Enantioselective total synthesis of (-)-candelalides A, B and C: Potential Kvl.3 blocking immunosuppressive agents

DOI: 10.1002/chem.200802122

Enantioselective Total Synthesis of (ꢀ)-Candelalides A, B and C:

Potential Kv1.3 Blocking Immunosuppressive Agents

Takamasa Oguchi, Kazuhiro Watanabe, Kꢀichi Ohkubo, Hideki Abe, and

Tadashi Katoh*^[a]

Abstract: Novel Kv1.3 blocking immu-

at C9 and the exo-methylene function

at C8 present in the decalin portion; ii)

a straightforward coupling of a trans-

decalin portion (BC ring) and a g-

bond to assemble the requisite carbon

nosuppressants, (ꢀ)-candelalides A, B

and C, were efficiently synthesized for

the first time in a convergent and uni-

fied manner starting from (+)-5-

methyl-Wieland–Miescher ketone. The

synthetic method involved the follow-

ing key steps: i) a strategic [2,3]-Wittig

framework; and iii) a construction of a

characteristic di or tetrahydropyran

ring (A ring) by internal nucleophilic

ring closure of a hydroxy aldehyde or a

hydroxy epoxide. The present total syn-

thesis has fully established the absolute

configuration of these natural products.

ꢀ

pyrone moiety through the C16 C3’

Keywords: candelalides · immuno-

suppressive agents · natural prod-

ucts · total synthesis

rearrangement of

a

stannylmethyl

ether to install the stereogenic center

Introduction

The gross structure and relative stereochemistry of 1–3

have been determined by extensive spectroscopic studies, in-

In 2001, the Merck research group reported the isolation

and structural elucidation of candelalides A (1), B (2) and C

(3) (Figure 1) from the culture broth of Sesquicillium cande-

labrum.^[1]These substances were found to be novel blockers

of the voltage-gated potassium channel Kv1.3 (IC₅₀=3.7 mm

for 1, 1.2 mm for 2 and 2.5 mm for 3).^[1]In human T cells,

Kv1.3 channels exist as tetramers of four identical subunits

that control the resting membrane potential of the cells.^[2]

Membrane depolarization that results from blockage of

Kv1.3 channels causes a reduction in Ca²⁺entry into T cell,

thereby decreasing the intracellular Ca²⁺levels required for

T-cell activation and proliferation.^[3]Consequently, these

natural products show promise as new agents for potential

treatments of T cell-mediated autoimmune diseases such as

multiple sclerosis, rheumatoid arthritis and insulin-depen-

dent diabetes.^[1–3]

[a] T. Oguchi, Dr. K. Watanabe, K. Ohkubo, Dr. H. Abe,

Prof. Dr. T. Katoh

Laboratory of Synthetic Medicinal Chemistry

Department of Chemical Pharmaceutical Science

Tohoku Pharmaceutical University, 4-4-1 Komatsushima

Aoba-ku, Sendai, 981-8558 (Japan)

Fax : (+81)22-727-0135

E-mail: katoh@tohoku-pharm.ac.jp

Supporting information for this article is available on the WWW

under http://dx.doi.org/10.1002/chem.200802122.

Figure 1. Candelalides A (1), B (2), C (3), sesquicillin (4) and nalantha-

lide (5).

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cluding 2D NMR experiments (COSY, HMBC, NOESY and

HETCOR spectra), whereas their absolute configurations

have not yet been confirmed.^[1]These natural products pos-

sess a novel tricyclic decahydro- or dodecahydro-1H-ben-

zo[f]chromene skeleton (ABC ring system) connected to a

fully substituted g-pyrone ring via a methylene linkage in-

volving five to seven asymmetric carbon centers.^[1]Interest-

ingly, the structurally most complex candelalide B exhibits

the most potent Kv1.3 blocking activity.^[1]

Structurally related and biologically attractive diterpenoid

pyrones have been studied: In 2002, Danishefsky and Zhang

reported an elegant total synthesis of (ꢁ)-sesquicillin (4)

containing an a-pyrone ring, a glucocorticoid antagonist

from Acremonium sp.^[4]The desirable biological properties,

unique structural features and the necessity of confirming

the absolute configurations prompted us to undertake a

project directed towards the total synthesis of optically

active 1–3. We have previously reported our preliminary re-

sults on the enantioselective total syntheses of (ꢀ)-1^[5]and

(ꢀ)-nalanthalide (5),^[6]potential Kv1.3 blocking immunosup-

pressants, which led to the establishment of their absolute

configurations. In this paper, we describe in full detail our

first unified total synthesis of (ꢀ)-1–3 using a convergent

and enantioselective scheme.

Results and Discussion

Synthesis of (ꢀ)-candelalides A (1) and C (3): Our initial

synthetic efforts were targeted towards candelalides A (1)

and C (3), because the structures of these compounds are

less complex than that of candelalide B (2).

Synthetic plan: In our synthetic plan for candelalides A (1)

and C (3), we envisioned that the first target molecule 1

would be derived from hydroxy aldehyde 6 (accessible from

disilyl ether 8) by construction of the characteristic dihydro-

pyran ring (A ring) via intramolecular hemiacetal formation

followed by dehydration (Scheme 1). Intermediate 8 would

be produced through a coupling reaction between the ap-

propriately functionalized decalin segment 11, available

from alcohol 12, and the fully substituted 3-lithio-g-pyrone

9, accessible from bromide 10. From the synthetic point of

view, this coupling reaction poses a considerable challenge

because the C9 formyl group in decalin 11 lies in a sterically

congested axial orientation. Intermediate 12, having both a

hydroxylmethyl group at C9 and an exo-methylene moiety

at C8, would be formed through the strategic [2,3]-Wittig re-

arrangement of stannylmethyl ether 13. We expected that

the C9 stereogenic center and the C8 exo-methylene func-

tion in product 12 would be simultaneously established. In-

termediate 13 would, in turn, be derived from the known

trans-decalone 14,^[7]which is readily prepared from the

Scheme 1. Synthetic plan for candelalides A (1) and C (3). TES=triethyl-

silyl, TBS=tert-butyldimethylsilyl.

(A ring) through a 6-exo cyclization of hydroxy epoxide 7,

where the requisite stereogenic center at C13 in 3 is created.

Intermediate 7 would be derived from the common inter-

mediate 8 by sequential functional group manipulation and

deprotection or vice versa.

Synthesis of decalin segment 11: We first pursued the syn-

thesis of decalin segment 11 starting from the known enatio-

merically pure trans-decalone 14^[7](> 99% ee), wherein the

route to allyl alcohol 26 was based on Danishefskyꢁs synthe-

sis of (ꢁ)-sesquicillin (4) (Scheme 2).^[4]Thus, stereoselective

reduction of the C3 carbonyl group in 14 with L-selectride

enantiomerically

pure

(+)-5-methyl-Wieland–Miescher

ketone (15)^[8](> 99% ee).

In a parallel synthesis, the second target molecule 3 would

be produced by the construction of the tetrahydropyran ring

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T. Katoh et al.

tion of the ethylene acetal moiety in 17 by acid hydrolysis

(91%), the two hydroxy groups in the resulting ketone 18

were differentially protected as the tert-butyldimethylsilyl

(TBS) and triethylsilyl (TES) ethers, providing the corre-

sponding disilyl ether 20 in 76% yield in two steps via the

monosilyl ether 19. To introduce a formyl group at the C8

position, compound 20 was treated with ethyl formate in the

presence of sodium hydride to yield enol 21 (97%).

The hydroxy group on enol 21 was then protected as

ethoxyethyl (EE) ether to furnish enol ether 22 in 96%

yield. Subsequent sodium borohydride reduction of 22 pro-

duced alcohol 23 in 98% yield as a single stereoisomer,

which was then subjected to dehydration employing metha-

nesulfonyl chloride (MsCl) and triethylamine to produce the

desired a,b-unsaturated aldehyde 25 in 90% yield via the in-

termediary methanesulfonate 24. Compound 25 was further

converted to the requisite stannylmethyl ether 13, the sub-

strate for the critical [2,3]-Wittig rearrangement, in 84%

overall yield via a two-step sequence involving sodium boro-

hydride reduction of the formyl group in 25 followed by

stannylmethylation^[9]of the resulting alcohol 26 with iodo-

methyltributyltin in the presence of potassium hydride and

[18]crown-6.

Having obtained intermediate 13, we next examined the

critical [2,3]-Wittig rearrangement^[10,11]to construct the

requisite decalin system 12 having both a hydroxymethyl

group at C9 with the correct stereochemistry and an exo-

methylene functionality at C8. After screening several reac-

tion conditions (Table 1), we found that the proposed [2,3]-

Wittig rearrangement of 13 proceeded smoothly and cleanly

in a stereoselective manner by treatment with n-butyllithium

in hexane at ꢀ50 to 08C for 5 h (entry 1), yielding the de-

sired product 12 (78%) with a small amount of its C9

Table 1. ACHTNUTRGNE[NUG 2,3]-Wittig rearrangement of stannylmethyl ether 13.

