmol) and m-CPBA (0.57 mmol) in

CH₂Cl₂(6 mL) at −78 °C for 30 min. Substrate (20 μmol) and DMDO (30 μmol) in acetone (1 mL) at RT for 1 h. 7a (50 μmol) and DMDO

(50 μmol) in acetone (1 mL) at −78 °C. Epoxy orientation conﬁrmed by X-ray crystallographic analysis of the two bis-epoxides (14c and 14d, vide

infra). 1a or 1d (20 μmol) and m-CPBA (40 μmol) in above solvents (1 mL) at RT for 30 min. Determined by GC-MS/FID. Based on 75%

conversion.

Scheme 1. Synthesis of Epoxides (13a,b) and Bis-epoxides (14a−14d) Derived from Guaiene 7a

Conditions: (a) m-CPBA (1 equiv), CH₂Cl₂, −78 °C, 13a:13b = 35:65; (b) m-CPBA (6 equiv), CH₂Cl₂, RT, (14a + 14b):(14c + 14d) = 36:64.

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Scheme 2. Synthesis of Guaia-4(5)-en-11-ol (2a), Guaia-5(6)-en-11-ol (3), and Aciphyllene (4a)

Reagents and conditions: (a) m-CPBA, Et₂O, −78 °C to RT, 80 min; (b) Na, MeOH, RT, 12 h; (c) LiAlH₄, AlCl₃anhydrous, THF, 4 h: (d) BnBr,

Bu₄NI, NaH, DMF, RT, 12 h: (e) SOCl₂, Et₃N, benzene, RT, 20 min: (f)TsOH·H₂O, CH₃CN, RT, 6 h; (g) Li wire, naphthalene, THF, −78 °C to

RT, 18 h; (h) LiAlH₄, THF, RT, 12 h; (i) SOCl₂, benzene, pyridine, RT, 10 min.

and merely reﬂects that the more electron-rich bridged CC is

epoxidized at a much faster rate than the external isopropylene

unit (Scheme 1). The facial selectivity of epoxidation of 7a was

lifted to 98% α-orientation (14b) when employing DMDO as

oxidant at −78 °C; however, isolatable yields were diminished

by the formation of several other uncharacterized products. The

orientations of the α- and β-epoxides derived from substrates

1a−1e and 7a were conﬁrmed by comparison with the known

epoxides 8a and 8b,²³the observed trend that the β-oriented

epoxides of guaiol derivatives (1a−1e) all displayed shorter GC

rention times than their α-oriented counterparts, and also via

X-ray crystallographic analysis of the bis-epoxides (14c and

14d; see Supporting Information) derived from the α-oriented

bridged mono-epoxide (13b) as depicted in Scheme 1.

The diﬀerences in whether α or β π facial selectivity is

preferred in the epoxidation reactions of these guaiene

substrates can be attributed to a number of factors based on

the combined eﬀects of the types of remote protecting groups

on the hydroxyisopropyl side chain, choice of solvent, and

epoxidizing reagent, with the latter inﬂuencing the stereo-

chemical outcome to the greatest extent. Theoretical

calculations to determine the equilibrium conformation of

guaiol (1a) reveal that the β-face of the central bridged double

bond is sterically encumbered by the C-4 and C-10 methyl

substituents (Supporting Information). Similar calculations of

the α- and β-epoxides of 1a, namely, 8a and 8b, reveal that the

α-epoxide 8b is the thermodynamic product by some 1.06 kcal/

mol (Supporting Information). Thus, given that DMDO has a

spiro geometrical relationship between its gem-dimethyl groups

and the dioxirane ring, its approach to the β-face of the central

double bond of guaiol (1a) is sterically disfavored by the C-4

and C-10 methyl substituents, resulting in approach to the

sterically less hindered α-face and formation of the

thermodynamically more stable α-epoxides. However, α or β

π facial selectivity when employing m-CPBA as the epoxidizing

agent is clearly inﬂuenced by the sterics of the protecting group

on the remote hydroxyisopropyl side chain as we ﬁrst thought.

It appears that the sterics of the remote protecting groups aid in

blocking the approach of m-CPBA to the α-face; thus the more

“cylindrically planar” peracid moiety is forced to approach

between the C-4 and C-10 methyl groups, resulting in the

formation of the β-epoxides as the major products. The most

dramatic demonstration of this eﬀect is seen when the

protected hydroxyisopropyl moiety is replaced with an

isopropylene unit as in 7a (entry 6), which results in a

complete reversal of the β-facial selectivity seen for substrates

1a−1e to once again favor approach from the less hindered α-

face and formation of the thermodynamic epoxide 13b. The

fact that guaiol (1a), with an unprotected hydroxy group,

displays the poorest β vs α facial selectivity when compared to

the protected derivatives also supports this argument. Solvent

choice was also found to have a small but still signiﬁcant

inﬂuence for these stereoselective epoxidations.

With a preference for α- or β-epoxide stereoselectivity now

achievable based on choice of protecting group, we decided to

further reﬁne the potential for β-stereoselectivity based on

solvent choice. Even though 1e gave the highest β-orientation

for epoxidation with m-CPBA, the acetate 1d was chosen as the

optimal protecting group owing to the higher yield (99%) for

the synthesis of 1d from guaiol (1a). Solvent screening (entries

13−22, Table 1) using 1a as substrate across a wide spectrum

of general solvents suggested DMF, MeOH, EtOAc, and Et₂O

may be optimal solvents with β-stereoselectivities of >65%.

Further trials using 1d as substrate with a range of solvents

(entries 23−26, Table 1) distinguished Et₂O as the optimal

solvent, furnishing a π facial selectivity of 84% for the β-

orientation. Attempts to improve this selectivity by lowering

the reaction temperature to −78 °C gave a slight enhancement

of 2% to 86% β-orientation.

Synthesis of Guaia-4(5)-en-11-ol (2a), Guaia-5(6)-en-

11-ol (3), and Aciphyllene (4a) from β-Epoxyguaiol (8a),

and 1-epi-Guaia-4(5)-en-11-ol (2b) and 1-epi-Aciphyl-

lene (4b) from Bridged α-Epoxyguaiol (8b). With the β-

epoxide of acetate 1d identiﬁed as an optimal precursor to

various naturally occurring bridged sesquiterpenes, we next

focused on the synthesis of the natural sesquiterpenes guaia-

4(5)-en-11-ol (2a), guaia-5(6)-en-11-ol (3), and aciphyllene

(4a) employing an epoxidation, ring-opening, and elimination

sequence (Scheme 2). Epoxidation of 1d followed by basic

hydrolysis of the acetate moiety of 11a aﬀorded β-epoxyguaiol

(8a) in 84% yield over two steps. Reductive ring-opening of 8a

furnished diol 15a as the predominant product in 79% yield

and whose hydroxy moiety was introduced at C-5 with β-

orientation. Regioselective hydride delivery to the α-face of

epoxide 8a at C-1 as opposed to delivery at C-5 is presumably a

reﬂection of steric crowding around C-5. The C-5 tertiary

hydroxy group is more sterically hindered than the terminal

hydroxyisopropyl group, allowing for selective benzylation via

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in situ generation of benzyl iodide using Ogawa’s method³⁴in

73% yield and high regioselectivity. Dehydration of 16 with

SOCl₂in benzene gave predominantly the 5,6-ene (17) in 69%

yield, whereas treatment of 16 with a trace of TsOH·H₂O in

MeCN aﬀorded a mixture of 1a, 4,5-ene 18, and α-bulnesol³⁵as

the major products in a ratio of 22%, 66%, and 7%, respectively,

by GC analysis. Fractionation of this alkenic mixture with

AgNO₃-impregnated silica (SNIS) column chromatography

furnished pure 18 in a good yield of 58%. At this stage we thus

had control of installing the double bond as either a 4,5- or a

5,6-ene unit within these bicyclic sesquiterpenes. Cleavage of

the benzyl ether function of 17 with Li and naphthalene

furnished guaia-5(6)-en-11-ol (3) in 64% yield over two steps,

while treatment of isomeric 18 with excess LiAlH₄in THF

furnished guaia-4(5)-en-11-ol (2a) in 91% yield.³⁶This

represents the ﬁrst synthesis of the naturally occurring

sesquiterpene guaia-5(6)-en-11-ol (3) and also oﬀers access

to natural guaia-4(5)-en-11-ol (2a) in one sequence in 31% and

26% overall yields, respectively. Dehydration of alcohol 2a

followed by puriﬁcation on SNIS chromatography also aﬀorded

the natural product aciphyllene (4a) in 72% yield. Overall, our

synthetic approach oﬀers a more rapid route to aciphyllene

(4a) in 18% overall yield over seven steps from guaiol (1a)

when compared with the 2% overall yield over 15 steps

reported when starting with (R)-limonene.^11,37

Scheme 3. Synthesis of 1-epi-Guaia-4(5)-en-11-ol (2b) and

1-epi-Aciphyllene (4b)

In order to further explore the feasibility for rapid access to

additional guaiol analogues, we repeated the sequence

beginning with the α-epoxides of various guaiol derivatives

(8b−13b), which upon ring-opening should aﬀord the β-

oriented C-1 epimeric counterparts of the natural sesquiter-

penes synthesized above (Scheme 3). As highlighted in Table 1,

α-epoxyguaiol (8b) may be prepared with a π facial selectivity

of 95% α-orientation in 65% overall yield when using DMDO

as oxidant. Ring-opening of 8b with AlH₃in THF simply led to

the formation of tricyclic guaioxide (19) via nucleophilic attack

of the terminal hydroxy moiety on the bridged epoxy moiety

without the formation of the expected diol (15b) (Scheme 3).

Employing the α-epoxybenzyl ether (10b) under the same

conditions (AlH₃in THF) resulted in no reaction at RT, while

employing elevated temperatures simply resulted in dehydra-

tion to regenerate the bridged oleﬁn (1c). Employing α-guaiene

(7a), which does not have the exocyclic tertiary alcohol moiety,

furnished alcohol 20 in 43% yield with a 5-OH moiety and the

appropriate H-1β orientation, along with isomeric 21 in 23%

yield when employing regioselective epoxidation of 7a with m-

CPBA at −78 °C followed by ring-opening with AlH₃in THF

under reﬂux.³⁸Dehydration of 20 with SOCl₂in Et₂O followed

by SNIS chromatography furnished the yet to be naturally

identiﬁed 1-epi-aciphyllene (4b) in 87% yield, whereas guaia-

11-en-1-ol (21) gave an inseparable mixture of various dienes

regardless of the types of solvent and reagents (e.g., SOCl₂,

POCl₃, MeSO₂Cl) employed. Epoxidation of 20 aﬀorded a

mixture of epoxide epimers (22a,b) in near-quantitative yield

with the C-1 conﬁgurations conﬁrmed by X-ray diﬀraction

analysis of the individual epoxy alcohols (22a and 22b; see

Supporting Information). Dehydration of a mixture of 22a,b

with SOCl₂/Et₃N in CH₂Cl₂installed the C4−C5 double bond

regioselectively, furnishing epoxide epimers 23, which upon

reduction of the epoxide moiety with AlH₃followed by SNIS

chromatography aﬀorded 1-epi-guaia-4(5)-en-11-ol (2b) in a

73% yield over three steps.

(a) LiAlH₄, AlCl₃, THF, RT, 4 h; (b) m-CPBA, CH₂Cl₂, −78 °C, 2 h;

min; (e) m-CPBA, CH₂Cl₂, RT, 1 h; (f) SOCl₂, Et₃N, CH₂Cl₂, RT, 10

min.

over ﬁve steps) and guaia-4(5)-en-11-ol (2b, 19%, over seven

steps) from guaiol (1a). Overall, these short syntheses utilizing

bridged sesquiterpene epoxides demonstrate the ease with

which the C-1 stereochemistry along with instillation of the

appropriate double bonds at either the 4,5- or 5,6-positions of

these sesquiterpenes may be controlled.

Potential of 1-epi-Aciphyllene (4b) and Aciphyllene

(4a) as Precursors for the Synthesis of Melicodenones C

(5b) and E (6b) and 1-epi-Melicodenones C (5a) and E

(6a) and Related Derivatives, Respectively. With

aciphyllene (4a) and 1-epi-aciphyllene (4b) in hand, we next

explored a possible concise synthesis of the recently isolated

natural sesquiterpenoids melicodenones C and E via functional

group manipulation. Owing to the fact that 1-epi-aciphyllene

(4b) shares the same β-orientation of H-1 as that of the natural

melicodenones, we expected that allylic oxidation of 1-epi-

aciphyllene would furnish natural melicodenone C (5b) in two

steps. However, allylic oxidation of 4b with PDC and TBHP

aﬀorded enone 24 with the carbonyl moiety selectively installed

at C-3 (53% yield) rather than C-6 (Scheme 4). Alternatively,

treatment of 4b with SeO₂and TBHP³⁹aﬀorded the two

epimeric allylic alcohols 25 and 26 in a ratio of 3:1. Attempts to

access isomeric derivative 27 of melicodenone E (6b) via

further oxidation of 24 with CrO₃and DMP did not generate

the target enedione with almost full recovery of the starting

At this stage, we have obtained rapid access to two epimeric

analogues of the natural sesquiterpenes aciphyllene (4b, 22%,

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improve the yield of the allylic oxidation⁴⁴of 4a employing

TBHP coupled with various metal-based oxidants including

PDC, CrO₃, Mn(OAc)₃, Co(OAc)₂, Pd(OAc)₂, or the metal-

free co-oxidant diacetoxyiodobenzene (DIB)⁴⁵proved to be

unsatisfactory and either aﬀorded complex mixtures of

oxidation products or suﬀered from low conversion or recovery.

Nonetheless, access to 1-epi-melicodenone C (5a) was readily

achieved via oxidation of 29 employing Dess−Martin period-

inane in 72% yield. The α-oriented H-1 of 5a was substantially

Scheme 4. Attempted Synthesis of Melicodenone C (5b) via

Allylic Oxidation of 1-epi-Aciphyllene (4b)

deshielded and displayed a H NMR chemical shift at 3.29

ppm, which diﬀered signiﬁcantly from the shielded 2.60−2.80

ppm multiplet displayed for the more shielded β-oriented H-1

of natural melicodenone C (5b).³¹The C-1 conﬁguration also

aﬀected the chemical environments of nearby C-10 and C-15

such that 0.52 and 0.17 ppm diﬀerences in the H NMR

chemical shifts for H-10 and H-15 between the two C-1

epimers were observed, respectively (see Supporting Informa-

tion for table of H and ¹³C NMR data for 5a and 5b).

Treatment of 5a with NaOMe (1 M in EtOH) resulted in the

migration of the terminal double bond to aﬀord the related

dienone 30 in near-quantitative yield. No epimerization to 5b

was observed in this reaction.

With the related dienone 30 as precursor to the

melicodenone series of derivatives in hand we now had the

opportunity to carry out oxidation at C-3 to accomplish the ﬁrst

synthesis of 1-epi-melicodenone E (6a) (Scheme 5). Thus,

dienone 30 was subjected to exhaustive oxidation with CrO₃(8

equiv) and 3,5-dimethylpyrazole (DMP) (9 equiv) in

CH₂Cl₂,^46,47which furnished a mixture of 1-epi-melicodenone

E (6a), epoxyenone 31, and epoxyenedione 32 in 13%, 24%,

and 15% yields, respectively. Altering the stoichiometry of the

oxidation reagents led to a signiﬁcantly diﬀerent product

distribution as depicted in Scheme 5. 1-epi-Melicodenone E

(6a) was generated as the main isolable product in 32% yield

(based on 16% recovery of 30) when 13 equiv of CrO₃and 28

equiv of DMP were employed. Furthermore, oxidation of 30

with excess CrO₃(19 equiv) and DMP (19 equiv) resulted in

the further oxidation of any 31 and 6a formed and aﬀorded

highly oxidized 32 as the dominant product in 40% isolated

yield. While epoxidations have been observed when employing

CrO₃previously,⁴⁸given the complex nature of the species

involved in these oxidative processes,⁴⁶it is diﬃcult to clearly

rationalize why the product outcomes are so aﬀected by the

stoichiometry of the reagents employed here. However, it may

simply be a case that lower levels of DMP result in less ligation

with the CrO₃, thus allowing epoxidation to compete with

allylic oxidation. Comparison of the ¹H NMR chemical shifts of

epi-6a to those of the natural product 6b³¹again displayed the

same pattern of chemical shift diﬀerences for H-1, H-10, and H-

15 as those highlighted above for 5a and 5b (Supporting

Information). X-ray analysis of 32 conﬁrmed its full structural

assignment (Supporting Information).

Reagents and conditions: (a) PDC, TBHP, 3 Å molecular sieves,

CH₂Cl₂, 0 °C, 5 h; (b) SeO₂, TBHP, CH₂Cl₂, 0 °C, 4 h; (c) SeO₂,

TBHP, CH₂Cl₂, 0 °C, 8 h.

material. Allylic oxidation of 24 with SeO₂and TBHP simply

furnished allylic alcohol 28, with a 7-OH moiety, as observed

previously.⁴⁰Installation of the hydroxy moiety on the α-face

was conﬁrmed from the ROESY correlations between OH and

H-6b, H-6a, and H-13 as well as H-6a and H-15 (Figure 2).

Further attempts at oxidation including Pd(OH)₂/C with

TBHP,⁴¹PDC in DMF,⁴²and CrO₃in HOAc⁴³all failed to

generate the target enedione (27).

In stark contrast to the attempted allylic oxidation at C-6

described for 1-epi-aciphyllene (4b), allylic oxidation of

aciphyllene (4a) employing stoichiometric SeO₂and TBHP

as oxidants³⁹aﬀorded allylic alcohol 29 in 33% yield (Scheme

5). The α-orientation of the C-6 hydroxy moiety was

established via ROESY, which showed interactions between

H-6 and the β-oriented H-15. The dramatic diﬀerences of

potential allylic oxidation sites between aciphyllene (4a) and 1-

epi-aciphyllene (4b) may be a combined result of steric eﬀects

and subtle changes in bond strengths of the allylic C−H bonds

at C-6 vs C-7 caused by varying through-bond hyperconjugative

eﬀects after conformational adjustment of the [5.3.0] bicyclic

core depending on whether H-1 is α- or β-oriented. Indeed, the

calculated equilibrium comformers of aciphyllene (4a) and 1-

epi-aciphyllene (4b) at the semiempirical AM1 level of theory

clearly show pronounced diﬀerences in the sterics surrounding

C-6 and C-7 along with signiﬁcant changes in the associated

C−H bond lengths (see Supporting Information). Attempts to

Figure 2. Key ROESY correlations for compounds 28 and 33−36.

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Scheme 5. Synthesis of 1-epi-Melicodenones C (5a) and E (6a)

Reagents and conditions: (a) SeO₂, TBHP, CH₂Cl₂, 0 °C, 4 h; (b) Dess−Martin periodinane, CH₂Cl₂, RT, 4 h; (c) NaOMe, EtOH, RT, 14 h; (d)

CrO₃(8 equiv), 3,5-dimethylpyrazole (DMP, 9 equiv), CH₂Cl₂, reﬂux, 24 h; (e) CrO₃(13 equiv), DMP (28 equiv), CH₂Cl₂, relux, 24 h; (f) CrO₃

(19 equiv), DMP (19 equiv), CH₂Cl₂, reﬂux, 24 h; (g) CeCl₃·H₂O, MeOH, 0 °C, 30 min, then NaBH₄, 10 min; (h) IBX, DMSO, RT, 3 h; (i) 3%

KOH (in MeOH), 40 °C, 1 h; (j) TsOH·H₂O (cat.), CH₂Cl₂, RT, 1 h.

Given that the conjugated enone moiety has now been

installed for 6a, epimerization at H-1 was expected to have

readily taken place under basic conditions given literature

precedents;⁴⁹⁻⁵²however, extensive trials with bases from mild

NaHCO₃to stronger NaOMe and acids including TsOH·H₂O

under various conditions failed to aﬀect epimerization at C-1. It

was found that enediones 6a and 32 decomposed considerably

over time under various basic conditions possibly due to intra-

or intermolecular Aldol-type condensations. However, com-

pound 6a remained intact under acidic conditions. As an

alternative we considered that removal of the fully conjugated

enedione systems from these derivatives while still maintaining

the en-3-one conjugated system would hinder decomposition

and in turn allow C-1 epimerization. Concealing the C-6

carbonyl moiety as a ketal proved infeasible, as experimental

trials showed that the C-6 carbonyl moiety of 6a was much

harder to ketalize than the C-3 enone using various alcohols

and diols under acidic conditions.

Alternatively, reducing the two carbonyl moieties to form a

diol followed by selective oxidation of the less hindered alcohol

appeared attractive. Interestingly, Luche reduction of 6a with

NaBH₄and CeCl₃·7H₂O saw the full recovery of 6a; however,

reduction of epoxyenedione 32 was eﬀective in furnishing

epoxydiol 33 in 77% yield. Oxidation of 33 with IBX in DMSO

yielded epoxyenone 34 in 29% yield accompanied by

regeneration of 32 in 36% yield. Epimerization of C-1 of

enone alcohol 34 under basic and acidic conditions, however,

again failed to aﬀord the targeted C-1 epimer. Treatment of

allylic alcohol 34 with 3% methanolic KOH^49,51simply

furnished 35, in which the allylic C-6 secondary alcohol moiety

underwent preferential epimerization. Attempts to epimerize C-

1 of 34 under acid-catalyzed conditions⁵²with TsOH·H₂O in

CH₂Cl₂aﬀorded the rearranged product 36 in 71% yield

without epimerization at C-1. The stereochemistries of 33−36

were established on the basis of ROESY analyses as outlined in

Figure 2. ROESY correlation from H-6 to H-15 was observed

for both 33 and 34, indicative of the α-orientation of the 3-

hydroxy moiety for both 33 and 34. The ROESY spectrum of

33 also displayed correlations from H-3 to H-1, suggesting the

3-OH moiety is β-oriented. The β-orientation of H-13 of 36

was deduced from the ROESY correlations observed between

H-13 and H-8a, H-13 and H-6, H-8a and H-9b, and H-9b and

H-15, whereas that of the 6-OH moiety of 35 was established

based on the ROESY correlations seen between H-8a and H-

15, and H-6 and H-8b. Together with the fact that 34 is the

precursor of 35 and 36 and the similar H and ¹³C NMR

spectra of 35 and 34, the stereochemistry of 35 and 36 were

thus elucidated as shown in Figure 2.

Herein we have demonstrated that a simple epoxidation,

ring-opening/elimination sequence on naturally occurring

guaiol (1a) allows for the eﬃcient synthesis of a range of

bridged sesquiterpenes in a facile manner. Key features include

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= 13.5, 9.6, 7.8, 3.0 Hz), 1.56−1.51 (2H, m), 1.39 (1H, m), 1.28 (1H,

ddt, J = 12.6, 9.0, 5.4 Hz), 1.17 (3H, s), 1.16 (3H, s), 0.99 (3H, d, J =

7.2 Hz), 0.96 (3H, d, J = 7.2 Hz), 0.01 (9H, s); ¹³C NMR (CDCl₃, 150

MHz) δ 139.8, 139.3, 76.7, 50.1, 46.3, 35.4, 33.85, 33.77, 31.1, 27.76,

27.67, 27.3, 26.3, 19.9, 19.7, 2.6; EIMS m/z (rel intensity) 204 (20),

189 (6), 161 (35), 147 (5), 131 (100), 117 (6), 105 (13), 91 (8), 79

(5), 73 (38); HRMS (ESI-TOF) m/z [M − OTMS]⁺205.1938 (calcd

for C₁₅H₂₅205.1956).

that the epoxidation of the centrally bridged double bond of

guaiol (1a) may be diastereoselectively controlled by

manipulating the epoxidizing reagent, solvent choice, and the

steric eﬀects of the remote protecting groups on the

hydroxyisopropyl moiety. Notably, the geometries of m-

CPBA and DMDO play an important role in the facial

selectivity of epoxidation of sterically biased bicyclic ring

systems such as guaiol (1a). The ring-opening of the central

epoxide and subsequent dehydration may be highly controlled,

allowing for the rapid synthesis of guaia-4(5)-en-11-ol (2a),

guaia-5(6)-en-11-ol (3), aciphyllene (4a), and their epimers

(2b and 4b). The potential of 1-epi-aciphyllene (4b) and

aciphyllene (4a) as precursors for the synthesis of melicode-

nones C (5b) and E (6b) and 1-epi-melicodenones C (5a) and

E (6a) and related derivatives was also explored, with

aciphyllene (4a) being an excellent precursor for the ﬁrst

synthesis of 5a and 6a. Interestingly, the conformationl

diﬀerences between 4a and 4b caused by the C-1 conﬁguration

dramatically manifest themselves in potential allylic oxidation

sites when employing SeO₂and TBHP as oxidants.

(1S,4S,7R)-7-[2-(Benzyloxy)propan-2-yl]-1,4-dimethyl-

1,2,3,4,5,6,7,8-octahydroazulene (1c). NaH (60% dispersion in

mineral oil, 2.2 g, 55 mmol) and 1a (1.15 g, 5.2 mmol) were

dissolved in dry DMF (25 mL). To the resulting solution were added

BnBr (3 mL, 25 mmol) and Bu₄NI (85 mg, 0.23 mmol) sequentially.

The resulting mixture was stirred at RT until TLC indicated no

starting material remained. The reaction was quenched by the slow

addition of brine (40 mL), and the products were extracted with

Et₂O/petroleum ether (20:80, 3 × 100 mL). The combined organic

layers were washed with brine (80 mL), dried over MgSO₄anhydrous,

and ﬁltered. The volatiles were removed in vacuo followed by short-

path distillation (190 °C, 0.7 Torr, Kugelroh), giving a distillate

containing 1a, which was further puriﬁed by SCC to recover 1a (401

mg, 35%). The higher boiling nondistilled fraction of the benzyl guaiol

(1c) was puriﬁed by SCC (petroleum ether) to furnish 1c (736 mg,

74%) as a colorless liquid: H NMR (CDCl₃, 500 MHz) δ 7.35−7.24

EXPERIMENTAL SECTION

■

(5ArH), 4.39 (2H, s), 2.54 (1H, appr sext, J = 7.8 Hz), 2.44 (1H, m),

2.32 (1H, appr quint, J = 9.0 Hz), 2.20 (1H, d, J = 18.0 Hz), 2.13 (1H,

m), 2.01−1.92 (2H, m), 1.90−1.79 (2H, m), 1.74 (1H, m), 1.62−1.50

(2H, m), 1.30 (1H, m), 1.23 (3H, s), 1.20 (3H, s), 1.01 (3H, d, J = 8.4

Hz), 0.96 (3H, d, J = 8.4 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 140.0,

139.9, 139.3, 128.2, 127.3, 127.0, 78.0, 63.0, 46.5, 46.6, 35.5, 33.81,

33.79, 31.0, 27.6, 27.1, 23.2, 22.7, 19.9, 19.6; EIMS m/z (rel intensity)

204 (29), 189 (8), 161 (41), 149 (11), 119 (9), 107 (18), 91 (100), 79

(15), 67 (5); HRMS (ESI-TOF) m/z [M − OBn]⁺205.1973 (calcd

for C₁₅H₂₅205.1956).

General Experimental Procedures. All reagents were purchased

from commercial sources and were used directly unless otherwise

stated. Solvents for synthesis were dried according to known

procedures where necessary.⁵³Solvents for general chromatography

were AR grade except that those used for GC-MS and HRMS analysis

were HPLC grade. All reactions were conducted under a N₂

atmosphere. SNIS and DMDO (50 μM in acetone) were prepared

according to the literature.^54,55Guaiol (1a) was obtained by repeated

recrystallization of commercial guaiac wood essential oil from

MeCN.²¹Melting points are uncorrected and were obtained on a

Buchi B-540 melting point apparatus. Silica column chromatography

(SCC) was performed using either LC60A 40−63 μm silica (Grace

Davison) or silica gel 60 (0.015−0.040 mm) from Merck. TLC was

conducted with TLC silica gel 60 F₂₅₄plates (Merck KGaA) using

standard vanillin stain for visualization. GC-MS/FID analysis was

performed with a 6890 GC coupled with a 5973N MSD or a 7890A

GC-FID (Agilent Technologies). DB-5 or HP-5 capillary columns

were used for GC-MS/FID analysis throughout this study. HRMS

(ESI-TOF) analysis was performed with a Triple TOF 5600 mass

spectrometer from AB Sciex Instruments. Density functional theory

(DFT) calculations of guaiol (1a) and 8a,b were carried out at the

B3LYP/6-31G(d) level. Geometry optimization of 4a,b was carried

out at the semiempirical AM1 level. All calculations were performed

using the Spartan 08 package of programs. NMR spectra were

recorded with a Varian-Inova 500/600 MHz spectrometer. All

compounds for NMR analysis were dissolved in either CDCl₃or

benzene-d₆. All ¹H and ¹³C NMR spectra were calibrated with residual

deuterated solvent signals set at 7.26 and 77.0 ppm for CDCl₃and

7.16 and 128.06 ppm for benzene-d₆, respectively. COSY, ROESY,

HSQC, and HMBC were common 2D NMR techniques used

Guaiyl Acetate (1d) and α-Guaiene (7a). Both 1d and 7a were

prepared according to a literature procedure.⁵⁶Guaiol (1a, 10.2 g, 50

mmol) was added to a mixture of Ac₂O (100 mL, 847 mmol) and

DMAP (245 mg, 1.7 mmol) under N₂and heated under reﬂux at 150

°C for 6 h until TLC analysis showed the reaction to be complete. The

reaction mixture was allowed to cool to RT and extracted with n-

hexane (4 × 100 mL). The organic extracts were combined, and silica

(ca. 50 g) added. The resulting suspension was well mixed before

being ﬁltered through a pad of silica (ca. 50 g). The silica sorbent was

further rinsed with n-hexane (3 × 200 mL) and ﬁltered through the

same pad of silica. The combined ﬁltrate was concentrated in vacuo to

furnish acetate 1d (13.1 g, 99%) as a yellowish oil. Crude 1d (ca. 30 g)

prepared as described above using 1 (21.0 g, 95 mmol), Ac₂O (80 mL,

847 mmol), and DMAP (210 mg, 1.7 mmol) was subjected to

pyrolysis without puriﬁcation. The crude 1d was heated to 220 °C

under N₂for 6 h, while the acetic acid liberated was collected by

distillation into a receiving ﬂask. The resulting mixture was cooled to

ambient temperature, and n-hexane (100 mL) and silica (50 g) were

added. The suspension was well mixed before being ﬁltered through a

plug of silica (ca. 70 g) under reduced pressure and further rinsed with

n-hexane (4 × 150 mL). The n-hexane fractions were combined, and

the volatiles removed in vacuo to furnish 7a as a colorless oil (17.8 g,

wherever full assignment of H and ¹³C NMR signals were made.