Scheme 2. Synthesis of decalin segment 11. a) L-Selectride, THF, ꢀ108C,

3 h, 91%; b) BH₃·THF, THF, 08C, 1 h; 30% aq. H₂O₂, 3m NaOH, THF,

08C, 1 h, 96%; c) 5% aq. HCl, THF, RT, 4 h, 91%; d) TBSCl, imidazole,

DMF, RT, 14 h, 93%; e) TESOTf, 2,6-lutidine, CH₂Cl₂, 08C, 30 min,

82%; f) ethyl formate, NaH, THF, 08C ! RT, 1 h, 97%; g) ethyl vinyl

ether, PPTS, THF, RT, 1.5 h, 96%; h) NaBH₄, THF/H₂O 10:1, 08C !

RT, 2 h, 98%; i) MsCl, Et₃N, CH₂Cl₂, 08C, 30 min, 90%; j) NaBH₄, THF/

H₂O 10:1, 08C ! RT, 30 min, 98%; k) nBu₃SnCH₂I, KH, [18]crown-6,

THF, 08C ! RT, 3 h, 86%; l) nBuLi, hexane, ꢀ50 ! 08C, 5 h, 78% (see

entry 1 in Table 1); m) Dess–Martin periodinane, CH₂Cl₂, RT, 1 h, 98%.

DMF=N,N-dimethylformamide, Tf=trifluoromethanesulfonyl, PPTS=

pyridinium p-toluenesulfonate, Ms=methanesulfonyl, EE=1-ethoxyeth-

yl.

Entry

Solvent

Yield^[a][%]

12

27

28

26

produced the desired a-alcohol 16 in 91% yield as a single

stereoisomer. Subsequent hydroboration of 16, followed by

oxidative treatment with 30% aqueous hydrogen peroxide,

produced the requisite diol 17 in 96% yield. After deprotec-

1

2

3

hexane

THF

Et₂O

78

29

50

9

6

16

0

32

5

3

11

2

[a] Isolated yield.

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Immunosuppressive Agents

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epimer 27 (9%) and the hydroxy compound 26 (3%); these

products were readily separated by silica gel column chro-

matography. The structure and stereochemistry of the rear-

rangement products 12 and 27 were unambiguously con-

firmed by extensive spectroscopic analysis, including

600 MHz ¹H NMR NOESY spectra (selected NOESY corre-

lation, Figure 2).

Scheme 3. Synthesis of g-pyrone segment 10. a) (MeO)₂CO, NaN-

AHCTUNGTRENNUNG

Figure 2. Selected NOESY correlation of 12 and 27.

Compound 31 was successfully converted to g-pyrone seg-

ment 10 in 63% overall yield via a two-step operation in-

volving regioselective methyl etherification of the ambiden-

tate hydroxy group under the conditions of Beak et al.^[15]

(MeOSO₂F, CH₂Cl₂, RT), followed by bromination of the

resulting methyl ether 32 with N-bromosuccinimide (NBS).

The stereoselectivity for this [2,3]-Wittig rearrangement

can be rationalized by assuming that the attack of the inter-

mediate carboanion 13A (cf. Table 1), generated in situ by

tin/lithium exchange of stannane 13, on the C9 olefinic

carbon occurs preferentially from the less hindered a-face

on the molecule under the influence of the b-oriented axial

methyl group at the decalin junction, yielding 12 as the

major product. It should be noted that the use of hexane as

the solvent was crucial in this reaction. When THF or Et₂O

was used instead of hexane, the yield of the desired rear-

rangement product 12 was reduced (29–50%); moreover,

the undesired methyl ether 28 was produced (5–32%) as a

by-product (entries 2 and 3). By-product 28 was probably

formed by protonation of carboanion 13A; this reactive spe-

cies might have caused proton abstraction from the ethereal

solvents such as THF and Et₂O, because the methylene posi-

tion adjacent to the oxygen atom in those solvents is slightly

activated. To continue the synthesis (cf. Scheme 2), the rear-

rangement product 12 was then subjected to Dess–Martin

oxidation^[12]to provide the desired decalin segment 11 in

98% yield.

Synthesis of (ꢀ)-candelalide A (1): Having obtained both

decalin segment 11 and g-pyrone segment 10 in an efficient

way, we next investigated the synthesis of the first target

candelalide A (1) (Scheme 4). The sequence involved the

challenging coupling of the two segments and the crucial

construction of the dihydropyran ring (A ring). To this end,

the coupling reaction of 11 with 3-lithio-g-pyrone 9 was suc-

cessfully achieved by an initial bromine/lithium exchange on

10 and subsequent reaction with 11 at ꢀ78 to ꢀ308C for 2 h.

The expected coupling product 33 was obtained in 95%

yield as a mixture of epimeric alcohols (ca. 8:1 by 400 MHz

¹H NMR) that was very difficult to separate. It is notewor-

thy that the regiochemical integrity of the sensitive C8 exo-

methylene functionality was maintained during the coupling

reaction. Removal of the sterically hindered hydroxy group

in 33 was achieved by applying the Barton–McCombie pro-

cedure^[16]with some improvements in the reaction condi-

tions. Thus, treatment of a mixture of 33 and carbon disul-

Synthesis of g-pyrone segment 10: With decalin segment 11

synthesized, we next performed the synthesis of g-pyrone

segment 10, the coupling partner of 11 (Scheme 3). a-

Pyrone 31 has been previously prepared by Hagiwara

et al.^[13]starting from methyl 3-oxopentanoate and acetalde-

hyde in three steps with 19% overall yield. Recently, Shishi-

do et al.^[14]reported an improved synthesis of 31 starting

from 3-methylpentane-2,4-dione (29) in two steps with 57%

overall yield. Therefore, we decided to apply the improved

method to our synthesis. Thus, methoxycarbonylation of 29

with dimethyl carbonate in the presence of sodium bis(tri-

fide with NaN

(SiMe₃)₂at ꢀ788C, followed by addition of io-

domethane at the same temperature, provided the corre-

sponding methyl xanthate 34 in 93% yield. This was further

treated with tri-n-butyltin hydride in the presence of 2,2’-

azobis(isobutyronitrile) (AIBN) in refluxing toluene to pro-

duce the desired deoxygenated product 8 in 77% yield.

Having successfully obtained, the advanced key inter-

mediate 8, which has the whole carbon framework with the

requisite substituents and asymmetric carbons, we next un-

dertook the crucial construction of the dihydropyran ring to

complete the total synthesis of 1. Thus, selective deprotec-

tion of the TBS group in 8 by exposure to aqueous acetic

acid in THF, followed by Dess–Martin oxidation of the re-

sulting alcohol 35, provided the corresponding aldehyde 36

in 81% yield in two steps. Subsequent deprotection of the

methylsilyl)amide [NaN

30 in 85% yield. Subsequent cyclization of 30 by treatment

with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in refluxing

benzene produced the desired a-pyrone 31 in 86% yield.

ACHTUNGTRNE(NUNG SiMe₃)₂] afforded b,d-diketoester

AHCTUNGTRENNUNG

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T. Katoh et al.

1 {[a]²_D²=ꢀ25.1 (c=0.35 in CH₃OH)} showed good agree-

ment with that of natural 1 {lit.^[1][a]_D²²=ꢀ23.1 (c=0.26 in

CH₃OH)}; we therefore assigned the absolute configuration

of natural 1 (Scheme 4).

Synthesis of (ꢀ)-candelalide C (3): Having synthesized the

first target candelalide A (1), we next examined the synthe-

sis of the second target candelalide C (3) starting from the

common intermediate 36 (Scheme 5). The sequence in-

volved the stereocontrolled formation of the isopropanol-

substituted tetrahydropyran ring (A ring) present in 3 as the

crucial step. Thus, to set up the requisite homoprenyl side

Scheme 4. Synthesis of candelalide A (1). a) 3-Bromo-2-methoxy-5,6-di-

methyl-4H-pyran-4-one (10), nBuLi, THF, ꢀ788C; at ꢀ788C, add 11,

ꢀ78 ! ꢀ308C, 2 h, 95%; b) NaN(SiMe₃)₂, THF, ꢀ788C, 1 h; CS₂, THF,

G

ꢀ788C, 1 h; MeI, ꢀ788C, 1 h, 93%; c) nBu₃SnH, AIBN, toluene, reflux,

1 h, 77%; d) AcOH/THF/H₂O 3:2:2, RT, 2 h, 84%; e) Dess–Martin peri-

odinane, NaHCO₃, CH₂Cl₂, RT, 1 h, 96%; f) TBAF, THF, 08C ! RT,

40 min, 99%; g) MsCl, Et₃N, THF, 08C ! RT, 1 h, 87%. AIBN=2,2’-

azobis(isobutyronitrile), TBAF=tetrabutylammonium fluoride.