{2-[(3S,5R,8S)-3,8-Dimethyl-1,2,3,4,5,6,7,8-octahydroazulen-5-yl]-

propan-2-yl-oxy}(trimethyl)silane (1b). A mixture of 1a (21.5 mg, 0.1

mmol), hexamethyldisilane (HMDS, 55 μL, 269 μmol), MgBr₂.Et₂O

(21 mg, 81 μmol), and N,O-bistrimethylsilyl triﬂuoroacetamide

(BSTFA, 25 μL, 94 μmol) was stirred at RT until TLC showed

complete consumption of 1a. The reaction was quenched with brine

(10 mL) and extracted with petroleum ether (3 × 15 mL). The

combined organic extracts were washed with brine (20 mL), dried

over anhydrous MgSO₄, and ﬁltered through a short silica plug, and

the volatiles were removed in vacuo to aﬀord 1b (20.8 mg, 73%) as a

colorless liquid: ¹H NMR (CDCl₃, 600 MHz) δ 2.53 (1H, appr sext, J

= 6.6 Hz), 2.41 (1H, m), 2.28 (1H, appr quint, J = 7.8 Hz), 2.15 (1H,

d, J = 9.0 Hz), 2.11 (1H, m), 1.97 (1H, dddd, J = 12.6, 9.6, 8.4, 5.4

Hz), 1.86 (1H, t, J = 13.5 Hz), 1.79−1.72 (1H, m), 1.69 (1H, dddd, J

92%, 2 steps): H NMR (CDCl₃, 600 MHz) δ 4.68 (1H, dq, J = 1.2,

0.9 Hz, H-12α), 4.62 (1H, dq, J = 2.1, 1.5 Hz, H-12β), 2.56 (1H, m,

H-4), 2.44 (1H, dtd, J = 14.4, 6.0, 2.4 Hz, H-2α), 2.35 (1H, qd, J = 7.2,

6.0 Hz, H-10), 2.19−2.14 (2H, m, H-6α and H-2β), 2.13 (1H, m, H-

7), 1.99−1.96 (2H, m, H-3α and H-6β), 1.73 (3H, dd, J = 1.5, 0.9 Hz,

H-13), 1.71 (2H, m, H-8α and H-8β), 1.68 (1H, m, H-9α), 1.61 (1H,

m, H-9β), 1.29 (1H, m, H-3β), 1.01 (3H, d, J = 7.2 Hz, H-15), 0.94

(3H, d, J = 7.2 Hz, H-14); ¹³C NMR (CDCl₃, 150 MHz) δ 152.4 (C-

11), 140.5 (C-1), 138.5 (C-5), 107.9 (C-12), 46.5 (C-7), 46.1 (C-4),

36.2 (C-2), 33.8 (C-9), 33.7 (C-10), 33.3 (C-6), 31.1 (C-8), 31.0 (C-

3), 20.4 (C-13), 19.8 (C-14), 18.5 (C-15); EIMS m/z (rel intensity)

204 (57), 189 (51), 175 (8), 161 (28), 147 (89), 133 (58), 119 (36),

105 (100), 93 (64), 79 (47), 67 (23), 55 (23).

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2-[(3S,5R,8S)-3,8-Dimethyl-1,2,3,4,5,6,7,8-octahydroazulen-5-yl]-

propan-2-yl Benzoate (1e). The synthesis was conducted according

to that in the literature.⁵⁷To a stirred solution of 1a (53 mg, 239

μmol) in pyridine (1 mL, 13 mmol) was added BzCl (150 μL, 1.3

mmol). The resulting mixture was heated to 50 °C until TLC

indicated the consumption of 1a. The reaction was quenched with

saturated aqueous NaHCO₃solution (5 mL). Standard workup and

puriﬁcation yielded 1e (58.8 mg, 76%) as a colorless oil. Spectroscopic

data were in agreement with those reported.⁵⁷

76.7, 73.8, 71.8, 47.8, 40.9, 32.8, 31.7, 29.9, 29.7, 28.0, 27.7, 27.4, 25.2,

17.1, 16.2, 2.9.

10a: H NMR (benzene-d₆, 500 MHz) δ 7.38 (2H, br d, J = 8.0

Hz), 7.23 (2H, t, J = 7.5 Hz), 7.12 (1H, tt, J = 7.7, 3.5 Hz), 4.29 (2H,

d, J = 4.5 Hz), 2.30 (1H, d, J = 14.0 Hz), 1.93 (1H, dd, J = 13.0, 8.2

Hz), 1.90−1.65 (4H, m), 1.64 (1H, dd, J = 14.5, 11.8 Hz), 1.53 (1H,

dd, J = 14.2, 11.0 Hz), 1.45 (1H, m), 1.28−1.21 (2H, m), 1.13 (2H,

m), 1.11 (3H, d, J = 6.8 Hz), 1.10 (3H, d, J = 6.8 Hz), 1.01 (3H, s),

0.96 (3H, s); ¹³C NMR (benzene-d₆, 125 MHz) δ 140.63, 128.6,

128.5, 127.3, 127.2, 77.5, 73.7, 72.2, 63.3, 44.3, 38.1, 35.0, 31.3, 28.5,

28.3, 28.1, 26.4, 22.9, 21.0, 19.0, 13.9.

2-[(3S,3aS,5R,8S,8aS)-3,8-Dimethylhexahydro-1H,4H-3a,8a-ep-

oxyazulen-5-yl]propan-2-ol (8a). To a stirred solution of 1d (4.0 g,

15.2 mmol) in Et₂O (40 mL) at −78 °C was added dropwise a

solution of m-CPBA (77%, 3.56 g, 15.9 mmol) in Et₂O (50 mL). The

solution was allowed to warm to RT over 80 min. After cessation of

the reaction (TLC), the reaction was quenched with solid KI (500

mg) and washed with saturated Na₂S₂O₃solution (100 mL) followed

by saturated NaHCO₃solution (100 mL). Standard workup aﬀorded

the crude epoxy-guaiyl acetate diastereomeric mixture (β:α, 84:16,

based on GC-MS), which was used directly without further

puriﬁcation due to its sensitivity on silica. To a stirred solution of

the crude mixture of epoxy-guaiyl acetates (4.3 g) in MeOH (50 mL)

under N₂was added Na metal (1.8 g, 78 mmol) in portions. The

resulting mixture was stirred at RT until TLC indicated the

consumption of the starting materials (ca. 12 h). The reaction mixture

was then concentrated in vacuo to ca. 10 mL. Brine (80 mL) was

added, and the mixture extracted with Et₂O (3 × 50 mL). The

combined ether extracts were dried over anhydrous MgSO₄, ﬁltered,

and concentrated in vacuo to yield 3.6 g of crude products. Puriﬁcation

by SCC (Et₂O/petroleum ether, 15:85) furnished pure 8a (3.03 g,

84%) as a pale yellow oil: EIMS m/z (rel intensity) 220 (14), 202 (6),

187 (12), 159 (16), 138 (35), 123 (62), 105 (28), 95 (48), 59 (100).

¹H and ¹³C NMR spectroscopic data were in accord with those

10b: To a stirred solution of 1c (51 mg, 0.16 mmol) in acetone (1

mL) at 0 °C was added DMDO (50 μmol, 6 mL, 0.3 mmol). The

reaction mixture was stirred for 2 h and allowed to warm to RT. After

2 h, the reaction crude mixture was concentrated in vacuo and puriﬁed

on neutral alumina (Et₂O/petroleum ether, 5−8%) to give 10b (24

mg, 45%) as a colorless oil: H NMR (benzene-d₆, 500 MHz) δ 7.38

(2H, d, J = 8.0 Hz), 7.20 (2H, t, J = 7.5 Hz), 7.10 (1H, t, J = 7.5 Hz),

4.34, 4.29 (2H, ABq, J = 11.5 Hz), 2.37 (1H, br d, J = 15.0 Hz), 2.29

(1H, m), 2.12 (1H, tt, J = 11.5, 1.5 Hz), 2.08 (1H, quint, J = 7.0 Hz),

1.96 (1H, tt, J = 13.5, 2.8 Hz), 1.87−1.77 (2H, m), 1.71−1.58 (3H,

m), 1.42 (1H, m), 1.11 (3H, s), 1.10 (3H, s), 0.99−0.94 (2H, m), 0.92

(3H, d, J = 7.0 Hz), 0.73 (3H, d, J = 7.0 Hz); ¹³C NMR (benzene-d₆,

125 MHz) δ 140.6, 128.5, 127.6, 127.2, 77.5, 73.0, 72.0, 63.3, 43.1,

40.8, 32.9, 31.8, 29.7, 29.6, 27.7, 25.1, 23.7, 23.5, 17.0, 16.2.

Following the above procedure with 1c (68 mg, 0.22 mmol),

acetone (2 mL), and DMDO (0.05 M, 6 mL) gave crude 10b (66 mg),

which was directly used for reduction with AlH₃. To a stirred solution

of LiAlH₄(95 mg, 2.5 mmol) in dry THF (1 mL) was added dropwise

a solution of anhydrous AlCl₃(25 mg, 0.19 mmol) in dry THF (1 mL)

at RT. The resulting mixture was stirred for 5 min before the further

dropwise addition of a solution of crude 10b (66 mg) in dry THF (2

mL). The reaction was stirred at RT for 6 h and then heated under

reﬂux at 70 °C for an additional 7 h. The reaction was quenched with

H₂O (5 mL), and resulting solution was extracted with Et₂O (3 × 10

mL). The combined ether layers were washed with brine (10 mL),

dried over anhydrous MgSO₄, and ﬁltered. The ﬁltrate was

concentrated in vacuo, and the residue puriﬁed by SCC (petroleum

ether) to recover 1c (23 mg, 34% over 2 steps).

reported previously.⁵⁸

2-[(3S,3aR,5R,8S,8aR)-3,8-Dimethylhexahydro-1H,4H-3a,8a-ep-

oxyazulen-5-yl]propan-2-ol (8b). 1a (228 mg, 1.0 mmol) and

DMDO (0.05 M in acetone, 25 mL, 1.3 mmol) were mixed at 0 °C

under N₂. The mixture was allowed to warm to RT over 3 h and then

concentrated in vacuo, and the residue puriﬁed by SCC (Et₂O/

petroleum ether, 20:80) to aﬀord 8b (158.8 mg, 65%) as a white solid.

11a: ¹H NMR (benzene-d₆, 500 MHz) δ 2.30 (1H, m), 1.98 (1H, d,

J = 14.0 Hz), 1.91−1.84 (2H, m), 1.74 (1H, ddd, J = 10.5, 7.0, 1.8 Hz),

1.70 (3H, s), 1.60 (1H, m), 1.48 (1H, dd, J = 14.5, 11.2 Hz), 1.47−

1.39 (2H, m), 1.36 (3H, s), 1.24 (3H, s), 1.22 (1H, ddd, J = 13.5, 10.5,

8.0 Hz), 1.17−1.08 (3H, m), 1.08 (3H, d, J = 7.0 Hz), 1.06 (3H, d, J =

7.0 Hz); ¹³C NMR (benzene-d₆, 125 MHz) δ 169.6, 84.8, 72.3, 72.1,

43.1, 37.9, 34.7, 31.1, 28.3, 28.0, 27.9, 26.7, 23.6, 22.4, 22.1, 18.9, 13.8.

11b: ¹H NMR (benzene-d₆, 500 MHz) δ 2.36 (1H, tt, J = 11.5, 1.8

Hz), 2.24 (1H, m), 2.21 (1H, dtd, J = 14.5, 2.4, 1.0 Hz), 2.10 (1H,

quint, J = 6.7 Hz), 1.92 (1H, tdd, J = 12.6, 3.3, 2.0 Hz), 1.85−1.75

(2H, m), 1.68 (3H, s), 1.64−1.53 (3H, m), 1.42 (3H, s), 1.41 (3H, s),

1.41−1.35 (2H, m), 0.95 (1H, m), 0.89 (3H, d, J = 7.0 Hz), 0.75 (3H,

d, J = 7.0 Hz); ¹³C NMR (benzene-d₆, 125 MHz) δ 169.5, 84.7, 72.8,

71.6, 45.0, 40.8, 32.7, 31.4, 29.6, 29.5, 27.6, 24.6, 23.6, 23.4, 22.2, 17.0,

16.2.

8b: mp 83.1−85.5 °C; H NMR (benzene-d₆, 600 MHz) δ 2.39 (1H,

br d, J = 14.4 Hz), 2.27 (1H, m), 2.10 (1H, quint, J = 7.2 Hz), 1.92

(1H, tdd, J = 13.2, 3.6, 2.4 Hz), 1.86−1.78 (2H, m), 1.69−1.60 (3H,

m), 1.57 (1H, dd, J = 14.4, 12.0 Hz), 1.43−1.38 (1H, m), 0.99 (3H, s),

0.98 (3H, s), 0.96 (1H, m), 0.90 (3H, d, J = 7.2 Hz), 0.89−0.84 (1H,

m), 0.74 (3H, d, J = 7.2 Hz); ¹³C NMR (benzene-d₆, 150 MHz) δ

72.8, 72.4, 72.0, 47.4, 40.8, 32.8, 31.7, 29.74, 29.67, 27.8, 27.7, 26.5,

25.3, 17.0, 16.2; EIMS m/z (rel intensity) 220 (27), 202 (15), 187

(28), 159 (58), 138 (32), 123 (57), 105 (46), 95 (47), 59 (100).

General Procedure for 9a−12b. To a stirred solution of

substrate (0.1 mmol) in CH₂Cl₂(1 mL) was added m-CPBA (77%,

40 mg, 0.18 mmol) at RT. After 10 min, the reaction was quenched

with solid KI (5 mg) and washed with saturated Na₂S₂O₃solution (1

mL) followed by saturated NaHCO₃solution (2 mL). The resulting

mixture was extracted with Et₂O (3 × 5 mL). The combined ether

layers were further washed with brine (5 mL), dried over anhydrous

MgSO₄, and ﬁltered. The ﬁltrate was concentrated in vacuo and

puriﬁed on neutral alumina to furnish the epoxides of guaiol

derivatives 9a and 9b (29.3 mg, 96%), 10a and 10b (30 mg, 95%),

11a (20 mg, 75%) and 11b (5 mg, 19%), and 12a and 12b (9 mg,

12a: H NMR (benzene-d₆, 500 MHz) δ 8.16 (1H, t, J = 1.5 Hz),

8.15 (1H, t, J = 1.5 Hz), 7.14−7.06 (3H, m), 2.38 (1H, td, J = 11.5, 6.5

Hz), 2.11 (1H, d, J = 14.5 Hz), 1.93−1.87 (2H, m), 1.83−1.55 (4H,

m), 1.48 (3H, s), 1.42 (1H, m), 1.37 (3H, s), 1.26−1.17 (2H, m), 1.10

(2H, m), 1.07 (3H, d, J = 7.0 Hz), 1.02 (3H, d, J = 7.0 Hz); ¹³C NMR

(benzene-d₆, 125 MHz) δ 165.5, 132.6, 129.7, 128.5, 85.8, 73.3, 72.1,

43.6, 37.9, 34.7, 31.1, 28.3, 28.1, 27.9, 26.7, 23.8, 22.2, 18.9, 13.7.

95%) as colorless oils. 9a: H NMR (benzene-d₆, 500 MHz) δ 2.23

(1H, d, J = 13.0 Hz), 2.00−1.4 (11H, m), 1.22 (1H, ddd, J = 13.5,

10.5, 8.0 Hz), 1.17 (3H, d, J = 6.5 Hz), 1.10 (3H, d, J = 6.5 Hz), 1.09

(3H, s), 0.92 (3H, s), 0.17 (9H, s); ¹³C NMR (benzene-d₆, 125 MHz)

δ 76.5, 72.7, 72.1, 47.83, 37.8, 34.9, 31.2, 28.7, 28.3, 28.2, 28.1, 26.5,

25.1, 19.1, 13.9, 2.7.

12b: H NMR (benzene-d₆, 500 MHz) δ 8.18 (1H, t, J = 1.5 Hz),

8.17 (1H, t, J = 1.5 Hz), 7.15−7.03 (3H, m), 2.54 (1H, tt, J = 11.5, 1.8

Hz), 2.38 (1H, td, J = 11.5, 6.5 Hz), 2.30 (1H, dt, J = 14.5, 3.0 Hz),

2.25 (1H, m), 2.06 (1H, t, J = 7.0 Hz), 1.95 (1H, m), 1.88 (1H, m),

1.80 (1H, m), 1.80−1.50 (3H, m), 1.54 (3H, s), 1.52 (3H, s), 1.48

(1H, m), 1.18 (1H, m), 0.94 (1H, m), 0.89 (3H, d, J = 7.0 Hz), 0.72

(3H, d, J = 7.0 Hz); ¹³C NMR (benzene-d₆, 125 MHz) δ 165.3, 132.8,

132.7, 132.5, 129.8, 85.8, 72.8, 71.6, 45.3, 40.8, 32.7, 31.4, 29.7, 29.6,

27.6, 24.8, 23.6, 23.5, 17.0, 16.2.

9b: H NMR (benzene-d₆, 500 MHz) δ 2.41 (1H, br d, J = 13.0

Hz), 2.27 (1H, m), 2.14 (1H, quint, J = 7.0 Hz), 2.00−1.4 (9H, m),

1.14 (1H, m) 1.16 (3H, s), 1.13 (3H, s), 0.92 (3H, d, J = 7.0 Hz), 0.79

(3H, d, J = 7.0 Hz), 0.20 (9H, s); ¹³C NMR (benzene-d₆, 125 MHz) δ

2530

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13a,b: Prepared as described by us previously.⁵⁹

= 7.2 Hz, H-15), 1.03 (3H, s, H-12), 0.99 (3H, s, H-13), 0.93 (3H, d, J

= 6.6 Hz, H-14); ¹³C NMR (benzene-d₆, 150 MHz) δ 82.8 (C-5), 72.9

(C-11), 52.5 (C-1), 46.8 (C-7), 44.9 (C-4), 36.0 (C-8), 34.4 (C-9),

33.5 (C-10), 29.9 (C-3), 29.1 (C-12), 27.8 (C-13), 25.9 (C-2), 23.6

(C-6), 16.2 (C-15), 13.0 (C-14); EIMS m/z (rel intensity) 222 (10),

207 (51), 189 (41), 151 (59), 125 (91), 109 (82), 95 (77), 81 (96), 55

(100). Other physical data were in accord with those reported

previously.²³

(1S,3aR,4S,7R,8aR)-1,4-Dimethyl-7-[(2R)-2-methyloxiran-2-yl]-

hexahydro-1H,4H-3a,8a-epoxyazulene (14c) and (1S,3aR,4S,7-

R,8aR)-1,4-Dimethyl-7-[(2S)-2-methyloxiran-2-yl]hexahydro-1H,4H-

3a,8a-epoxyazulene (14d). To a stirred solution of α-guaiene (7a,

51.8 mg, 250 μmol) in CH₂Cl₂(3 mL) was added m-CPBA (320 mg,

1.4 mmol). The mixture was stirred at ambient temperature for 30 min

and quenched with KI (30 mg), saturated Na₂S₂O₃, and NaHCO₃

solution. The resulting mixture was extracted with Et₂O (3 × 50 mL),

and the combined ether layers were further washed with brine (100

mL) and dried over anhydrous MgSO₄. The volatiles were removed in

vacuo with the residue puriﬁed by silica column chromatography (silica

pretreated with 5% Et₃N/hexanes, eluted with 8% Et₂O/hexanes) to

yield 14c (14 mg, 24%) as a colorless liquid and 14d (12 mg, 20%) as

a colorless liquid along with a mixture of bis-epoxides (14a,b, 12 mg,

20%) as a colorless oil. Crystals of 14c and 14d were obtained by slow

evaporation from an n-hexane solution. 14a (or 14b): ¹H NMR

(CDCl₃, 600 MHz) δ 2.59, 2.57 (2H, ABq, J = 4.8 Hz), 2.13 (1H, d, J

= 8.4 Hz), 2.05−1.91 (3H, m), 1.88 (1H, m), 1.77 (1H, m), 1.64−1.54

(1H, m), 1.54−1.43 (3H, m), 1.36−1.24 (2H, m), 1.21 (3H, s), 1.03

(6H, d, J = 7.2 Hz), 0.94 (1H, m); ¹³C NMR (CDCl₃, 150 MHz) δ

73.2, 73.1, 59.8, 54.5, 43.0, 37.8, 34.0, 31.1, 28.7, 28.5, 27.7, 27.8, 18.0,

16.6, 13.5; EIMS m/z (rel intensity) 236 (6), 207 (19), 179 (34), 163

(44), 137 (50), 107 (80), 81 (83), 67 (83), 55 (100). 14b (or 14a):

¹H NMR (CDCl₃, 600 MHz) δ 2.55 (2H, s), 2.05−1.91 (3H, m),

(3S,3aS,5R,8S,8aS)-5-[2-(Benzyloxy)propan-2-yl]-3,8-dimethyl-

octahydroazulen-3a(1H)-ol (16). This synthesis followed the same

procedure as for 1c except that NaH (163 mg, 4.1 mmol), 15a (106

mg, 442 μmol), dry DMF (2 mL), BnBr (250 μL, 2.1 mmol), and

Bu₄NI (6 mg, 16 μmol) were utilized. The reaction was quenched by

the slow addition of brine (10 mL), after which the products were

extracted with Et₂O/petroleum ether (20:80, 3 × 25 mL). The

combined organic layers were washed with brine (30 mL), dried over

anhydrous MgSO₄, and ﬁltered. The volatiles were removed in vacuo,

and the residue was puriﬁed by SCC (petroleum ether/Et₂O, gradient

elution from 100:0 to 92:8), aﬀording 16 (107 mg, 73%) as a colorless

oil: ¹H NMR (benzene-d₆, 600 MHz) δ 7.33−7.09 (5ArH), 4.23 (2H,

s), 1.93−1.84 (3H, m), 1.83−1.78 (2H, m), 1.77−1.73 (1H, m), 1.70

(1H, dd, J = 15.0, 7.8 Hz), 1.66−1.61 (2H, m), 1.61−1.58 (1H, m),

1.57−1.50 (2H, m), 1.45 (1H, dtd, J = 12.6, 9.0, 4.2 Hz), 1.37 (1H,

dddd, J = 12.6, 11.4, 9.6, 4.2 Hz), 1.24 (3H, d, J = 7.2 Hz), 1.08 (3H,

s), 1.05 (3H, s), 0.87 (3H, d, J = 6.6 Hz); ¹³C NMR (benzene-d₆, 150

MHz) δ 140.0, 128.6, 128.3, 127.5, 82.6, 78.2, 63.9, 51.7, 45.5, 44.8,

36.2, 34.8, 33.6, 29.9, 25.9, 24.4, 23.9, 23.0, 16.5, 12.9; EIMS m/z (rel

intensity) 222 (1), 207 (6), 189 (4), 161 (6), 149 (25), 125 (6), 107

(15), 91 (100), 79 (18), 55 (15); HRMS (ESI-TOF) m/z [M + H]⁺

331.2653 (calcd for C₂₂H₃₅O₂, 331.2637).

(1S,3aS,4S,7R)-7-[2-(Benzyloxy)propan-2-yl]-1,4-dimethyl-

1,2,3,3a,4,5,6,7-octahydroazulene (17). To a stirred solution of 16

(12.5 mg, 38 μmol) in benzene (1 mL) were added Et₃N (20 μL, 0.21

mmol) and SOCl₂(20 μL, 0.28 mmol). The resulting mixture was

stirred at RT for 20 min, and then the reaction was quenched with

saturated aqueous NaHCO₃solution (10 mL) and extracted with Et₂O

(3 × 30 mL). The combined ether layers were washed with brine (30

mL), dried over anhydrous MgSO₄, and ﬁltered. Removal of the

volatiles in vacuo followed by puriﬁcation by SCC (n-hexane) aﬀorded

17 (8.1 mg, 69%) as a colorless oil: ¹H NMR (benzene-d₆, 600 MHz)

δ 7.40−7.10 (5ArH), 5.77 (1H, d, J = 1.8 Hz, H-6), 4.35 (2H, s,

PhCH₂), 2.84 (1H, m, H-7), 2.51−2.45 (2H, m, H-1 and H-10),

1.87−1.84 (1H, m, H-8a), 1.78−1.70 (3H, m, H-4, H-8b and H-2a),

1.68−1.62 (2H, m, H-3a and H-9a), 1.51−1.47 (1H, m, H-2b), 1.37

(1H, td, J = 6.6, 2.4 Hz, H-9b), 1.29 (1H, dq, J = 12.0, 7.8 Hz, H-3b),

1.21 (3H, s, H-12), 1.19 (3H, s, H-13), 1.06 (3H, d, J = 6.6 Hz, H-15),

0.86 (3H, J = 6.6 Hz, H-14); ¹³C NMR (benzene-d₆, 150 MHz) δ

151.1 (C-5), 140.7 (ArC), 128.6 (ArC), 128.5 (ArC), 128.3 (ArC),

127.7 (ArC), 127.2 (ArC), 123.3 (C-6), 77.5 (C-11), 63.5 (phCH₂),

49.3(C-10), 48.4 (C-7), 41.0 (C-1), 39.6 (C-8), 34.6 (C-3), 33.8 (C-

4), 31.3(C-2), 23.6 (C-12), 22.8 (C-13), 22.1(C-19), 19.5 (C-15),

14.6 (C-14); EIMS m/z (rel intensity) 204 (3), 189 (2), 163 (9), 149

(16), 119 (4), 107 (14), 91 (100), 79 (9), 67 (4); HRMS (ESI-TOF)

m/z [M −OBn]⁺205.1918 (calcd for C₁₅H₂₅, 205.1956).

1.64−1.54 (4H, m), 1.54−1.43 (3H, m), 1.36−1.24 (2H, m), 1.24

(3H, s), 1.03 (3H, d, J = 6.6 Hz), 1.01 (3H, d, J = 6.6 Hz), 0.94 (1H,

m); ¹³C NMR (CDCl₃, 150 MHz) δ 73.1, 73.0, 59.8, 53.2, 41.6, 37.8,

34.0, 31.1, 28.4, 28.0, 27.9, 27.8, 18.0, 17.9(5), 13.5; EIMS m/z (rel

intensity) 236 (15), 207 (35), 179 (37), 163 (71), 135 (49), 107 (89),

81 (86), 67 (78), 55 (100). 14c: R_f0.57 (30% Et₂O/hexanes); mp

61.3−61.5 °C; ¹H NMR (CDCl₃, 600 MHz) δ 2.61, 2.58 (2H, ABq, J

= 4.8 Hz), 2.38 (1H, qt, J = 7.2, 3.6 Hz), 2.23 (1H, d, J = 14.4 Hz),

2.15 (1H, quint, J = 7.2 Hz), 1.99 (1H, dd, J = 8.4, 3.6 Hz), 1.87 (1H,

dd, J = 14.4, 12.0 Hz), 1.73 (1H, ddd, J = 13.2, 12.0, 3.0 Hz), 1.67−

1.60 (2H, m), 1.51−1.42 (2H, m), 1.32 (1H, t, J = 12.0 Hz), 1.22 (3H,

s), 1.17 (1H, q, J = 12.6 Hz), 1.10 (1H, m), 1.08 (3H, d, J = 7.2 Hz),

0.93 (3H, d, J = 7.2 Hz); ¹³C NMR (CDCl₃, 150 MHz) δ 73.4, 72.3,

60.3, 55.3, 42.8, 39.9, 32.1, 30.5, 29.9, 29.3, 27.2, 26.6, 17.2, 16.8, 15.7;

EIMS m/z (rel intensity) 236 (3), 207 (15), 179 (43), 161 (46), 145

(58), 137 (48), 123 (100), 93 (94), 79 (73), 67 (73), 55 (96). 14d: R_f

0.49 (30% Et₂O/hexanes); mp 61.1−61.3 °C; H NMR (CDCl₃, 600

MHz) δ 2.62, 2.58 (2H, ABq, J = 4.8 Hz), 2.39 (1H, qt, J = 7.2, 3.6

Hz), 2.13 (1H, quint, J = 7.2 Hz), 2.04 (1H, br d, J = 14.4 Hz), 1.99

(1H, dd, J = 8.4, 3.6 Hz), 1.81 (1H, dd, J = 14.4, 12.0 Hz), 1.73 (1H,

tt, J = 13.2, 3.0 Hz), 1.70−1.60 (3H, m), 1.50 (1H, m), 1.32 (1H, tt, J

= 12.0, 1.8 Hz), 1.25 (1H, m), 1.22 (3H, s), 1.11 (1H, m), 1.08 (3H, d,

J = 7.2 Hz), 0.92 (3H, d, J = 7.2 Hz); ¹³C NMR (CDCl₃, 150 MHz) δ

73.8, 72.1, 60.6, 55.1, 42.9, 40.0, 32.1, 31.3, 30.5, 29.4, 27.2, 25.5, 17.3,

16.8, 15.9; EIMS m/z (rel intensity) 236 (2), 203 (18), 179 (35), 161

(46), 145 (48), 137 (45), 123 (80), 109 (80), 93 (87), 79 (76), 67

(75), 55 (100).