TES group in 36 with tetrabutylammonium fluoride (TBAF)

resulted in the expected cyclized hemiacetal 37 in 99% yield

via the intermediary hydroxy aldehyde 6. Finally, dehydra-

tion of 37 was efficiently achieved by treatment with MsCl

in THF containing triethylamine at 08C warming to room

temperature over 1 h, leading to the first target candelalide

Scheme 5. Synthesis of candelalide C (3). a) Ph₃PCHMe₂I, nBuLi, THF,

ꢀ20 ! ꢀ58C, 1 h, 82%; b) mCPBA, NaHCO₃, CH₂Cl₂, 08C, 2 h, 98 %;

c) TBAF, THF, RT, 1 h, 43% for 3. mCPBA=3-chloroperoxybenzoic

acid.

1

A (1) in 87% yield. The spectroscopic properties (IR, H

and ¹³C NMR, HRMS) of the synthetic sample 1 were iden-

tical to those of natural 1.^[1]The optical rotation of synthetic

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chain at C4, compound 36 was initially subjected to a Wittig

reaction using isopropylidene(triphenyl)phosphorane, which

provided the product 38 in 82% yield. Subsequent chemose-

methyl groups and the cyclohexane ring; this phenomenon

would prohibit the formation of 40 (13-epi-candelalide C).

ꢀ

lective epoxidation of the C13 C14 olefinic double bond in

38 was efficiently achieved by treatment with 3-chloroperoxy-

Synthesis of (ꢀ)-candelalide B (2)

A

Synthetic plan: Our synthetic plan for the final target cande-

lalide B (2), representing the most complex structure among

candelalides A–C, is based on the synthesis of candelalides

A (1) and C (3) mentioned above (Scheme 6). We envisaged

for 2 h, producing the desired epoxide 39 in 98% yield as a

mixture of diastereomers, which was difficult to separate (a-

epoxide/b-epoxide = ca. 1:1 by 400 MHz ¹H NMR). It is

noteworthy that the C8 sensitive exo-olefin moiety remained

intact during the epoxidation reaction. Finally, removal of

the TES protecting group in 39 by exposure to TBAF at

room temperature triggered the expected 6-exo cyclization

of the liberated alcohol 7 to produce the target candelalide

C (3) as the sole product in 43% yield. The spectroscopic

properties (IR, H and ¹³C NMR, HRMS) of the synthetic

sample 3 were identical to those of natural 3. The optical ro-

tation of synthetic 3 {[a]²_D²= ꢀ68.8 (c=0.98 in CH₃OH)]

was essentially identical to that of natural 3 {lit.^[1][a]_D²²=

ꢀ67.0 (c=1.03 in CH₃OH)}, confirming the absolute config-

uration of natural 3 (Scheme 5). In this reaction, another

possible cyclization product such as 40 (13-epi-candelalide

C) via the diastereomeric epoxide 7A was not obtained

from the reaction mixture. It is well known that this type of

epoxide-mediated cyclization is accompanied by inversion of

the stereochemistry at the carbon undergoing nucleophilic

attack (S_N2-type cyclization mode);^[17]therefore, we believed

that the desired cyclized product 3 (candelalide C) should

be obtained from intermediate 7.

From these results, it is evident that the stereochemistry

at the epoxide moiety in substrate 39 plays an important

role in the cyclization event. The difference in reactivity be-

tween hydroxy epoxides 7 and 7A can be rationalized by a

plausible mechanism (Figure 3). Thus, in the case of 7, the

internal nucleophilic attack of the C3 hydroxy group at the

C13 position would occur from the backside of the epoxide

ring, leading to desired 3 with inversion of the stereochemis-

try at C13. On the other hand, in the case of 7A, the inter-

nal nucleophilic attack at the C13-epoxide carbon would be

precluded by a severe steric interaction between the C14

Scheme 6. Synthetic plan for candelalide B (2).

that the target molecule 2 would be produced through the 6-

exo cyclization of epoxy alcohol 41, followed by inversion of

configuration at the C12 hydroxy group. The advanced key

intermediate 41 would be derived from aldehyde 42, accessi-

ble from diene 43 by functional group manipulation and de-

protection or vice versa. Intermediate 43 would be formed

through a coupling reaction of decalin segment 44, accessi-

ble from alcohol 45, and the common g-pyrone segment 9.

Intermediate 45 would be synthesized through the [2,3]-

Wittig rearrangement of stannylmethyl ether 46, available

from decalin alcohol 16, in the same manner as described

above.

Synthesis of decalin segment 44: First, the synthesis of deca-

lin segment 44 was investigated starting from the common

Figure 3. Possible mechanisms for the difference in reactivity between 7

and 7A in the ether cyclization reaction.

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T. Katoh et al.

intermediate 16 (Scheme 7) by employing a reaction se-

quence similar to that described in the section on the syn-

thesis of decalin segment 11 (cf. Scheme 2). Thus, compound

employed in the section on the synthesis of decalin segment

11 (cf. 13 ! 12, Scheme 2 and Table 1). The desired product

45 was obtained in 76% yield, along with the C9 epimer 54

(17%) and the hydroxy compound 53 (5%). The stereo-

structure of the rearrangement products 45 and 54 was con-

firmed by NOESY experiments (Figure 4), in a manner simi-

lar to that described above (cf. Figure 2). Finally, Dess–

Martin oxidation^[12]of 45 provided decalin segment 44 in

91% yield.

Figure 4. Selected NOESY correlation of 45 and 54.

Synthesis of (ꢀ)-candelalide B (2): After obtaining the

requisite decalin segment 44, we next performed the synthe-

sis of epoxy alcohol 59, which has the appropriate stereo-

chemistry at the epoxide ring (Scheme 8). Compound 59

represents an O-TES protecting variant of the advanced key

intermediate 41, designed as a substrate for the critical ether

cyclization (cf. Scheme 6 and the section on our synthetic

plan). To this end, the coupling reaction of 44 and g-pyrone

pyrone 10 was achieved under the same conditions de-

scribed in the section on the synthesis of (ꢀ)-candelalide A

(1) [cf. 11 + 9 (10) ! 33, Scheme 4]. The desired coupling

product 55 was obtained in 86% yield as an inseparable

Scheme 7. Synthesis of decalin segment 44. a) PPTS, acetone/H₂O 5:1,

reflux, 4 h; b) TESOTf, iPr₂NEt, CH₂Cl₂, 08C, 30 min, 97% (2 steps); c)

ethyl formate, NaH, THF, 08C ! RT, 1 h, 92%; d) ethyl vinyl ether,

PPTS, THF, RT, 1.5 h, 96%; e) NaBH₄, THF/H₂O 10:1, 08C ! RT, 3 h,

98%; f) MsCl, Et₃N, CH₂Cl₂, 08C, 30 min, 96%; g) NaBH₄, THF/H₂O

10:1, 08C ! RT, 30 min, 98%; h) nBu₃SnCH₂I, KH, [18]crown-6, THF,

08C ! RT, 3 h, 83%; i) nBuLi, hexane, ꢀ50 ! 08C, 9 h, 76% for 45,

17% for 54, 5% for 53; j) Dess–Martin periodinane, NaHCO₃, CH₂Cl₂,

RT, 1 h, 91%.

1

mixture of epimeric alcohol (ca. 8:1 by 400 MHz H NMR).

Removal of the hydroxy group in 55 was similarly carried

out by the method described above (cf. 33 ! 34 ! 8,

Scheme 4), which provided the desired deoxygenated prod-

uct 43 in 68% overall yield via methyl xanthate 56. After

Lemieux–Johnson oxidation^[18](OsO₄, NaIO₄, 2,6-lutidine,

dioxane/H₂O, RT, 85 %) of 43, the resulting aldehyde 42 was

reacted with a Grignard reagent (2-methyl-1-propenyl mag-

nesium bromide) to furnish the desired products 57 (42%)

and 58 (40%) as mixture of epimeric alcohols that can be

separated by silica gel column chromatography. The stereo-

chemistry newly formed at C12 in both products 57 and 58

could not be assigned at this stage; therefore, the assignment

was made at a later stage by NOESY studies of the trans-

formed cyclic compounds 61 and 64, respectively (see below,

cf. Schemes 9 and 10 and Figure 6). Hydroxy-directed epoxi-

16 was converted to decalone 48 in 97% overall yield via a

two-step operation involving acid hydrolysis of the ethylene

acetal moiety in 16 and TES protection of the resulting alco-

hol 47. Subsequent formylation at C8 in 48 and EE protec-

tion of the resulting enol 49 yielded enol ether 50 in 88%

yield in two steps. After sodium borohydride reduction of

the C9 carbonyl group in 50 (98%), the resulting alcohol 51

was subjected to dehydration, providing the desired a,b-un-

saturated aldehyde 52 in 96% yield. Compound 52 was then

successfully converted to stannylmethyl ether 46 in 81%

overall yield via a two-step sequence involving sodium boro-

hydride reduction and stannylmethylation^[9]of the resulting

alcohol 53. The crucial [2,3]-Wittig rearrangement of 46 pro-

ceeded smoothly and cleanly under the optimized conditions

dation^[19][VO

G

58 delivered the corresponding epoxides 59 (84%) and 60

(80%) as a single diastereomer, respectively.

We next investigated the final route that led to comple-

tion of the total synthesis of 2 (Scheme 9). Critical to the se-

quence was the construction of the highly substituted tetra-

hydropyran ring present in 2. To this end, the TES-protect-

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Chem. Eur. J. 2009, 15, 2826 – 2845

Immunosuppressive Agents

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Scheme 9. Synthesis of candelalide B (2). a) TBAF, THF, 08C ! RT, 1 h,

100%; b) PPTS, CH₂Cl₂, 08C ! RT, 4 h, 79%; c) TPAP, NMO, 4 ꢂ MS,

CH₂Cl₂, RT, 30 min, 82%; d) NaBH₄, THF/H₂O 10:1, ꢀ308C, 1 h, 88 %.

TPAP=tetra-n-propylammonium perruthenate, NMO=N-methylmor-

pholine N-oxide, MS=molecular sieves.

under basic conditions (cf. K₂CO₃, NaOMe, in MeOH;

DBU in THF; LiN

G

N

reflux) were unsuccessful; the starting material 41 was re-

covered at temperatures between 08C to room temperature,

and unidentified decomposition products were detected at

higher temperatures. After several experiments, the desired

6-exo ether cyclization was successfully realized under

mildly acidic conditions. Thus, exposure of 41 to PPTS at

08C warming to room temperature for 4 h resulted in the

formation of the requisite cyclization product 61 in 79%

yield. The structure of this product and its stereochemistry

were confirmed by NOESY experiments, which showed

clear NOE interactions between C3-H and C13-H, and be-

tween C12-H and C5-H, C14-Me. The elucidation of this

structure also verified the stereochemistry at C12 of the

Grignard reaction product 57 (cf. Scheme 8).

The reason for the distinctly different reactivity of 41

under basic (or neutral) and acidic conditions is unclear, but

a plausible explanation is the conformational change in the

substrate (Figure 5). Under basic (or neutral) conditions, the

substrate would mainly occupy conformation 41A, wherein

the epoxide ring takes an anti position to the C12 hydroxy

Scheme 8. Synthesis of intermediate 59. a) 10, nBuLi, THF, ꢀ788C; at

ꢀ788C, add 44, ꢀ78 ! ꢀ308C, 2 h, 86%; b) CS₂, THF, ꢀ788C; NaN-

G

1 h, 68% (2 steps); d) OsO₄, NaIO₄, 2,6-lutidine, dioxane/H₂O 3:1, RT,

1 h, 85%; e) Me₂C=CHMgBr, THF, RT, 1 h, 42% for 57, 40% for 58; f)

VO

G

acac=acetylacetonyl, TBHP=tert-butylhydroperoxide.

ing group in 59, having favorable stereochemistries at the

epoxide ring for the subsequent ether cyclization, was re-

moved by treatment with TBAF at room temperature for

1 h, producing the liberated epoxy alcohol 41 in quantitative

yield. In contrast to the case of candelalide C (3) (cf. 39 !

7 ! 3, Scheme 5), no ether cyclization products were pro-

duced during the deprotection step. Several attempts to

obtain the desired cyclized product 61 by treatment of 41

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2833

T. Katoh et al.

Figure 5. Possible mechanism for the difference in reactivity for the fa-

vored conformations 41A and 41B in the ether cyclization reaction.

ꢀ

group resulting from the C O/C O dipole–dipole repulsion.

That conformation would preclude any possibility of epox-

ide ring opening by an S_N2-type nucleophilic attack of the

C3 hydroxy group. However, under acidic conditions, the

substrate, upon protonation of the epoxide ring, would pre-

dominantly take conformation 41B, wherein the epoxide

ring is in a syn orientation to the C12-hydroxy group due to

an internal hydrogen bond between the C12-hydroxy group

and the epoxonium hydrogen. That conformation may facili-

tate the nucleophilic ether cyclization to yield the desired

product 61.

Scheme 10. Conversion of 60 to candelalide B analogue 64. a) TBAF,

THF, 08C ! RT, 1 h, 100%; b) PPTS, CH₂Cl₂, 08C ! RT, 3 h, 86%.

To complete the synthesis (cf. Scheme 9), inversion of the

configuration at the C12-hydroxy group in 61 was next ach-

ieved by oxidation with tetra-n-propyl ammonium per-

ruthenate (TPAP)^[20](82%) followed by sodium borohy-

dride reduction of the resulting ketone 62 with complete ste-

reoselectivity, resulting in the production (88%) of the final

target candelalide B (2). The spectroscopic properties (IR,

¹H and ¹³C NMR, HRMS) of the synthetic sample 2 were

identical to those of the natural product 2. The optical rota-

tion of synthetic 2 {[a]²_D²=ꢀ56.3 (c=0.75 in CH₃OH)} was

in good agreement with that of natural 2 {lit.^[1][a]_D²²=ꢀ50.9

(c=0.49 in CH₃OH)}, which confirmed its absolute configu-

ration (2, Figure 1).

Interestingly, as shown in Scheme 10, the same acid treat-

ment of the diastereomeric hydroxy epoxide 63, derived

from 60 by O-TES deprotection (quantitative yield) as de-

scribed for the cyclization of 41 to 61, provided the unex-

pected seven-membered cyclized product 64 in 86% yield.

The structure and stereochemistry of 64 was unambiguously

confirmed by extensive spectroscopic analysis, including

high-resolution MS and 2D NMR experiments. The selected

NOESY correlation of 64 (Figure 6), wherein clear NOE in-

teractions between C12-H and C3-H, C14-b-Me, between

C3-H and C14-b-Me, and between C13-H and C14-a-Me

are observed, permitting also determination of the stereo-

chemistry at C12 of the Grignard reaction product 58 (cf.

Scheme 8). It should be noted that this reaction proceeded

through a 7-endo cyclization process without producing the

alternative 6-exo ring-closure product.

Figure 6. Selected NOESY correlation of 64.

The unique acid-induced cyclization reaction of 63 leading

to 64 must be attributed to the stereostructural nature inher-

ent in substrate 63. Thus, conformation 63A might be pref-

erentially formed through an internal hydrogen bond be-

tween the C12-hydroxy group and the epoxonium hydrogen

(Figure 7). That conformation is obviously unfavorable for

6-exo ring closure by nucleophilic attack of the C3-hydroxy

group at the C13-epoxide carbon, as a result of well-known

stereoelectronic factors. Consequently, intermediate 63A

can undergo epoxide ring opening to produce the putative

intermediate 63B, wherein the C14-carbocation center must

be trapped by the C3-hydroxy group, forming the seven-

membered cyclized product 64.

Conclusion

We have accomplished the first total synthesis of (ꢀ)-cande-

lalides A (1), B (2) and C (3), which are novel Kv1.3 block-

ing immunosuppressive agents, in a convergent and unified

manner starting from (+)-5-methyl-Wieland–Miescher

ketone (15). The method explored features: i) strategic

[2,3]-Wittig rearrangement of stannylmethyl ethers 13 and

2834

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Immunosuppressive Agents

FULL PAPER

porting Information. Infrared (IR) spectra measurements were carried

out with a JASCO FT/IR-4100 spectrometer. Low- and High-resolution

mass (MS and HRMS) spectra were measured on a JEOL JMS-DX 303/

JMA-DA 5000 SYSTEM high resolution mass spectrometer. Elemental

analyses were performed with a Perkin Elmer 2400II apparatus.