(3S,3aS,5R,8S,8aS)-5-(2-Hydroxypropan-2-yl)-3,8-dimethyl-

octahydroazulen-3a(1H)-ol (15a). To a stirred solution of LiAlH₄

(165 mg, 4.1 mmol) in dry THF (3 mL) was added dropwise a

solution of anhydrous AlCl₃(197 mg, 1.5 mmol) in dry THF (3 mL)

at RT. The resulting mixture was stirred for 5 min before the further

dropwise addition of a solution of 8a (476 mg, 2.0 mmol) in dry THF

(2 mL). After stirring at RT for 4 h, the reaction was quenched by

slowly adding a H₂SO₄solution (6 N, 0.5 mL) and H₂O (5 mL)

sequentially at 0 °C. The crude mixture was extracted with Et₂O (3 ×

50 mL), and the combined organic layers were washed with brine (50

mL), dried over anhydrous MgSO₄, and ﬁltered. The volatiles were

removed in vacuo, and the residue was puriﬁed by SCC (Et₂O/

petroleum ether, 17:83) to yield 15a (377 mg, 79%) as a yellow oil: ¹H

NMR (benzene-d₆, 600 MHz) δ 2.05 (1H, br s, OH), 1.95−1.89 (1H,

m, H-10), 1.88−1.81 (2H, m, H-2a and H-6a), 1.81−1.72 (3H, m, H-

3a, H-8a and H-9a), 1.63−1.55 (3H, m, H-1, H-6b and H-8b), 1.54−

1.50 (2H, m, H-4 and H-9b), 1.46 (1H, ddd, J = 13.2, 8.4, 4.9 Hz, H-

2b), 1.41−1.36 (1H, m, H-7), 1.36−1.32 (1H, m, H-3b), 1.25 (3H, d, J

2-[(3S,5R,8S,8aS)-3,8-Dimethyl-1,2,3,5,6,7,8,8a-octahydroazulen-

5-yl]propan-2-ol; Guaia-5(6)-en-11-ol (3). This synthesis followed

the procedure of 17 except that 16 (41 mg, 0.13 mmol), benzene (2

mL), Et₃N (50 μL, 0.53 mmol), and SOCl₂(40 μL, 0.56 mmol) were

used to yield crude 17 (40 mg), which was used in the next step

without further puriﬁcation. Crude 17 (40 mg) was dissolved in dry

THF (3 mL), and naphthalene (23 mg, 0.18 mmol) and Li wire (30

mg, 4.3 mmol) were added at −78 °C, after which time the mixture

was allowed to attain room temperature. After stirring for a total of 18

h, the reaction was quenched with H₂O (3 mL) and extracted with

Et₂O (3 × 10 mL). The combined ether layers were washed with brine

(10 mL), dried over anhydrous MgSO₄, and ﬁltered. The volatiles

were removed in vacuo, and the residue was puriﬁed by SNIS to

furnish 3 (17 mg, 64% over 2 steps) as a colorless oil: H NMR

(CDCl₃, 500 MHz) δ 5.51 (1H, br s), 2.86 (1H, m), 2.45 (1H, appr

sext, J = 7.2 Hz), 2.15 (1H, br d, J = 11.0 Hz), 1.87 (1H, m), 1.85−

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1.76 (3H, m), 1.74 (1H, m), 1.69 (1H, m), 1.53 (1H, ddd, J = 12.5,

5.0, 2.3 Hz), 1.31−1.25 (2H, m), 1.22 (3H, s), 1.21 (3H, s), 1.02 (3H,

d, J = 7.0 Hz), 0.82 (3H, d, J = 7.0 Hz); ¹³C NMR (CDCl₃, 125 MHz)

δ 151.7, 122.2, 73.3, 52.5, 48.0, 40.5, 39.3, 34.3, 33.4, 30.9, 27.0, 26.7,

22.1, 19.0, 14.4; EIMS m/z (rel intensity) 204 (11), 189 (6), 175 (1),

164 (30), 149 (55), 135 (26), 121 (21), 107 (38), 93 (26), 81 (29), 67

(16), 59 (100).

same procedure as for diol 15a except that LiAlH₄(41 mg, 1.1 mmol),

anhydrous AlCl₃(22 mg, 166 μmol), and 8b (29 mg, 122 μmol) were

used. Puriﬁcation by SCC (petroleum ether) yielded 19 (22.1 mg,

76%) as a colorless oil: ¹H NMR (benzene-d₆, 600 MHz) δ 2.45 (1H,

tq, J = 9.0, 7.2 Hz), 2.05 (1H, ddd, J = 13.2, 11.4, 7.2 Hz), 1.98 (1H,

dd, J = 13.2, 6.0 Hz), 1.90 (1H, d, J = 13.2 Hz), 1.86 (1H, dtd, J = 12.6,

9.0, 7.2 Hz), 1.82−1.73 (2H, m), 1.65 (1H, td, J = 6.0, 3.0 Hz), 1.62−

1.52 (2H, m), 1.42 (1H, dddd, J = 12.6, 11.4, 9.0, 3.0 Hz), 1.31−1.25

(1H, m), 1.26 (3H, s), 1.15 (1H, ddd, J = 13.2, 9.0, 3.0 Hz), 1.07 (3H,

s), 1.04 (3H, d, J = 7.2 Hz), 1.03 (3H, d, J = 7.2 Hz), 0.69 (1H, s); ¹³C

NMR (benzene-d₆, 150 MHz) δ 94.9, 85.9, 82.5, 44.3, 42.6, 37.9, 31.5,

31.18, 31.14, 29.48, 29.43, 28.8, 23.4, 18.3, 15.0; EIMS m/z (rel

intensity) 238 (M⁺, 15%), 220 (57), 205 (100), 187 (35), 159 (75),

139 (61), 125 (35), 109 (68), 85 (53); other physical and

spectroscopic data were in agreement with reported data.⁶¹

(3S,3aR,5R,8S,8aR)-3,8-Dimethyl-5-(prop-1-en-2-yl)octahydro-

azulen-3a(1H)-ol (20) and (1S,3aR,4S,7R,8aR)-1,4-Dimethyl-7-

(prop-1-en-2-yl)octahydroazulen-3a(1H)-ol (21). To a stirred

solution of α-guaiene (7a, 618 mg, 3.0 mmol) in CH₂Cl₂(20 mL)

at −78 °C was added dropwise a solution of m-CPBA (690 mg, 3.1

mmol) in CH₂Cl₂(20 mL). The cooling bath was removed upon the

completion of addition, and the resulting mixture stirred for 2 h and

allowed to attain RT. Solid KI (ca. 50 mg), saturated aqueous Na₂S₂O₃

solution (20 mL), and saturated aqueous NaHCO₃solution (40 mL)

were then added, and the resulting mixture was stirred for 1 h before

being extracted with Et₂O (3 × 25 mL). The combined ether layers

were washed with brine (30 mL), dried over anhydrous MgSO₄, and

ﬁltered. The volatiles were removed in vacuo, and the crude epoxide

mixture (13a,b, ca. 650 mg, ratio 35:65) was used directly for the next

step without puriﬁcation due to their vulnerability to silica gel.

Following the same procedure as for the ring-opening of 15a except

that LiAlH₄(868 mg, 22.8 mmol), anhydrous AlCl₃(300 mg, 1.6

mmol), and the above crude epoxidation products were used, the

reaction was heated under reﬂux at 90 °C for 22 h after the complete

addition of all reagents. Puriﬁcation by SCC (20−40 μm, petroleum

ether/Et₂O, gradient elution from 100:0 to 85:15) yielded 20 (191.3

mg, 43% over 2 steps) as a colorless oil and 21 (98.8 mg, 23% over 2

steps) as a colorless oil. Note that the yields here have been corrected

for the fact that 13b was formed as only 65% of the combined mixture

of epoxides 13a and 13b. Isomeric alcohols resulting from reductive

ring-opening of 13a were also present but not characterized.

(5R,8S,8aS)-5-[2-(Benzyloxy)propan-2-yl]-3,8-dimethyl-

1,2,4,5,6,7,8,8a-octahydroazulene (18). To a stirred solution of 16

(1.12 g, 3.4 mmol) in MeCN (10 mL) was added TsOH·H₂O (39 mg,

0.21 mmol). The resulting mixture was stirred under N₂at RT until

TLC indicated the consumption of the starting material (6 h). The

reaction was quenched with saturated NaHCO₃solution (20 mL) and

extracted with Et₂O (3 × 30 mL). The combined ether layers were

washed with brine (20 mL), dried over anhydrous MgSO₄, and

ﬁltered. The volatiles were removed in vacuo, and the concentrate was

puriﬁed by SNIS (n-hexane) to give 18 (611 mg, 58%) as a pale yellow

oil: ¹H NMR (benzene-d₆, 600 MHz) δ 7.38−7.10 (5ArH), 4.31 (2H,

s, PhCH₂), 2.96 (1H, br s, H-1), 2.75 (1H, d, J = 16.8 Hz, H-2a),

2.34−2.18 (2H, m, H-9a and H-9b), 2.00−1.84 (4H, m, H-2b, H-6a,

H-8a and H-10), 1.78 (1H, td, J = 10.8, 2.4 Hz, H-7), 1.71 (1H, dddd,

J = 13.8, 4.8, 4.2, 3.0 Hz, H-3a), 1.60 (3H, s, H-14), 1.55−1.47 (2H, m,

H-3b and H-8b), 1.23 (1H, m, J = H-6b), 1.13 (3H, s, H-12), 1.12

(3H, s, H-13), 0.84 (3H, d, J = 7.2 Hz, H-15); ¹³C NMR (benzene-d₆,

150 MHz) δ 140.6 (ArC), 135.6 (C-4), 132.6(C-5), 128.5(ArC),

127.6(ArC), 127.2(ArC), 77.9 (C-11), 63.4 (PhCH₂), 53.4 (C-1), 45.9

(C-7), 37.8 (C-9), 37.4 (C-3), 37.3 (C-10), 30.7 (C-2), 28.9 (C-8),

27.4 (C-6), 22.9 (C-12), 22.8 (C-13), 14.3 (C-14), 13.6 (C-5); EIMS

m/z (rel intensity) 204 (66), 189 (26), 175 (3), 161 (24), 149 (11),

133 (8), 119 (8), 105 (18), 91 (100), 79 (18), 65 (8), 55 (9); HRMS

(ESI-TOF) m/z [M − OBn]⁺205.1970 (calcd for C₁₅H₂₅, 205.1956).

2-[(5R,8S,8aS)-3,8-Dimethyl-1,2,4,5,6,7,8,8a-octahydroazulen-5-

yl]propan-2-ol; Guaia-4(5)-en-11-ol (2a). To a stirred solution of

LiAlH₄(47.2 mg, 1.2 mmol) in dry THF (1.5 mL) was added

dropwise a solution of 18 (21.7 mg, 70 μmol) in dry THF (1.5 mL).

The resulting solution was stirred at RT for 12 h before being

quenched with 6 N aqueous H₂SO₄(ca. 300 μL) and H₂O (5 mL)

sequentially at 0 °C. The resulting mixture was extracted with Et₂O (3

× 15 mL), and the combined ether layers were washed with brine (20

mL), dried over anhydrous MgSO₄, and ﬁltered. The organics were

concentrated in vacuo, and the residue was puriﬁed by fractional

distillation (to remove benzyl alcohol) under high vacuum to yield 2a

(14 mg, 91%) as a white solid. 2a: mp 73.1−74.5 °C; ¹H NMR

(benzene-d₆, 600 MHz) δ 2.92 (1H, br s, H-7), 2.69 (1H, br d, J =

16.2 Hz, H-6a), 2.36−2.29 (1H, m, H-3a), 2.25−2.18 (1H, m, H-3b),

1.97 (1H, dddd, J = 12.6, 9.6, 8.4, 5.4 Hz, H-2a), 1.90−1.78 (3H, m,

H-6a, H-8a and H-10), 1.69 (1H, dtd, J = 13.2, 4.5, 3.0 Hz, H-9a), 1.60

(3H, s, H-14), 1.53−1.46 (2H, m, H-2b and H-9b), 1.39 (1H, ddd, J =

10.8, 9.6, 3.0 Hz, H-1), 1.14 (1H, tdd, J = 13.2, 10.2, 3.0 Hz, H-8b),

1.03 (3H, s, H-12), 1.02 (3H, s, H-13), 0.83 (3H, d, J = 7.2 Hz, H-15);

¹³C NMR (benzene-d₆, 150 MHz) δ 135.5 (C-5), 132.5 (C-4), 72.9

20: ¹H NMR (benzene-d₆, 600 MHz) δ 4.85 (1H, br s, H-12a), 4.77

(1H, br s, H-12b), 2.47 (1H, m, H-7), 2.02 (1H, dddd, J = 15.6, 9.6,

7.8, 5.4 Hz, H-3a), 1.89 (1H, dddd, J = 14.4, 10.2, 6.0, 2.6 Hz, H-9a),

1.86−1.80 (1H, m, H-6a), 1.75−1.69 (3H, m, H-2a, H-6b/8a and H-

10), 1.70 (3H, s, H-13), 1.60 (1H, dqd, J = 7.8, 7.2, 3.0 Hz, H-4), 1.49

(1H, dddd, J = 13.2, 10.2, 9.0, 2.4 Hz, H-8a/6b), 1.44−1.33 (4H, m,

H-1, H-2b, H-8b and H-9b), 1.06 (1H, dddd, J = 15.6, 8.4, 5.4, 3.0 Hz,

H-3b), 0.90 (3H, d, J = 6.6 Hz, H-15), 0.74 (3H, d, J = 7.2 Hz, H-14);

¹³C NMR (benzene-d₆, 150 MHz) δ 152.2 (C-11), 108.7 (C-12), 82.8

(C-5), 51.7 (C-1), 49.8 (C-4), 43.4 (C-7), 42.7 (C-2), 34.9 (C-9), 34.2

(C-10), 31.1 (C-3), 30.34 (C-6) 30.31 (C-8), 22.9 (C-15), 20.9 (C-

13), 18.2 (C-14); EIMS m/z (rel intensity) 207 (2), 204 (85), 189

(100), 175 (18), 161 (70), 147 (46), 133 (30), 121 (48), 107 (58), 95

(75), 81 (59), 55 (65); HRMS (ESI-TOF) m/z [M + H]⁺223.2057

(calcd for C₁₅H₂₇O, 223.2062).

(C-11), 53.3 (C-7), 49.7 (C-1), 37.9 (C-3), 37.4(9) (C-9), 37.4(8)

(C-10), 30.9 (C-6), 28.9 (C-2), 27.5 (C-8), 26.9 (C-12), 26.7 (C-13),

14.3 (C-14), 13.6 (C-15); EIMS m/z (rel intensity) 222 (3), 204

(100), 189 (84), 175 (13), 161 (84), 147 (32), 133 (29), 119 (34),

105 (49), 91 (49), 79 (46), 59 (57). Other physical and spectroscopic

data were in accord with those reported previously.⁶⁰

21: H NMR (benzene-d₆, 600 MHz) δ 4.85 (1H, s, H-12a), 4.83

(1H, s, H-12b), 2.62 (1H, dddd, J = 10.8, 8.4, 7.2, 2.4 Hz, H-7), 1.92

(1H, dddd, J = 13.8, 12.0, 4.8, 1.8 Hz, H-9a), 1.86 (1H, ddd, J = 13.8,

9.6, 4.2 Hz, H-2a), 1.79−1.74 (3H, m, H-3a, H-6a and H-10), 1.70

(3H, s, H-13), 1.70−1.64 (1H, m, H-4), 1.58−1.52 (2H, m, H-6b and

H-8a), 1.43 (1H, dddd, J = 14.4, 7.2, 2.4, 1.8 Hz, H-8b), 1.37 (1H,

ddd, J = 13.8, 7.2, 1.2 Hz, H-9b), 1.31 (1H, dt, J = 13.8, 8.4 Hz, H-2b),

1.27 (1H, td, J = 10.8, 5.4 Hz, H-5), 0.96−0.89 (1H, m, H-3b), 0.91

(3H, d, J = 6.6 Hz, H-14), 0.79 (3H, d, J = 7.2 Hz, H-15); ¹³C NMR

(benzene-d₆, 150 MHz) δ 152.5 (C-11), 108.3 (C-12), 85.6 (C-1),

47.5 (C-5), 45.7 (C-7), 40.73 (C-4), 40.5(C-2 and C-10), 33.2 (C-3),

32.2 (C-9), 31.2 (C-6), 26.6 (C-8), 20.0 (C-13), 19.0 (C-14), 15.9 (C-

15); EIMS m/z (rel intensity) 204 (35), 189 (61), 175 (9), 161 (82),

147 (44), 133 (28), 122 (53), 107 (100), 93 (57), 81 (49), 55 (44);

(5R,8S,8aS)-3,8-Dimethyl-5-(prop-1-en-2-yl)-1,2,4,5,6,7,8,8a-oc-

tahydroazulene; Aciphyllene (4a). To a stirred solution of 2a (130

mg, 586 μmol) in benzene (3 mL) under N₂were added pyridine (50

μL, 620 μmol) and SOCl₂(120 μL, 1.7 mmol) sequentially. After 10

min the reaction was quenched with saturated aqueous NaHCO₃(5

mL) and extracted with Et₂O (3 × 30 mL). The combined ether layers

were washed with brine (20 mL), dried over anhydrous MgSO₄, and

ﬁltered. Solvent removal under reduced pressure followed by

puriﬁcation by SNIS chromatography (n-hexane) yielded 4a (86.3

mg, 72%) as a colorless oil. Spectroscopic data were in agreement with

those reported previously.¹¹

(1S,3aS,4S,7R,8aR)-1,4,9,9-Tetramethylhexahydro-1H-3a,7-

(epoxymethano)azulen-8a(4H)-ol (19). This synthesis followed the

2532

dx.doi.org/10.1021/np500611z | J. Nat. Prod. 2014, 77, 2522−2536

Journal of Natural Products

Article

HRMS (ESI-TOF) m/z [M + H]⁺223.2048 (calcd for C₁₅H₂₇O,

223.2062).