(4aS,5S,6R,8aS)-5-Allyl-5,8a-dimethyl-6-(hydroxy)decahydronaphthalen-

1-one 1-ethyleneacetal (16): L-Selectride in THF (1.0m solution, 34.0 mL,

34 mmol) was added dropwise to a stirred solution of 14^[7](5.90 g,

21 mmol) in dry THF (220 mL) at ꢀ108C under argon. After 3 h, 3m

NaOH (50 mL) and 30% aqueous H₂O₂(12 mL) was added to the mix-

ture at 08C, and stirring was continued for 30 min at the same tempera-

ture. The reaction was diluted with water (150 mL) at 08C, and the re-

sulting mixture was extracted with EtOAc (3ꢃ200 mL). The combined

extracts were washed with brine (2ꢃ50 mL), then dried over MgSO₄.

Concentration of the solvent in vacuo afforded a residue, which was puri-

fied by column chromatography (hexane/EtOAc 5:1!4:1) to give 16

(5.41 g, 91%) as a white solid. Recrystallization from hexane afforded

colorless prisms. M.p. 77–788C; [a]_D²⁰

=

ꢀ23.6 (c=1.00 in CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=0.87 (s, 3H), 1.09 (s, 3H), 1.14–1.19 (m,

1H), 1.29 (dq, J=13.0, 3.4 Hz, 1H), 1.43–1.55 (m, 3H), 1.58–1.72 (m,

3H), 1.80–1.97 (m, 4H), 2.07–2.18 (m, 2H), 3.49–3.51 (m, 1H), 3.81–3.86

(m, 1H), 3.90–4.02 (m, 2H), 5.08–5.15 (m, 2H), 5.94–6.05 ppm (m, 1H);

¹³C NMR (100 MHz, CDCl₃): d=16.7, 18.9, 20.0, 23.0, 23.1, 24.6, 30.4,

40.4, 42.6, 43.2, 44.8, 64.8, 65.3, 72.3, 113.2, 117.3, 136.2 ppm; IR (KBr):

n˜ =3491, 3448, 3073, 2956, 2936, 2882, 2366, 1637, 1475, 1398, 1383, 1184,

1138, 1084, 910, 733, 509 cm^ꢀ1; HRMS (EI): m/z: calcd for C₁₇H₂₈O₃:

280.2038, found 280.2040 [M]⁺.

Figure 7. Possible mechanism for the ether cyclization reaction of 63 lead-

ing to 64 via 63A and 63B.

46 to deliver to the requisite decalin portions 11 and 44,

having both a hydroxy group at C9 with the correct stereo-

chemistry and an exo-methylene function at C8 (13 ! 12,

Scheme 2, Table 1; 46 ! 45, Scheme 7), ii) coupling reaction

of decalin portions 11 and 44 with a common g-pyrone por-

tion 9 (10) to build up the desired carbon frameworks 33

and 55 [11 + 9 (10) ! 33, Scheme 4; 44 + 9 (10) ! 55,

Scheme 8] and iii) formation of the characteristic di- or tet-

rahydropyran rings by cyclization of hydroxy aldehyde 6

and hydroxy epoxides 7 and 41 to produce the target mole-

cules 1–3 (36 ! [6] ! 37 ! 1, Scheme 4; 39 ! [7] ! 3,

Scheme 5; 41 ! 61, Scheme 9). The synthesis fully con-

firmed the absolute configurations of these natural products.

On the basis of the present research, synthesis of candela-

lide analogues with the aim of exploring the structure-activi-

ty relationships is currently under investigation in our labo-

ratory.

(4aS,5S,6R,8aS)-5,8a-Dimethyl-6-hydroxy-5-(3-hydroxypropyl)decahydro-

naphthalen-1-one 1-ethyleneacetal (17): A solution of BH₃·THF in THF

(0.93m solution, 7.80 mL, 7.3 mmol) was added dropwise to a stirred solu-

tion of 16 (744 mg, 2.6 mmol) in dry THF (20 mL) at 08C under argon.

After 1 h, 3m NaOH (4.0 mL) and 30% aqueous H₂O₂(4.0 mL) was

added to the reaction mixture at 08C, and stirring was continued for 1 h

at the same temperature. The reaction was quenched with water (10 mL)

at 08C, and the resulting mixture was extracted with EtOAc (3ꢃ60 mL).

The combined extracts were washed with brine (2ꢃ50 mL), then dried

over MgSO₄. Concentration of the solvent in vacuo afforded a residue,

which was purified by column chromatography (hexane/EtOAc 2:1!1:2)

to give 17 (760 mg, 96%) as a white amorphous solid. [a]²_D⁰=ꢀ24.6 (c=

1.10 in CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=0.83 (s, 3H), 1.10 (s,

3H), 1.16–1.20 (m, 1H), 1.24–1.32 (m, 1H), 1.35–1.55 (m, 6H), 1.55–1.71

(m, 6H), 1.79 (dd, J=12.6, 2.4 Hz, 1H), 1.88 (d, J=9.8 Hz, 2H), 3.56–

3.63 (m, 2H), 3.64–3.70 (m, 1H), 3.80–3.86 (m, 1H), 3.90–4.01 ppm (m,

3H); ¹³C NMR (100 MHz, CDCl₃): d=16.7, 18.6, 19.9, 22.8, 22.9, 24.6,

25.4, 30.2, 35.0, 39.1, 42.7, 43.1, 63.1, 64.6, 65.0, 71.3, 113.3 ppm; IR

(KBr): n˜ =3385, 2949, 2878, 1657, 1447, 1383, 1337, 1283, 1211, 1184,

1136, 1111, 1076, 993, 951, 909, 862, 797, 756, 666, 581, 513, 471 cm^ꢀ1

;

HRMS (EI): m/z: calcd for C₁₇H₃₀O₄: 298.2144, found 298.2144 [M]⁺.

Experimental Section

(4aS,5S,6R,8aS)-5,8a-Dimethyl-6-hydroxy-5-(3-hydroxypropyl)decahydro-

napthalen-1-one (18): 5% Aqueous HCl (14 mL) was added dropwise to

a stirred solution of 17 (480 mg, 1.6 mmol) in THF (12 mL) at room tem-

perature. After 4 h, 3m NaOH (5 mL) and saturated aqueous NaHCO₃

(5 mL) were added slowly to the mixture at 08C. The resulting mixture

was extracted with EtOAc (4ꢃ50 mL). The combined extracts were

washed with saturated aqueous NaHCO₃(2ꢃ50 mL) and brine (2ꢃ

50 mL), then dried over MgSO₄. Concentration of the solvent in vacuo

General techniques: All reactions involving air- and moisture-sensitive

reagents were carried out using oven dried glassware and standard sy-

ringe–septum cap techniques. Routine monitoring of reaction were car-

ried out using glass-supported Merck silica gel 60 F₂₅₄TLC plates. Flash

column chromatography was performed on Kanto Chemical Silica Gel

60N (spherical, neutral 40–50 mm) with the solvents indicated.

All solvents and reagents were used as supplied with following excep-

tions. Tetrahydrofuran (THF) and Et₂O were freshly distilled from Na/

benzophenone under argon. Toluene was distilled from Na metal under

argon. N,N-Dimethylformamide (DMF), CH₂Cl₂, pyridine, and hexane

were distilled from CaH under argon.

afforded

a residue, which was purified by column chromatography

(hexane/EtOAc 1:1!1:2) to give 18 (372 mg, 91%) as a white solid. Re-

crystallization from THF afforded colorless needles. M.p. 169–1708C;

[a]²_D⁰=ꢀ47.8 (c=1.00 in CH₃OH); ¹H NMR (400 MHz, CD₃OD): d=

0.94 (s, 3H), 1.20 (s, 3H), 1.24–1.28 (m, 1H), 1.32–1.40 (m, 2H), 1.42–

1.56 (m, 2H), 1.58–1.67 (m, 3H), 1.68–1.76 (m, 2H), 1.86–1.95 (m, 1H),

2.00 (dd, J=13.9, 3.4 Hz, 1H), 2.06–2.15 (m, 2H), 2.66 (td, J=13.9,

7.3 Hz, 1H), 3.46–3.56 ppm (m, 3H); ¹³C NMR (100 MHz, CD₃OD): d=

19.55, 19.64, 21.1, 25.9, 26.90, 26.94, 27.3, 31.7, 38.5, 41.2, 48.5, 50.2, 63.9,

72.1, 218.1 ppm; IR (KBr): n˜ =3387, 2959, 2934, 2880, 1696, 1451, 1433,

Measurements of optical rotations were performed with a JASCO DIP-

370 automatic digital polarimeter. Melting points were taken on

a

1

Yanaco MP-3 micro melting point apparatus and are uncorrected. H and

¹³C NMR spectra were measured with a JEOL AL-400 or a JEOL JNM-

LA600 spectrometer. Chemical shifts were expressed in ppm using Me₄Si

(d=0) as an internal standard. The following abbreviations are used: sin-

glet (s), triplet (t), quartet (q), multiplet (m), and broad (br). Copies of

¹H and ¹³C NMR spectra for all new compounds are shown in the Sup-

1385, 1306, 1242, 1117, 1055, 1015, 976, 961, 920, 822, 748, 556 cm^ꢀ1

HRMS (EI): m/z: calcd for C₁₅H₂₆O₃: 254.1882, found 254.1887 [M]⁺; el-

;

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2835

T. Katoh et al.

emental analysis calcd (%) for C₁₅H₂₆O₃: C 70.83, H 10.30; found C

70.85, H 9.89.