ﬁltered. The volatiles were removed under reduced pressure, and the

crude product 23 was used for the next step without further

puriﬁcation.

(5R,8S,8aR)-3,8-Dimethyl-5-(prop-1-en-2-yl)-1,2,4,5,6,7,8,8a-

octahydroazulene; 1-epi-Aciphyllene (4b). To a stirred solution of 20

(315 mg, 1.4 mmol) in Et₂O (10 mL) at 0 °C under N₂were added

Et₃N (600 μL, 4.34 mmol) and SOCl₂(250 μL, 3.5 mmol)

sequentially. After stirring at 0 °C for 30 min, the reaction was

quenched with saturated aqueous NaHCO₃(10 mL) solution, and the

resulting mixture extracted with petroleum ether (3 × 15 mL). The

combined organic layers were washed with brine (20 mL), dried over

anhydrous MgSO₄, and ﬁltered. Removal of the volatiles in vacuo and

puriﬁcation of the residue by SNIS chromatography (petroleum ether)

2-[(5R,8S,8aR)-3,8-Dimethyl-1,2,4,5,6,7,8,8a-octahydroazulen-5-

yl]propan-2-ol; 1-epi-Guaia-4(5)-en-11-ol (2b). To a stirred solution

of LiAlH₄(147 mg, 3.9 mmol) in THF (2 mL) was added a solution of

AlCl₃(80 mg, 0.6 mmol) in THF (1 mL) dropwise. The resulting

mixture was stirred for 5 min before the dropwise addition of crude 23

in THF (1 mL, rinsed with 3 × 1 mL). The resulting mixture was

stirred for 1 h followed by quenching with distilled H₂O. The

quenched mixture was extracted with Et₂O (3 × 25 mL), and the

combined ether layers were washed with brine, dried over anhydrous

MgSO₄, and ﬁltered. The volatiles were removed under reduced

pressure followed by puriﬁcation of the residue on silver nitrate-

impregnated silica column chromatography (petroleum ether/Et₂O,

gradient elution from 94:6 to 87:13) to aﬀord pure 2b (133 mg, 73%

yielded 4b (251 mg, 87%) as a colorless oil: H NMR (CDCl₃, 600

MHz) δ 4.69 (1H, dq, J = 1.8, 0.9 Hz, H-12a), 4.66 (1H, quint, J = 1.8

Hz, H-12b), 2.42 (1H, dd, J = 12.6, 3.6 Hz, H-6a), 2.24 (m, 1H, H-3a),

2.16 (1H, m, H-1), 2.16−2.10 (2H, m, H-3b and H-7), 2.00 (1H, ddd,

J = 12.6, 8.4, 4.2 Hz, H-2a), 1.97 (1H, t, J = 12.6 Hz, H-6b), 1.74 (3H,

s, H-13), 1.66 (1H, dddd, J = 15.6, 7.8, 6.0, 4.2 Hz, H-8a), 1.61 (3H, s,

H-14), 1.58 (1H, ddd, J = 15.6, 6.0, 4.2 Hz, H-8b), 1.50 (2H, m, H-9a

and H-9b), 1.39 (1H, ddd, J = 12.6, 9.0, 6.6 Hz, H-2b), 1.38 (1H, m,

H-10), 0.95 (3H, d, J = 6.6 Hz, H-15); ¹³C NMR (CDCl₃, 150 MHz)

δ 151.3 (C-11), 138.3 (C-5), 131.9 (C-4), 108.2 (C-12), 57.2 (C-1),

45.1 (C-7), 39.2 (C-10), 36.5 (C-3), 32.1 (C-9), 31.1 (C-6), 30.6 (C-

8), 30.2 (C-2), 22.2 (C-15), 20.6 (C-13), 13.9 (C-14); EIMS m/z (rel

intensity) 204 (100), 189 (92), 175 (16), 161 (46), 147 (38), 133

(35), 119 (39), 105 (59), 95 (66), 79 (65), 55 (28); HRMS (ESI-

TOF) m/z [M + H]⁺205.1935 (calcd for C₁₅H₂₅, 205.1956).

(3S,3aR,5R,8S,8aR)-3,8-Dimethyl-5-[(2R)-2-methyloxiran-2-yl]-

octahydroazulen-3a(1H)-ol (22a) and (3S,3aR,5R,8S,8aR)-3,8-Di-

methyl-5-[(2S)-2-methyloxiran-2-yl]octahydroazulen-3a(1H)-ol

(22b). Alcohol 20 (225 mg, 1 mmol) was dissolved in CH₂Cl₂(5 mL)

followed by the addition of m-CPBA (77%, 335 mg, 1.5 mmol) in one

portion. After 1 h of stirring, the reaction was quenched with KI solid,

saturated aqueous Na₂S₂O₃solution, and saturated aqueous NaHCO₃

solution and left stirring for an additional 1 h. The resulting mixture

was extracted with Et₂O (3 × 50 mL), and the combined ether layers

were further washed with saturated aqueous NaHCO₃solution and

brine, dried over anhydrous MgSO₄, and ﬁltered. The organics were

concentrated under reduced pressure to give 22a,b (241 mg, 99%) as a

diastereomeric mixture in a ratio of 1:1.

over 2 steps) as a colorless oil: H NMR (benzene-d₆, 600 MHz) δ

2.68 (1H, dd, J = 13.2, 1.7 Hz, H-3a), 2.26−2.15 (3H, m, H-1 and H-

6a, H-6b), 2.04 (1H, dtd, J = 12.0, 7.8, 4.0 Hz, H-8a), 1.65 (3H, s, H-

14), 1.62 (1H, br t, J = 13.2 Hz, H-3b), 1.55 (1H, m, H-9a), 1.51−1.38

(4H, m, H-2a H-2b, H-7, H-9b), 1.36 (1H, ddt, J = 12.0, 9.0, 7.8 Hz,

H-8b), 1.25 (1H, m, H-10), 1.03 (3H, s, H-12), 1.02 (3H, s, H-13),

0.94 (3H, d, J = 7.2 Hz, H-15); ¹³C NMR (benzene-d₆, 150 MHz) δ

139.5 (C-5), 130.9 (C-4), 73.0 (C-11), 58.2 (C-1), 48.9 (C-7), 39.6

(C-10), 37.0 (C-6), 33.1 (C-2), 30.4 (C-8), 27.8 (C-3), 27.7 (C-12),

26.7 (C-9), 26.1 (C-13), 22.7 (C-15), 14.1 (C-14); EI-MS m/z (rel

intensity) 222 (3), 204 (100), 189 (91), 175 (14), 161 (76), 147 (30),

133 (30), 119 (43), 105 (57), 91 (57), 79 (52), 55 (27); HRMS (ESI-

TOF) m/z [M + H]⁺223.2030 (calcd for C₁₅H₂₇O₁, 223.2062).

(5R,8S,8aR)-3,8-Dimethyl-5-(prop-1-en-2-yl)-4,5,6,7,8,8a-hexahy-

droazulen-2(1H)-one (24). Pyridinium dichromate (104 mg, 0.3

μmol) and CH₂Cl₂(3 mL) were combined under N₂, and the resulting

mixture was chilled in an ice-bath. To this stirred suspension was

added slowly a solution of TBHP (5−6 M in decane, 60 μL) in

CH₂Cl₂(1 mL) and a solution of 4b (64 mg, 0.3 μmol) in CH₂Cl₂(3

mL) after stirring for 20 min. The resulting mixture was stirred at 0 °C

under N₂for 4 h before adding a solution of TBHP (5−6 M in decane,

50 μL) in CH₂Cl₂(1 mL). After stirring for an additional 4 h at 0 °C,

petroleum ether (10 mL) was added, and the mixture ﬁltered through

a pad of Celite and further eluted with petroleum ether (3 × 10 mL).

Removal of the volatiles in vacuo followed by SCC (Et₂O/petroleum

ether, gradient elution from 0:100 to 12:88) recovered 4b (34 mg,

53%) and yielded the enone (24, 17 mg, 53% based on 47%

22a: mp 72.1−72.5 °C; H NMR (CDCl₃, 600 MHz) δ 2.63, 2.58

(2H, ABq, J = 5.1 Hz), 2.07 (1H, dddd, J = 15.6, 10.2, 7.8, 5.4 Hz),

1.94 (1H, dd, J = 13.8, 3.0 Hz), 1.91 (1H, m), 1.84 (1H, dqd, J = 7.8,

7.2, 3.0 Hz), 1.79−1.75 (1H, m), 1.70−1.64 (2H, m), 1.57−1.52 (1H,

m), 1.49 (1H, dd, J = 18.0, 9.6 Hz), 1.45−1.38 (4H, m), 1.24 (3H, s),

1.19 (1H, dddd, J = 15.6, 9.0, 6.0, 3.0 Hz), 0.92 (6H, d, J = 7.2 Hz);

¹³C NMR (CDCl₃, 150 MHz) δ 82.9, 60.6, 54.9, 51.6, 49.1, 41.6, 38.4,

34.3, 35.6, 30.5, 29.7, 27.4, 22.6, 18.3, 17.5; EIMS m/z (rel intensity)

220 (30), 202 (15), 189 (27), 175 (8), 162 (100), 147 (61), 133 (38),

119 (51), 105 (71), 91 (89), 79 (71), 55 (68); HRMS (ESI-TOF) m/

z [M + H]⁺239.1996 (calcd for C₁₅H₂₇O₂, 239.2011).

conversion) as a pale yellow oil. H and ¹³C NMR and mass spectral

data were identical to reported data.⁵¹

(5S,8S,8aR)-3,8-Dimethyl-5-(prop-1-en-2-yl)-1,2,4,5,6,7,8,8a-

octahydroazulen-5-ol (25) and (5R,8S,8aR)-3,8-Dimethyl-5-(prop-1-

en-2-yl)-1,2,4,5,6,7,8,8a-octahydroazulen-5-ol (26). SeO₂(2.3 mg,

21 μmol) was added to CH₂Cl₂(1 mL) under N₂at 0 °C. To the

stirred suspension was added dropwise a solution of TBHP (5−6 M in

decane, 40 μL, 200−240 μmol) in CH₂Cl₂(1 mL). After stirring for

10 min, a solution of 4b (8.5 mg, 44 μmol) in CH₂Cl₂(1 mL) was

added dropwise, and the resulting mixture was further stirred at 0 °C

for 4 h and then quenched by ﬁltering the mixture through a silica

plug. The ﬁltrate was concentrated in vacuo, and the residue puriﬁed

by SCC (20−40 μm, EtOAc/n-hexane, 5:95) to give 25 (3 mg, 32%)

22b: mp 113.5−113.9 °C; H NMR (CDCl₃, 600 MHz) δ 2.61,

2.59 (2H, ABq, J = 5.1 Hz), 2.06 (1H, dddd, J = 15.6, 10.2, 7.8, 5.4

Hz), 1.95 (1H, dtd, J = 13.2, 8.4, 5.4 Hz), 1.85 (1H, dqd, J = 7.8, 7.2,

4.2 Hz), 1.84−1.75 (3H, m), 1.64 (1H, m), 1.56−1.48 (2H, m), 1.48−

1.39 (3H, m), 1.34 (1H, t, J = 12.9 Hz), 1.24 (3H, s), 1.19 (1H, dddd,

J = 15.6, 9.0, 6.0, 3.0 Hz), 0.94 (3H, d, J = 6.6 Hz), 0.91 (3H, d, J = 7.2

Hz); ¹³C NMR (CDCl₃, 150 MHz) δ 83.0, 61.0, 54.9, 51.5, 48.7, 42.3,

39.6, 34.3, 33.6, 30.6, 29.8, 26.7, 22.7, 18.1, 17.4; EIMS m/z (rel

intensity) 220 (6), 204 (24), 189 (33), 175 (11), 161 (44), 147 (46),

133 (38), 119 (48), 105 (80), 91 (100), 79 (70), 55 (80); HRMS

(ESI-TOF) m/z [M + H]⁺239.1998 (calcd for C₁₅H₂₇O₂, 239.2011).

Epoxides 23. To a mixture of 22a and 22b (1:1, 204 mg, 857 μmol)

in CH₂Cl₂(12 mL) was added Et₃N (2 mL, 14.3 mmol) followed by

the dropwise addition of SOCl₂(ca. 80 μL, 1.1 mmol) under N₂. The

resulting mixture was stirred under N₂at RT and monitored with

TLC, which showed the full consumption of the starting materials in

10 min. The reaction was quenched with saturated aqueous NaHCO₃

solution and extracted with Et₂O (3 × 50 mL). The combined ether

layers were washed with brine, dried over anhydrous MgSO₄, and

and 26 (1 mg, 10%) as colorless oils. 25: H NMR (benzene-d₆, 600

MHz) δ 5.22 (1H, br s, H-12a), 4.86 (1H, br s, H-12b), 2.54 (1H, d, J

= 14.4 Hz, H-6a), 2.30 (1H, d, J = 14.4 Hz, H-6b), 2.18−2.13 (2H, m,

H-1 and H-3a), 2.07 (1H, m, H-3b), 2.03 (1H, ddd, J = 14.4, 9.6, 1.8

Hz, H-8a), 1.93 (1H, dddd, J = 12.6, 9.0, 7.8, 3.6 Hz, H-2a), 1.85 (3H,

s, H-13), 1.58 (3H, s, H-14), 1.56−1.48 (2H, m, H-8b and H-9a), 1.38

(1H, m, H-10), 1.30 (1H, ddt, J = 12.6, 9.0, 7.8 Hz, H-2b), 1.23 (1H,

dtd, J = 15.0, 9.6, 1.8 Hz, H-9b), 0.90 (3H, d, J = 6.6 Hz, H-15); ¹³C

NMR (benzene-d₆, 150 MHz) δ 152.0 (C-11), 137.2 (C-5), 134.7 (C-

4), 109.1 (C-12), 76.0 (C-7), 56.9 (C-1), 39.9 (C-10), 38.7 (C-8),

38.4 (C-6), 37.0 (C-3), 30.6 (C-2), 29.9 (C-9), 21.9 (C-15), 19.3 (C-

13), 14.6 (C-14); EIMS m/z (rel intensity) 220 (5), 202 (38), 187

(16), 173 (5), 159 (20), 146 (23), 135 (35), 105 (24), 95 (100), 79

2533

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(20), 55 (13); HRMS (ESI-TOF) m/z [M + H]⁺221.1871 (calcd for

ﬁltered. The volatiles were removed in vacuo, and the product was

puriﬁed by SCC (Et₂O/n-hexane, 8:92) to yield 5a (3.7 mg, 72%) as a

pale yellow oil: ¹H NMR (CDCl₃, 600 MHz) δ 4.90 (1H, br s, H-12a),

4.71(1H, br s, H-12b), 3.29 (1H, m, H-1), 3.16 (1H, dd, J = 10.5, 2.1

Hz, H-7), 2.45, 2.38 (2H, ABqdd, J = 17.4, 9.6, 7.2 Hz, H-3a, H-3b),

2.10−1.97 (1H, m, H-2a), 2.08 (3H, s, H-14), 1.97 (1H, qt, J = 7.2, 3.6

Hz, H-10), 1.86−1.83 (3H, m, H-8a, H-9a and H-9b), 1.78 (3H, s, H-

13), 1.75−1.69 (1H, m, H-8b), 1.51 (1H, dddd, J = 12.6, 9.6, 7.2, 6.0

Hz, H-2b), 0.75 (3H, d, J = 7.2 Hz, H-15); ¹³C NMR (CDCl₃, 150

MHz) δ 201.9 (C-6), 156.6 (C-5), 146.0 (C-11), 136.2 (C-4), 111.7

(C-12), 59.9 (C-7), 50.6 (C-1), 39.6 (C-3), 37.2 (C-9), 36.2 (C-10),

27.7 (C-2), 25.2 (C-8), 21.7 (C-13), 16.8 (C-14), 12.1 (C-15); EIMS

m/z (rel intensity) 218 (97), 203 (38), 189 (8), 175 (28), 161 (100),

147 (61), 133 (29), 121 (22), 109 (68), 79 (97); HRMS (ESI-TOF)

m/z [M + H]⁺219.1758 (calcd for C₁₅H₂₃O, 219.1749).