64.1, 72.9, 106.0, 184.5, 195.5 ppm; IR (neat): n˜ =2955, 2879, 1705, 1640,

1584, 1462, 1412, 1385, 1362, 1334, 1254, 1100, 1057, 1009, 966, 936, 907,

837, 797, 775, 739, 687, 556 cm^ꢀ1

; HRMS (EI): m/z: calcd for

(4aS,5S,6R,8aS)-5-(3-tert-Butyldimethylsiloxypropyl)-5,8a-dimethyl-6-(hy-

droxy)decahydronaphthalen-1-one (19): tert-Butyldimethylsilyl chloride

C₂₈H₅₄O₄Si₂: 510.3561, found 510.3563 [M]⁺.

(TBSCl) (426 mg, 3.8 mmol) was added to

a

stirred solution of 18

(Z)-(4aS,5S,6R,8aS)-5-(3-tert-Butyldimethylsiloxypropyl)-2-(ethoxyethan-

1-yl)oxymethylene-5,8a-dimethyl-6-(triethylsiloxy)decahydronaphthalen-

1-one (22): Pyridinium p-toluenesulfonate (PPTS) (22.0 mg, 88 mmol) was

added to a stirred solution of 21 (448 mg, 0.88 mmol) in dry THF

(12 mL) containing ethyl vinyl ether (1.44 mL, 18 mmol) at room temper-

ature. After 1.5 h, the reaction was quenched with saturated aqueous

NaHCO₃(8 mL) at 08C, and the resulting mixture was extracted with

EtOAc (3ꢃ50 mL). The combined extracts were washed with brine (3ꢃ

30 mL), then dried over MgSO₄. Concentration of the solvent in vacuo

(360 mg, 1.4 mmol) in dry DMF (8 mL) containing imidazole (240 mg,

3.6 mmol) at room temperature. After 14 h, the reaction was quenched

with saturated aqueous NH₄Cl (5 mL) at 08C, and the resulting mixture

was extracted with Et₂O (3ꢃ60 mL). The combined extracts were washed

successively with 3% aqueous HCl (2ꢃ50 mL), saturated aqueous

NaHCO₃(2ꢃ50 mL) and brine (2ꢃ50 mL), then dried over MgSO₄. Con-

centration of the solvent in vacuo afforded a residue, which was purified

by column chromatography (hexane/EtOAc 10:1) to give 19 (485 mg,

93%) as a white solid. Recrystallization from hexane/Et₂O 10:1 afforded

colorless needles. M.p. 75–778C; [a]²_D⁰=ꢀ27.8 (c=1.31 in CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=0.06 (s, 6H), 0.90 (s, 9H), 0.91 (s, 3H),

1.17 (s, 3H), 1.29–1.39 (m, 2H), 1.42–1.49 (m, 1H), 1.50–1.54 (m, 2H),

1.59–1.65 (m, 2H), 1.65–1.74 (m, 3H), 1.81–1.90 (m, 1H), 1.93 (d, J=

3.4 Hz, 1H), 1.97–2.09 (m, 2H), 2.18–2.26 (m, 1H), 2.57 (dt, J=13.7,

6.9 Hz, 1H), 3.52–3.66 ppm (m, 3H); ¹³C NMR (100 MHz, CDCl₃): d=

ꢀ5.2, ꢀ5.3, 18.4, 18.9, 19.1, 20.2, 24.7, 25.7, 25.8, 26.0 (3C), 34.9, 37.5,

40.3, 46.8, 48.8, 63.8, 71.0, 77.2, 215.2 ppm; IR (KBr): n˜ =3474, 2953,

2930, 2859, 1698, 1472, 1385, 1256, 1209, 1167, 1063, 1019, 966, 891, 837,

775, 735, 662, 559, 498, 421 cm^ꢀ1; HRMS (EI): m/z: calcd for C₂₁H₄₀O₃Si:

368.2747, found 368.2748 [M]⁺; elemental analysis calcd (%) for

C₂₁H₄₀O₃Si: C 68.42, H 10.94; found C 68.42, H 10.94.

afforded

a residue, which was purified by column chromatography

(hexane/EtOAc 20:1!10:1) to give 22 (1:1 diastereomeric mixture

caused by the EE group) (490 mg, 96%) as a pale yellow viscous liquid.

¹H NMR (400 MHz, CDCl₃): d=0.05 (s, 6H), 0.56–0.64 (m, 6H), 0.85 (s,

3H), 0.90 (s, 9H), 0.94 (t, J=7.9 Hz, 9H), 1.12 (s, 3H), 1.21 (t, J=7.1 Hz,

3H), 1.30–1.36 (m, 2H), 1.42 (d, J=5.2 Hz, ³= H), 1.43 (d, J=5.2 Hz,

2

³= H), 1.46–1.53 (m, 2H), 1.55–1.65 (m, 3H), 1.70–1.90 (m, 4H), 2.20–

2

2.30 (m, 1H), 2.64–2.72 (m, 1H), 3.45–3.55 (m, 2H), 3.56–3.63 (m, 2H),

3.68–3.75 (m, 1H), 5.07 (quint, J=5.2 Hz, 1H), 7.40–7.44 ppm (m, 1H);

¹³C NMR (100 MHz, CDCl₃): d=ꢀ5.2, ꢀ5.3, 5.4 (3C), 7.2 (3C), 14.9

(¹= C), 15.0 (¹= C), 18.0, 18.4, 19.4, 19.6 (¹= C), 19.7 (¹= C), 21.1, 22.2

2

(¹= C), 22.3 (¹= C), 25.6, 26.0 (3C), 26.7, 26.8, 35.0, 40.6, 42.1 (¹= C), 42.2

2

(¹= C), 46.4, 63.6 (¹= C), 63.7 (¹= C), 64.2, 73.0, 103.5 (¹= C), 103.7 (¹= C),

2

114.0 (¹= C), 114.1 (¹= C), 151.3 (¹= C), 151.4 (¹= C), 206.5 (¹= C),

2

(4aS,5S,6R,8aS)-5-(3-tert-Butyldimethylsiloxypropyl)-5,8a-dimethyl-6-

(triethylsiloxy)decahydronaphthalen-1-one (20): Triethylsilyl trifluorome-

thanesulfonate (TESOTf) (0.88 mL, 3.8 mmol) was added dropwise to a

stirred solution of 19 (460 mg, 1.3 mmol) in dry CH₂Cl₂(12 mL) contain-

ing 2,6-lutidine (0.47 mL, 4.2 mmol) at 08C under argon. After 30 min,

the reaction was quenched with saturated aqueous NH₄Cl (5 mL) at 08C,

and the resulting mixture was extracted with Et₂O (3ꢃ50 mL). The com-

bined extracts were washed successively with 3% aqueous HCl (2ꢃ

40 mL), saturated aqueous NaHCO₃(2ꢃ40 mL) and brine (2ꢃ40 mL),

then dried over MgSO₄. Concentration of the solvent in vacuo afforded a

residue, which was purified by column chromatography (hexane/EtOAc

50:1) to give 20 (494 mg, 82%) as a colorless viscous liquid. [a]²_D⁰=ꢀ19.4

(c=1.34 in CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=0.04 (s, 6H), 0.61

(dq, J=7.9, 5.3 Hz, 6H), 0.88 (s, 3H), 0.89 (s, 9H), 0.95 (t, J=7.9 Hz,

9H), 1.16 (s, 3H), 1.23–1.33 (m, 4H), 1.44–1.53 (m, 2H), 1.58–1.66 (m,

4H), 1.79 (ddt, J=14.4, 3.4, 2.1 Hz, 1H), 1.97–2.07 (m, 2H), 2.17–2.24

(m, 1H), 2.50–2.61 (m, 1H), 3.46–3.54 (m, 1H), 3.55–3.62 ppm (m, 2H);

¹³C NMR (100 MHz, CDCl₃): d=ꢀ5.2, ꢀ5.3, 5.4 (3C), 7.1 (3C), 18.3,

19.2, 19.3, 20.1, 25.3, 25.8, 25.9, 26.0 (3C), 26.7, 35.4, 37.5, 40.8, 46.4, 48.8,

64.1, 72.9, 215.6 ppm; IR (neat): n˜ =2955, 2878, 1711, 1462, 1385, 1362,

1306, 1252, 1096, 1007, 963, 941, 909, 837, 775, 739, 687, 559 cm^ꢀ1; HRMS

(EI): m/z: calcd for C₂₇H₅₄O₃Si₂: 482.3611, found 482.3608 [M]⁺.

206.6 ppm (¹= C); IR (neat): n˜ =2955, 2880, 1680, 1599, 1462, 1385, 1345,

2

1254, 1209, 1101, 1046, 1005, 972, 882, 837, 775, 739, 689 cm^ꢀ1; HRMS

(EI): m/z: calcd for C₃₂H₆₂O₅Si₂: 582.4136, found 582.4138 [M]⁺.

(Z)-(1R,4aR,5S,6R,8aS)-5-(3-tert-Butyldimethylsiloxypropyl)-2-(ethoxy-

AHCTUNGTERGeNNUN than-1-yl)oxymethylene-5,8a-dimethyl-6-(triethylsiloxy)decahydronaph-

thalen-1-ol (23): NaBH₄(1.10 g, 29 mmol) was added in small portions to

a stirred solution of 22 (3.40 g, 5.8 mmol) in THF (60 mL) containing

water (6 mL) at 08C, and stirring was continued for 2 h at room tempera-

ture. The reaction was quenched with saturated aqueous NH₄Cl (20 mL)

at 08C, and the resulting mixture was extracted with EtOAc (3ꢃ80 mL).

The combined extracts were washed with brine (2ꢃ60 mL), then dried

over MgSO₄. Concentration of the solvent in vacuo afforded a residue,

which was purified by column chromatography (hexane/EtOAc 8:1) to

give 23 (1:1 diastereomeric mixture caused by EE group) (3.34 g, 98%)

as a colorless viscous liquid. ¹H NMR (400 MHz, CDCl₃): d=0.04 (s,

6H), 0.58–0.65 (m, 6H), 0.77 (s, 3H), 0.78 (s, 3H), 0.89 (s, 9H), 0.97 (t,

3

J=7.9 Hz, 9H), 1.20 (t, J=7.1 Hz, = H), 1.21 (t, J=7.1 Hz, = H), 1.17–

2

1.32 (m, 4H), 1.36 (d, J=5.3 Hz, 3H), 1.40 (dd, J=5.2, 1.0 Hz, 1H),

1.43–1.52 (m, 5H), 1.57–1.68 (m, 2H), 1.75–1.85 (m, 1H), 2.90 (dd, J=

14.0, 2.9 Hz, 1H), 3.45–3.54 (m, 2H), 3.55–3.62 (m, 2H), 3.70–3.77 (m,

2H), 4.86–4.94 (m, 1H), 6.21–6.27 ppm (m, 1H); ¹³C NMR (100 MHz,

CDCl₃): d=ꢀ5.2, ꢀ5.3, 5.4 (3C), 7.2 (3C), 13.0 (¹= C), 13.1 (¹= C), 15.1

2

(Z)-(4aS,5S,6R,8aS)-5-(3-tert-Butyldimethylsiloxypropyl)-5,8a-dimethyl-

2-hydroxymethylene-6-(triethylsilyloxy)decahydronaphthalen-1-one (21):

A solution of 20 (460 mg, 0.48 mmol) in dry THF (12 mL) containing

ethyl formate (0.92 mL, 11 mmol) was added to a stirred suspension of

NaH (60% dispersion in mineral oil, 576 mg, 14 mmol) in dry THF

(12 mL) at 08C under argon, and stirring was continued for 1 h at room

temperature. The reaction was quenched with saturated aqueous NH₄Cl

(5 mL) at 08C, and the resulting mixture was extracted with EtOAc (3ꢃ

50 mL). The combined extracts were washed with brine (2ꢃ40 mL), then

dried over MgSO₄. Concentration of the solvent in vacuo afforded a resi-

due, which was purified by column chromatography (hexane/EtOAc

(¹= C), 15.2 (¹= C), 18.4, 19.0, 20.5 (¹= C), 20.6 (¹= C), 21.0 (¹= C), 21.1

2

(¹= C), 24.3, 25.9, 26.0 (3C), 26.8, 30.1 (¹= C), 30.2 (¹= C), 35.3, 39.7, 40.5

2

(¹= C), 40.6 (¹= C), 45.6, 62.3 (¹= C), 62.4 (¹= C), 64.3, 73.4, 80.8, 100.8

2

(¹= C), 100.9 (¹= C), 119.0 (¹= C), 119.1 (¹= C), 133.4 (¹= C), 133.7 ppm

2

(¹= C); IR (neat): n˜ =2955, 2878, 1686, 1462, 1383, 1341, 1254, 1086, 1007,

2

965, 936, 837, 808, 775, 739 cm^ꢀ1

; HRMS (EI): m/z: calcd for

C₃₂H₆₄O₅Si₂: 584.4292, found 584.4291 [M]⁺.

(4aR,5S,6R,8aR)-5-(3-tert-Butyldimethylsiloxypropyl)-5,8a-dimethyl-6-

triethylsiloxy-3,4,4a,5,6,7,8,8a-octahydronaphthalene-2-carbaldehyde (25):

Methanesulfonyl chloride (MsCl) (0.59 mL, 7.5 mmol) was added drop-

wise to a stirred solution of 23 (436 mg, 0.75 mmol) in dry CH₂Cl₂

(10 mL) containing Et₃N (1.25 mL, 8.9 mmol) at 08C under argon. After

30 min, the reaction was quenched with saturated aqueous NH₄Cl (5 mL)

at 08C, and the resulting mixture was extracted with CHCl₃(3ꢃ40 mL).

The combined extracts were washed with brine (2ꢃ30 mL), then dried

over MgSO₄. Concentration of the solvent in vacuo afforded a residue,

which was purified by column chromatography (hexane/EtOAc 20:1) to

give 25 (332 mg, 90%) as a colorless viscous liquid. [a]²_D⁰=+2.1 (c=1.36

in CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=0.05 (s, 6H), 0.61 (q, J=

10:1) to give 21 (472 mg, 97%) as a pale yellow viscous liquid. [a]_D²⁰

=

+6.9 (c=1.01 in CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=0.05 (s, 6H),

0.61 (dq, J=7.9, 2.3 Hz, 6H), 0.83 (s, 3H), 0.89 (s, 9H), 0.95 (t, J=

7.9 Hz, 9H), 1.21 (s, 3H), 1.27–1.34 (m, 3H), 1.41–1.53 (m, 3H), 1.57–

1.67 (m, 2H), 1.68–1.74 (m, 1H), 1.80–1.88 (m, 2H), 2.32 (ddd, J=15.2,

11.5, 7.0 Hz, 1H), 2.44 (ddd, J=15.2, 6.6, 1.8 Hz, 1H), 3.49–3.56 (m, 1H),

3.56–3.64 (m, 2H), 8.40 (d, J=4.5 Hz, 1H), 14.65 ppm (d, J=4.5 Hz,

1H); ¹³C NMR (100 MHz, CDCl₃): d=ꢀ5.2, ꢀ5.3, 5.4 (3C), 7.2 (3C),

17.8, 18.4, 19.0, 20.6, 23.1, 25.6, 26.0 (3C), 26.6, 35.0, 40.2, 42.0, 42.1, 48.7,

2836

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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 2826 – 2845

Immunosuppressive Agents

FULL PAPER

7.9 Hz, 6H), 0.82 (s, 3H), 0.90 (s, 9H), 0.95, (t, J=7.9 Hz, 9H), 1.06 (s,

3H), 1.24–1.33 (m, 3H), 1.33–1.44 (m, 1H), 1.45–1.55 (m, 2H), 1.56–1.62

(m, 1H), 1.64 (dd, J=12.8, 1.7 Hz, 1H), 1.72–1.86 (m, 2H), 1.90–1.99 (m,

1H), 2.06–2.16 (m, 1H), 2.39 (dd, J=18.2, 6.2 Hz, 1H), 3.48–3.56 (m,

1H), 3.56–3.66 (m, 2H), 6.39 (s, 1H), 9.39 ppm (s, 1H); ¹³C NMR

(100 MHz, CDCl₃): d=ꢀ5.2, ꢀ5.3, 5.4 (3C), 7.2 (3C), 17.0, 18.4, 18.5,

20.9, 23.1, 25.9, 26.0 (3C), 26.7, 31.5, 35.0, 36.6, 40.0, 43.9, 64.2, 73.4,

137.6, 162.8, 195.1 ppm; IR (neat): n˜ =2955, 2880, 2712, 1690, 1644, 1462,

1385, 1304, 1254, 1182, 1101, 1043, 1007, 965, 936, 837, 799, 775, 739, 567,

(2ꢃ20 mL), then dried over MgSO₄. Concentration of the solvent in

vacuo afforded a residue, which was purified by column chromatography

(hexane/EtOAc 20:1) to give 12 (57.7 mg, 78%), 27 (6.6 mg, 9%), and 26

(2.2 mg, 3%).