(8S,8aS)-3,8-Dimethyl-5-(propan-2-ylidene)-2,5,6,7,8,8a-

hexahydroazulen-4(1H)-one (30). Both 5a (5.5 mg, 25 μmol) and

NaOMe (27 mg, 0.5 mmol) were dissolved in EtOH (0.5 mL) under

N₂, and the resulting mixture was left standing at RT for 14 h. Brine (2

mL) was then added, and the aqueous solution extracted with Et₂O (3

× 5 mL). The combined ether extracts were dried over anhydrous

MgSO₄and ﬁltered. The volatiles were removed in vacuo, and the

residue was puriﬁed by SCC (Et₂O/n-hexane, 8:92) to yield 30 (5.2

mg, 95%) as a yellowish oil: ¹H NMR (CDCl₃, 600 MHz) δ 3.08 (1H,

d, J = 9.3 Hz, H-1), 2.52 (1H, br dt, J = 18.6, 9.6 Hz, H-3a), 2.40 (1H,

ddd, J = 15.0, 6.0, 3.0 Hz, H-8a), 2.42−2.32(1H, dddt, J = 18.6, 10.2,

3.6, 0.9 Hz, H-3b), 2.17, (3H, s, H-14), 2.08−1.95 (3H, m, H-2a, H-8b

and H-10), 1.73 (6H, s, H-12 and H-13), 1.76−1.68 (1H, m, H-9a),

1.67−1.63 (1H, m, H-9b), 1.60−1.52 (1H, m, H-2b), 0.85 (3H, d, J =

7.2 Hz, H-15); ¹³C NMR (CDCl₃, 150 MHz) δ 199.4 (C-6), 157.5(C-

5), 139.0 (C-7), 135.3 (C-4), 132.7 (C-11), 50.6 (C-1), 40.1 (C-3),

37.2 (C-10), 36.0 (C-9), 28.4 (C-2), 23.7 (C-8), 21.6 (C-12), 19.8 (C-

13), 16.8 (C-14), 12.7 (C-15); EIMS m/z (rel intensity) 218 (100),

203 (23), 189 (5), 175 (48), 161 (31), 147 (33), 133 (23), 121 (29),

109 (36), 79 (38); HRMS (ESI-TOF) m/z [M + H]⁺219.1738 (calcd

for C₁₅H₂₃O, 219.1749).

(8S,8aS)-3,8-Dimethyl-5-(propan-2-ylidene)-1,5,6,7,8,8a-hexahy-

droazulene-2,4-dione; 1-epi-Melicodenone E (6a), (5S,8S,8aS)-

3,3′,3′,8-Tetramethyl-1,2,6,7,8,8a-hexahydro-4H-spiro[azulene-

5,2′-oxiran]-4-one (31), and (5S,8S,8aS)-3,3′,3′,8-Tetramethyl-

6,7,8,8a-tetrahydro-1H-spiro[azulene-5,2′-oxirane]-2,4-dione (32).

To a stirred solution of 30 (44 mg, 0.2 mmol) in CH₂Cl₂(5 mL)

were added CrO₃(146 mg, 1.5 mmol) and 3,5-dimethylpyrazole (165

mg, 1.7 mmol). The resulting mixture was heated under reﬂux for 24

h. The reaction mixture was cooled to room temperature, diluted with

Et₂O (10 mL), percolated through a pad of silica, and further eluted

with Et₂O (3 × 20 mL). The volatiles were removed in vacuo, and the

residue was puriﬁed by SCC to recover 30 (5.9 mg, 13%) and aﬀord

6a (5.2 mg, 13%) and 31 (10 mg, 24%) as colorless crystals and 32

(6.7 mg, 15%) as yellowish crystals. 6a: ¹H NMR (CDCl₃, 600 MHz)

δ 3.19 (1H, ddq, J = 7.2, 1.8, 1.8 Hz, H-1), 2.59 (1H, dd, J = 19.2, 7.2

Hz, H-2a), 2.54 (1H, ddd, J = 15.0, 6.0, 3.0 Hz, H-8a), 2.28−2.24 (1H,

m, H-10), 2.21 (1H, dd, J = 19.2, 1.8 Hz, H-2b), 2.10 (3H, d, J = 1.8

Hz, H-14), 2.06 (1H, d, J = 15.0 Hz, H-8b), 1.87−1.81 (1H, m, H-9a),

1.82 (3H, s, H-12), 1.81 (3H, s, H-13), 1.78−1.73 (1H, m, H-9b), 0.72

(3H, d, J = 7.2 Hz, H-15); ¹³C NMR (CDCl₃, 150 MHz) δ 209.1 (C-

3), 198.8 (C-6), 160.8 (C-4), 147.7 (C-5), 137.7 (C-7), 136.9 (C-11),

43.1 (C-1), 41.5 (C-2), 35.8 (C-10), 35.2 (C-9), 23.5 (C-8), 21.9 (C-

12), 20.3 (C-13), 12.3 (C-15), 9.9 (C-14); EIMS m/z (rel intensity)

232 (79), 217 (18), 189 (35), 175 (18), 161 (30), 147 (28), 133 (16),

119 (20), 109 (15), 91 (24); HRMS (ESI-TOF) m/z [M + H]⁺

233.1536 (calcd for C₁₅H₂₁O₂, 233.1542).

C₁₅H₂₅O, 221.1905).

26: H NMR (benzene-d₆, 600 MHz) δ 5.04 (1H, s, H-12a), 4.75

(1H, s, H-12b), 2.63, 2.40 (2H, ABq, J = 12.3 Hz, H-6a and H-6b),

2.35−2.28 (1H, m, H-1), 2.18 (1H, m, H-3a), 2.09 (1H, ddd, J = 14.4,

8.4, 7.2 Hz, H-3b), 1.96 (1H, dddd, J = 12.0, 8.4, 7.8, 4.2 Hz, H-2a),

1.78 (3H, s, H-13), 1.71 (3H, dddd, J = 13.2, 11.4,11.4, 1.8 Hz, H-8a),

1.64 (1H, ddd, J = 13.2, 11.4, 2.4 Hz, H-9a), 1.58 (1H, dd, J = 13.2, 7.2

Hz, H-8b), 1.50 (3H, s, H-14), 1.48−1.35 (2H, m, H-2b and H-9b),

1.24−1.17 (1H, m, H-10), 0.92 (3H, d, J = 6.6 Hz, H-15); ¹³C NMR

(benzene-d₆, 150 MHz) δ 153.8 (C-11), 135.7 (C-5), 134.4 (C-4),

108.5 (C-12), 76.1 (C-7), 57.7 (C-1), 41.3 (C-10), 39.9 (C-8), 49.6

(C-6), 37.0 (C-3), 32.7 (C-9), 30.2 (C-2), 22.2 (C-15), 19.6 (C-13),

14.8 (C-14); EIMS m/z (rel intensity) 220 (5), 202 (43), 187 (32),

173 (10), 159 (45), 146 (74), 135 (30), 105 (43), 95 (100), 79 (31),

55 (18); HRMS (ESI-TOF) m/z [M + H]⁺221.1877 (calcd for

C₁₅H₂₅O, 221.1905).

(5S,8S,8aR)-5-Hydroxy-3,8-dimethyl-5-(prop-1-en-2-yl)-

4,5,6,7,8,8a-hexahydroazulen-2(1H)-one (28). SeO₂(10 mg, 91

μmol) was added to CH₂Cl₂(2 mL) under N₂at 0 °C. To the

resulting suspension was added dropwise a solution of TBHP (5−6 M

in decane, 50 μL, 250−300 μmol) in CH₂Cl₂(1.5 mL). After stirring

for 10 min, a solution of 25 (29 mg, 133 μmol) in CH₂Cl₂(2 mL) was

added dropwise, and the resulting mixture further stirred at 0 °C for 8

h and then quenched with saturated aqueous NaHCO₃solution (10

mL). The mixture was extracted with CH₂Cl₂(3 × 10 mL), and the

organic layers were combined, further washed with brine (10 mL),

dried over anhydrous MgSO₄, and ﬁltered. The ﬁltrate was

concentrated in vacuo, and the residue puriﬁed on alumina (EtOAc/

petroleum ether, gradient elution from 5:95 to 25:75) to recover 25 (6

mg, 21%) and furnish 28 (7 mg, 28%) as a pale yellow oil: H NMR

(benzene-d₆, 500 MHz) δ 4.86 (1H, dq, J = 1.3, 1.3 Hz), 4.73 (1H,

quint, J = 1.4 Hz), 2.58 (1H, d, J = 13.5 Hz), 2.34 (1H, dd, J = 18.2,

6.5 Hz), 2.19 (1H, d, J = 13.5 Hz), 1.89 (1H, dd, J = 14.5, 8.5 Hz),

1.82 (3H, d, J = 1.8 Hz), 1.75 (1H, br t, J = 8.0 Hz), 1.70 (3H, dd, J =

1.5, 0.2 Hz), 1.18 (1H, dddd, J = 14.5, 8.5, 2.5, 1.5 Hz), 1.11 (1H, ddd,

J = 14.5, 12.0, 1.5 Hz), 0.97 (1H, dddd, J = 14.5, 12.0, 10.5, 1.5 Hz),

0.85 (1H, br s), 0.83−0.76 (1H, m), 0.66 (3H, d, J = 6.5 Hz); ¹³C

NMR (benzene-d₆, 125 MHz) δ 206.3, 169.5, 151.0, 139.4, 109.8, 76.9,

50.2, 43.3, 42.6, 40.8, 39.9, 31.7, 22.6, 18.8, 8.8; EIMS m/z (rel

intensity) 234 (2), 216 (5), 178 (3), 150 (18), 137 (33), 110 (100), 95

(11), 69 (14); HRMS (ESI-TOF) m/z [M + H]⁺235.1695 (calcd for

C₁₅H₂₃O₂, 235.1698).

(4S,5S,8S,8aS)-3,8-Dimethyl-5-(prop-1-en-2-yl)-1,2,4,5,6,7,8,8a-

octahydroazulen-4-ol (29). This synthesis followed the same

procedure for 25 except that SeO₂(6 mg, 59 μmol), TBHP (5−6

M in decane, 40 μL), and 4a (22 mg, 108 μmol) were used.

Puriﬁcation by SCC (EtOAc/n-hexane, 5:95) gave 29 (7.8 mg, 33%)

as a pale yellow oil: H NMR (benzene-d₆, 600 MHz) δ 4.82 (1H, s,

H-12a), 4.75 (1H, s, H-12b), 4.28 (1H, d, J = 9.6 Hz, H-6), 3.01 (1H,

d, J = 9.6 Hz, H-1), 2.34−2.27 (2H, m, H-7 and H-3a), 2.11 (1H, dd, J

= 16.2, 9.6 Hz, H-3b), 2.02 (1H, ddd, J = 12.6, 9.6, 8.4 Hz, H-2a), 1.80

(1H, qd, J = 7.2, 3.6 Hz, H-10), 1.78 (3H, s, H-14), 1.61 (3H, s, H-13),

1.54−1.41 (3H, m, H-9a, H-9b and H-2b), 1.33−1.28 (2H, m, H-8a

and H-8b), 0.73 (3H, d, J = 7.2 Hz, H-15); ¹³C NMR (benzene-d₆, 150

MHz) δ 149.3 (C-11), 140.7 (C-4), 137.5 (C-5), 111.9 (C-12), 69.0

(C-6), 55.5 (C-7), 49.9 (C-1), 38.4 (C-10), 38.3 (C-3), 37.2 (C-9),

30.0 (C-2), 26.1 (C-8), 18.8 (C-13), 14.5 (C-14), 13.5 (C-15); EIMS

m/z (rel intensity) 220 (3), 202 (89), 187 (44), 159 (51), 145 (100),

131 (82), 105 (90), 91 (89), 77 (54); HRMS (ESI-TOF) m/z [M +

H]⁺221.1865 (calcd for C₁₅H₂₅O, 221.1905).

(5S,8S,8aS)-3,8-Dimethyl-5-(prop-1-en-2-yl)-2,5,6,7,8,8a-

hexahydroazulen-4(1H)-one; 1-epi-Melicodenone C (5a). To a

stirred solution of Dess−Martin periodinane (48 mg, 113 μmol) in

CH₂Cl₂(1 mL) at RT was added a solution of 6-hydroxyaciphyllene

29 (5.2 mg, 24 μmol) in CH₂Cl₂(1 mL). The resulting mixture was

stirred at RT until TLC showed no starting material remained (4 h).

The reaction was quenched with saturated aqueous NaHCO₃(5 mL)

and extracted with CH₂Cl₂(3 × 10 mL). The combined organic layers

were washed with brine (15 mL), dried over anhydrous MgSO₄, and

31: mp 100.8−101.0 °C (MeCN); ¹H NMR (CDCl₃, 600 MHz) δ

3.13−3.07 (1H, m, H-1), 2.57−2.51 (1H, m, H-3a), 2.40 (1H, dddt, J

= 18.6, 10.2, 5.4, 1.2 Hz, H-3b), 2.20−2.16 (1H, m, H-10), 2.17 (3H,

s, H-14), 2.16−2.10 (1H, m, H-8a), 2.02 (1H, qt, J = 7.2, 3.6 Hz, H-

10), 1.89 (1H, tt, J = 13.8, 3.6 Hz, H-9a), 1.77 (1H, dq, J = 13.8, 3.6

Hz, H-9b), 1.65−1.59 (1H, m, H-2b), 1.53 (1H, dt, J = 15.0, 3.6 Hz,

H-8b), 1.52 (3H, s, H-12), 1.13 (3H, s, H-13), 0.82 (3H, d, J = 7.2 Hz,

H-15); ¹³C NMR (CDCl₃, 150 MHz) δ 196.8 (C-6), 160.3 (C-5),

2534

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132.6 (C-4), 72.3 (C-7), 61.9 (C-11), 50.5 (C-1), 39.8 (C-3), 36.2 (C-

10), 33.1 (C-9), 28.3 (C-2), 25.3 (C-8), 20.7 (C-12), 20.2 (C-13),

17.1 (C-15), 12.1 (C-14); EIMS m/z (rel intensity) 234 (64), 219

(59), 203 (5), 175 (14), 161 (20), 147 (25), 133 (26), 121 (100), 107

(52), 79 (87); HRMS (ESI-TOF) m/z [M + H]⁺235.1689 (calcd for

C₁₅H₂₃O₂, 235.1698).

(CDCl₃, 600 MHz) δ 4.90 (1H, s, H-6), 3.04−2.98 (1H, m, H-1), 2.59

(1H, dd, J = 18.6, 6.6 Hz, H-2a), 2.28 (1H, m, H-10), 2.11 (1H, dd, J =

18.6, 2.4 Hz, H-2b), 1.99 (1H, ddd, J = 15.0, 6.6, 3.6 Hz, H-8a), 1.85

(3H, t, J = 1.2 Hz, H-14), 1.82 (1H, ddd, J = 15.0, 10.8, 6.6 Hz, H-8b),

1.69−1.59 (2H, m, H-9a and H-9b), 1.45 (3H, s, H-12), 1.41 (3H, s,

H-13), 0.80 (3H, d, J = 7.2 Hz, H-15); ¹³C NMR (CDCl₃, 150 MHz)

δ 208.6 (C-3), 168.6 (C-4), 140.3 (C-5), 72.5 (C-6), 67.5 (C-7), 63.1

(C-11), 44.3 (C-1), 40.0 (C-2), 34.2 (C-10), 30.3 (C-9), 29.9 (C-8),

22.1 (C-12), 20.4 (C-13), 14.5 (C-15), 9.1 (C-14); EIMS m/z (rel

intensity) 250 (3), 232 (5), 204 (14), 192 (44), 163 (95), 136 (75),

123 (53), 91 (32), 59 (100); HRMS (ESI-TOF) m/z [M + H]⁺

251.1637 (calcd for C₁₅H₂₃O₃, 251.1647).

32: mp 158.8−159.0 °C (MeCN); H NMR (CDCl₃, 600 MHz) δ

3.17 (1H, ddq, J = 7.2, 2.1 Hz, H-1), 2.75 (1H, dd, J = 19.2, 7.2 Hz, H-

2a), 2.32−2.27 (1H, m, H-10), 2.26 (1H, dd, J = 19.2, 2.1 Hz, H-2b),

2.23 (1H, dd, J = 13.8, 3.6 Hz, H-8a), 2.13 (3H, d, J = 2.1 Hz, H-14),

2.00 (1H, tt, J = 13.8, 3.6 Hz, H-9a), 1.87 (1H, dq, J = 13.8, 3.6 Hz, H-

9b), 1.69 (1H, dt, J = 13.8, 3.6 Hz, H-8b), 1.51 (3H, s, H-12), 1.16

(3H, s, H-13), 0.73 (3H, d, J = 7.2 Hz, H-15); ¹³C NMR (CDCl₃, 150

MHz) δ 208.2 (C-3), 197.9 (C-6), 156.1 (C-4), 149.9 (C-5), 72.4 (C-

7), 62.4 (C-11), 43.0 (C-1), 41.3 (C-2), 35.0 (C-10), 32.2 (C-9), 25.1

(C-8), 20.8 (C-12), 20.0 (C-13), 11.6 (C-15), 10.3 (C-14); EIMS m/z

(rel intensity) 248 (69), 233 (100), 207 (15), 179 (26), 161 (14), 149

(24), 135 (21), 121 (15), 105 (15), 91 (33); HRMS (ESI-TOF) m/z

[M + H]⁺249.1483 (calcd for C₁₅H₂₁O₃, 249.1491).

(4S,5R,8S,8aS)-4-Hydroxy-3,3′,3′,8-tetramethyl-6,7,8,8a-tetrahy-

dro-1H-spiro[azulene-5,2′-oxiran]-2(4H)-one (35). Epoxyenone 34

(3 mg, 12 μmol) was dissolved in 3% methanolic KOH (0.2 mL)

under N₂and heated to 40 °C in a sealed tube. After 1 h, brine (2 mL)

was added, and the resulting mixture extracted with Et₂O (3 × 5 mL).

The combined organic layers were dried over anhydrous MgSO₄and

ﬁltered. Removal of the volatiles in vacuo followed by puriﬁcation by

SCC (EtOAc/petroleum ether, 25:75) furnished 35 (2.6 mg, 87%) as

(8S,8aS)-3,8-Dimethyl-5-(propan-2-ylidene)-1,5,6,7,8,8a-hexahy-

droazulene-2,4-dione (6a). This synthesis followed the same

procedure as for the synthesis of 31 except that 30 (8.3 mg, 38

μmol), CH₂Cl₂(2 mL), CrO₃(48 mg, 480 μmol), and 3,5-

dimethylpyrazole (105 mg, 1.05 mmol) were used. Puriﬁcation by

SCC (Et₂O/petroleum ether, 12:88) recovered 30 (1.3 mg, 16%) and

furnished 6a (2.4 mg, 32%).

(8S,8aS)-3,3′,3′,8-Tetramethyl-6,7,8,8a-tetrahydro-1H-spiro-

[azulene-5,2′-oxirane]-2,4-dione (32). This synthesis followed the

same procedure as for the synthesis of 31 except that 30 (13.5 mg, 62

μmol), CH₂Cl₂(2 mL), 4 Å molecular sieves (104 mg), CrO₃(115

mg, 1.15 mmol), and 3,5-dimethylpyrazole (110 mg, 1.15 mmol) were

used and a second portion of CrO₃(82 mg, 0.8 mmol) was added after

12 h. The mixture was heated under reﬂux for an additional 12 h.

Puriﬁcation by SCC (Et₂O/petroleum ether, gradient elution from

20:80 to 50:50) furnished 32 (6.2 mg, 40%).

(2S,4R,5R,8S,8aS)-3,3′,3′,8-Tetramethyl-2,4,6,7,8,8a-hexahydro-

1H-spiro[azulene-5,2′-oxirane]-2,4-diol (33). To a stirred solution of

epoxyenedione (32) (38.3 mg, 154 μmol) in MeOH (10 mL) was

added CeCl₃·7H₂O (75 mg, 0.2 mmol). The resulting mixture was

cooled to 0 °C and stirred for 30 min. To this mixture was added

NaBH₄(28 mg, 737 μmol) in one portion. After 10 min the reaction

was quenched with saturated NH₄Cl solution (15 mL) and extracted

with Et₂O (3 × 20 mL). The combined organic extracts were dried

over anhydrous MgSO₄and ﬁltered, the volatiles were removed in

vacuo, and the residue was puriﬁed by SCC (EtOAc/petroleum ether,

gradient elution from 40:60 to 50:50) to yield 33 (30 mg, 77%) as a

colorless gum: ¹H NMR (CDCl₃, 600 MHz) δ 4.62 (1H, s, H-6), 4.49

(1H, t, J = 7.2 Hz, H-3), 2.82−2.76 (1H, m, H-1), 2.41 (1H, dt, J =

12.9, 7.2 Hz, H-2a), 2.20−2.12 (1H, m, H-10), 2.01 (1H, ddd, J =

15.0, 9.6, 3.0 Hz, H-8a), 1.77 (3H, d, J = 1.2 Hz, H-14), 1.68 (1H, ddd,

J = 15.0, 8.4, 2.4 Hz, H-8b), 1.62−1.54 (1H, m, H-9a), 1.47 (3H, s, H-

12), 1.41−1.37 (1H, m, H-9b), 1.37 (3H, s, H-13), 1.25 (1H, m, H-

2b), 0.89 (3H, d, J = 7.2 Hz, H-15); ¹³C NMR (CDCl₃, 150 MHz) δ

139.8 (C-4), 137.5 (C-5), 78.9 (C-3), 70.8 (C-6), 68.0 (C-7), 63.5 (C-

11), 47.3 (C-1), 37.2 (C-2), 35.7 (C-10), 30.1 (C-8), 28.8 (C-9), 21.9

(C-12), 20.5 (C-13), 17.4 (C-15), 11.8 (C-14); EIMS m/z (rel

intensity) 252 (9), 234 (19), 216 (44), 193 (30), 173 (58), 147 (58),

135 (100), 121 (87), 105 (86), 91 (89); HRMS (ESI-TOF) m/z [M +

H]⁺253.1789 (calcd for C₁₅H₂₅O₃, 253.1804).

a colorless oil: H NMR (CDCl₃, 600 MHz) δ 4.23 (1H, s, H-6),

3.14−3.09 (1H, m, H-1), 2.50 (1H, dd, J = 18.6, 6.6 Hz, H-2a), 2.14

(1H, dd, J = 18.6, 1.2 Hz, H-2b), 2.08−2.04 (2H, m, H-8a and H-10),

1.99 (1H, dd, J = 13.2, 2.4 Hz, H-8b), 1.87 (1H, ddt, J = 13.8, 12.6, 2.4

Hz, H-9a), 1.83 (3H, d, J = 1.2 Hz, H-14), 1.60 (1H, dtd, J = 13.8, 5.4,

2.4 Hz, H-9b), 1.37 (3H, s, H-12), 1.33 (3H, s, H-13), 0.56 (3H, d, J =

7.2 Hz, H-15); ¹³C NMR (CDCl₃, 150 MHz) δ 208.3 (C-3), 166.8

(C-4), 141.6 (C-5), 71.3 (C-7), 71.2 (C-11), 56.4 (C-6), 43.2 (C-1),

40.5 (C-2), 32.7 (C-10), 29.3 (C-9), 26.2 (C-12), 25.3 (C-13), 22.7

(C-8), 10.3 (C-15), 8.0 (C-14); EIMS m/z (rel intensity) 250 (13),

232 (8), 204 (6), 192 (18), 163 (60), 151 (100), 136 (40), 123 (73),

91 (45), 59 (89); HRMS (ESI-TOF) m/z [M + H]⁺251.1638 (calcd

for C₁₅H₂₃O₃, 251.1647).

(4R,5S,8S,8aS)-5-Acetyl-4-hydroxy-3,5,8-trimethyl-4,5,6,7,8,8a-

hexahydroazulen-2(1H)-one (36). To a stirred solution of 34 (3.9

mg, 16 μmol) in CH₂Cl₂(1 mL) was added several crystals of TsOH·

H₂O. The reaction was stirred under N₂at RT for 1 h. Saturated

aqueous NaHCO₃(2 mL) was then added, and the resulting mixture

extracted with Et₂O (3 × 5 mL). The combined organic extracts were

washed with brine (3 mL), dried over anhydrous MgSO₄, and ﬁltered.

The volatiles were removed in vacuo, and the residue was puriﬁed by

SCC (EtOAc/petroleum ether, gradient elution from 20:80 to 25:75)

to aﬀord 36 (2.7 mg, 71%) as a colorless oil: H NMR (CDCl₃, 600

MHz) δ 4.77 (1H, d, J = 3.6 Hz, H-6), 3.18−3.12 (1H, m, H-1), 2.77

(1H, ddd, J = 13.2, 12.6, 6.6 Hz, H-8a), 2.47−2.43 (1H, m, H-10),

2.44 (1H, dd, J = 18.6, 6.6 Hz, H-2a), 2.28 (1H, dd, J = 18.6, 4.2 Hz,

H-2b), 2.10 (1H, d, J = 3.6 Hz, OH), 1.93 (1H, td, J = 12.6, 6.6, 2.4

Hz, H-8b), 1.91−1.86 (1H, m, H-9a), 1.82 (3H, d, J = 2.4 Hz, H-13),

1.45−1.40 (1H, m, H-9b), 1.32 (3H, s, H-12), 1.21 (3H, s, H-14), 0.92

(3H, d, J = 6.6 Hz, H-15); ¹³C NMR (CDCl₃, 150 MHz) δ 214.3 (C-

11), 207.9 (C-3), 173.4 (C-5), 137.3 (C-4), 77.5 (C-6), 56.6 (C-7),

45.4 (C-1), 34.9 (C-8), 34.3 (C-2), 29.8 (C-10), 29.4 (C-9), 23.1 (C-

14), 21.5 (C-15), 21.0 (C-12), 10.4 (C-13); EIMS m/z (rel intensity)

250 (16), 232 (11), 207 (13), 189 (38), 161 (100), 136 (35), 123

(46), 91 (30), 55 (47); HRMS (ESI-TOF) m/z [M + H]⁺251.1639

(calcd for C₁₅H₂₃O₃, 251.1647)

ASSOCIATED CONTENT

■

* Supporting Information

(4R,5R,8S,8aS)-4-Hydroxy-3,3′,3′,8-tetramethyl-6,7,8,8a-tetrahy-

dro-1H-spiro[azulene-5,2′-oxiran]-2(4H)-one (34). To a stirred

solution of 33 (14.8 mg, 59 μmol) in DMSO (2 mL) was added

IBX (140 mg, 500 μmol) in one portion, and the resulting mixture

stirred under N₂at RT for 3 h. The reaction was quenched with

saturated aqueous NaHCO₃(5 mL) and extracted with Et₂O (3 × 10

mL). The combined organic layers were further washed with brine (10

mL), dried over anhydrous MgSO₄, and ﬁltered. The volatiles were

removed in vacuo, and the residue was puriﬁed by SCC (Et₂O/

petroleum ether, gradient elution from 32:68 to 50:50) to give 34 (4.2

DFT/B3LYP-6-31G* calculation details for 1a, 8a, and 8b;

semiempirical/AM1 calculations for 4a and 4b; H and ¹³C

NMR spectra for compounds 1b, 1c, 9 (a and b), 10 (a and b),

10b, 11a, 11b, 12 (a and b), 13a, 13b, 14 (a and b), 14c, 14d,

15−21, 3, 2a, 4b, 22a, 22b, 2b, 25, 26, 5a, 6a, and 28−36;

ROESY NMR spectra for 25, 28, 29, 33, and 36; X-ray data of

14c, 14d, 22a, 22b, and 32; tabulated ¹H and ¹³C NMR data of

5a, 5b, 6a, and 6b. This material is available free of charge via

the Internet at http://pubs.acs.org.

mg, 29%) as a colorless liquid and 32 (5.2 mg, 36%). 34: H NMR

2535

dx.doi.org/10.1021/np500611z | J. Nat. Prod. 2014, 77, 2522−2536

Journal of Natural Products

Article

(27) Kaur, S.; Dayal, R.; Varshney, V. K.; Bartley, J. P. Planta Med.

2001, 67, 883−886.

(28) Bure, C. M.; Sellier, N. M. J. Essent. Oil Res. 2004, 16, 17−19.

(29) Cardeal, Z. L.; Gomes da Silva, M. D. R.; Marriott, P. J. Rapid

Commun. Mass Spectrom. 2006, 20, 2823−2836.

(30) Grison-Pige, L.; Hossaert-McKey, M.; Greeff, J. M.; Bessiere, J.-

M. Phytochemistry 2002, 61, 61−71.

(31) Nakashima, K.-i.; Oyama, M.; Ito, T.; Witono, J. R.; Darnaedi,

D.; Tanaka, T.; Murata, J.; Iinuma, M. Chem. Biodiversity 2012, 9,

2195−2202.

(32) We have observed the sensitivity of epoxyguaiene (13a,b) and

epoxyguaiyl acetate (11a,b) to ring-opening when peracetic acid in

acetic acid is employed.

AUTHOR INFORMATION

■

Corresponding Author

*E-mail: dennis.taylor@adelaide.edu.au. Tel: (+61) 08

83137239. Fax: (+61) 08 83137116.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

This work was supported by the School of Agriculture, Food

and Wine, The University of Adelaide. A.C.H. is indebted to

the University of Adelaide and the China Scholarship Council

for a joint Ph.D. scholarship. C.J.S. acknowledges the ARC for

funding the Bragg Crystallography Facility (LE0989336 and

LE120100012). This research was also supported by High

Impact Research MoE Grant UM.C/625/1/HIR/MoE/SC/03

from the Ministry of Higher Education Malaysia and the

University of Malaya.

(33) Chekroun, A.; Jarid, A.; Benharref, A.; Boutalib, A. J. Org. Chem.

2000, 65, 4431−4434.

(34) Kanai, K.; Sakamoto, I.; Ogawa, S.; Suami, T. Bull. Chem. Soc.

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(35) α-Bulnesol was identiﬁed by comparing its retention time and

MS to a sample of the authentic compound.

(36) LiAlH₄may also be utilized for the cleavage of the benzyl ether

to aﬀord guaia-5(6)-en-ol (3) in comparable yield; however, workup

when using Li and naphthalene was found to be simpler.

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4914.

(38) Employing DMDO as oxidant gave a better dr of the bridged α-

guaiene epoxides; however, the low yields and poor regioselectivity

precluded us from using it as oxidant to access the bridged α-

epoxyguaienes.

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