When THF was used as a solvent instead of hexane, 12, 27, 28, and 26

were obtained in 29, 6, 32, and 11% yields, respectively. In the case of

using Et₂O as a solvent instead of hexane, 12, 27, 28, and 26 were ob-

tained in 50, 16, 5, and 2% yields, respectively.

Compound 12: white prisms (recrystallization from hexane); m.p. 49–

518C; [a]²_D⁰=ꢀ19.3 (c=1.20 in CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=

0.04 (s, 6H), 0.58–0.65 (m, 6H), 0.76 (s, 3H), 0.89 (s, 9H), 0.97 (t, J=

7.9 Hz, 9H), 0.98 (s, 3H), 1.21–1.27 (m, 3H), 1.27–1.39 (m, 1H), 1.44–

1.54 (m, 4H), 1.56–1.64 (m, 1H), 1.71 (dd, J=12.9, 2.8 Hz, 1H), 1.81–

1.91 (m, 2H), 1.95–2.04 (m, 1H), 2.10–2.20 (m, 1H), 2.29 (brd, J=13.9,

1H), 3.47–3.53 (m, 1H), 3.55–3.61 (m, 2H), 3.62–3.69 (m, 1H), 3.81 (dt,

J=10.0, 4.9 Hz, 1H), 4.74 (t, J=2.1 Hz, 1H), 4.91 ppm (t, J=2.1 Hz,

1H); ¹³C NMR (100 MHz, CDCl₃): d=ꢀ5.2, ꢀ5.3, 5.4 (3C), 7.2 (3C),

18.4, 19.1, 22.4, 23.2, 26.0 (3C), 26.1, 26.8, 29.0, 31.6, 35.4, 37.4, 40.0, 40.5,

59.0, 60.9, 64.3, 73.6, 112.7, 147.3 ppm; IR (KBr): n˜ =3341, 2957, 2880,

2361, 1653, 1462, 1414, 1358, 1360, 1256, 1101, 1034, 1011, 970, 936, 889,

837, 814, 777, 737, 666 cm^ꢀ1; HRMS (EI): m/z: calcd for C₂₉H₅₈O₃Si₂:

510.3925, found 510.3905 [M]⁺.

Compound 27: colorless viscous liquid; [a]²_D⁰=ꢀ17.3 (c=0.83 in CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=0.04 (s, 6H), 0.58–0.61 (m, 6H), 0.74 (s,

3H), 0.75 (s, 3H), 0.89 (s, 9H), 0.98 (t, J=7.9 Hz, 9H), 1.21–1.35 (m,

4H), 1.36–1.41 (m, 1H), 1.45–1.55 (m, 4H), 1.60–1.71 (m, 2H), 1.73–1.83

(m, 1H), 2.01–2.10 (m, 2H), 2.38–2.46 (m, 1H), 3.47–3.54 (m, 1H), 3.55–

3.61 (m, 2H), 3.73–3.80 (m, 1H), 3.81–3.88 (m, 1H), 4.64 (d, J=1.0 Hz,

1H), 4.93 ppm (d, J=1.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): d=

ꢀ5.2, ꢀ5.3, 5.4 (3C), 7.2 (3C), 16.0, 18.4, 19.0, 23.5, 26.0 (3C), 26.3, 26.8,

31.5, 35.6, 37.8, 38.8, 40.1, 48.2, 58.8, 59.2, 64.3, 73.3, 106.1, 148.0 ppm; IR

(neat): n˜ =3404, 2953, 2878, 1644, 1462, 1385, 1362, 1254, 1100, 1053,

1009, 965, 937, 891, 837, 814, 775, 739 cm^ꢀ1; HRMS (EI): m/z: calcd for

C₂₉H₅₈O₃Si₂: 510.3925, found 510.3938 [M]⁺.

426 cm^ꢀ1

; HRMS (EI): m/z: calcd for C₂₈H₅₄O₃Si₂: 494.3611, found

494.3611 [M]⁺.

(4aR,5S,6R,8aR)-5-(3-tert-Butyldimethylsiloxypropyl)-5,8a-dimethyl-6-

triethylsiloxy-3,4,4a,5,6,7,8,8a-octahydronaphthalene-2-methanol

(26):

NaBH₄(254 mg, 6.7 mmol) was added in small portions to a stirred solu-

tion of 25 (2.20 g, 4.5 mmol) in THF (50 mL) containing water (5 mL) at

08C, and stirring was continued for 30 min at room temperature. The re-

action was quenched with saturated aqueous NH₄Cl (15 mL) at 08C, and

the resulting mixture was extracted with EtOAc (3ꢃ80 mL). The com-

bined extracts were washed with brine (2ꢃ50 mL), then dried over

MgSO₄. Concentration of the solvent in vacuo afforded a residue, which

was purified by column chromatography (hexane/EtOAc 10:1!8:1) to

give 26 (2.16 g, 98%) as a colorless viscous liquid. [a]²_D⁰=ꢀ5.3 (c=1.19 in

CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=0.05 (s, 6H), 0.59–0.64 (m,

6H), 0.79 (s, 3H), 0.90 (s, 9H), 0.93–0.98 (m, 9H), 0.95 (s, 3H), 1.14 (dt,

J=12.5, 3.2 Hz, 1H), 1.22 (t, J=6.0 Hz, 1H), 1.25–1.30 (m, 2H), 1.34–

1.45 (m, 1H), 1.46–1.54 (m, 3H), 1.61 (dd, J=12.7, 1.5 Hz, 1H,), 1.64–

1.72 (m, 2H), 1.82–1.92 (m, 1H), 1.99–2.14 (m, 2H), 3.48–3.55 (m, 1H),

3.56–3.63 (m, 2H), 3.96 (brd, J=6.0 Hz, 2H), 5.34 ppm (s, 1H);

¹³C NMR (100 MHz, CDCl₃): d=ꢀ5.2, ꢀ5.3, 5.4 (3C), 7.2 (3C), 17.9,

18.4, 18.5, 21.9, 26.0 (3C), 26.3, 26.8, 27.4, 32.6, 34.9, 35.0, 39.7, 44.3, 64.4,

67.3, 73.8, 133.3, 136.9 ppm; IR (neat): n˜ =3328, 2955, 2280, 1462, 1414,

1385, 1360, 1254, 1186, 1101, 1041, 1007, 965, 837, 775, 739, 681 cm^ꢀ1

;

HRMS (EI): m/z: calcd for C₂₈H₅₆O₃Si₂: 496.3768, found 496.3763 [M]⁺.

(4aR,5S,6R,8aR)-5-(3-tert-Butyldimethylsiloxypropyl)-2-(tri-n-butylstan-

nylmethoxymethyl)-5,8a-dimethyl-6-triethylsiloxy-3,4,4a,5,6,7,8,8a-octahy-

dronaphthalene (13): KH (30% dispersion in mineral oil) (68.2 mg,

1.7 mmol), [18]crown-6 (450 mg, 1.7 mmol), and iodomethyl tri-n-butyltin

(0.49 mL, 1.1 mmol) were added successively to a stirred solution of 26

(282 mg, 0.57 mmol) in dry THF (10 mL) at 08C under argon, and stir-

ring was continued for 3 h at room temperature. The reaction was

quenched with saturated aqueous NH₄Cl (4 mL) at 08C, and resulting

mixture was extracted with EtOAc (3ꢃ50 mL). The combined extracts

were washed with brine (2ꢃ40 mL), then dried over MgSO₄. Concentra-

tion of the solvent in vacuo afforded a residue, which was purified by

column chromatography [hexane/EtOAc 100:1!50:1 (containing 0.2%

Et₃N)] to give 13 (391 mg, 86%) as a colorless viscous liquid. [a]²_D⁰=ꢀ3.6

(c=1.31 in CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=0.04 (s, 6H), 0.56–

0.64 (m, 6H), 0.78 (s, 3H), 0.86–0.91 (m, 21H), 0.93–0.99 (m, 13H), 1.13

(dt, J=12.5, 3.2 Hz, 1H), 1.24–1.35 (m, 9H), 1.45–1.56 (m, 11H), 1.59–

1.74 (m, 3H), 1.81–1.90 (m, 1H), 1.91–2.01 (m, 1H), 2.02–2.11 (m, 1H),

3.48–3.55 (m, 1H), 3.55–3.62 (m, 2H), 3.62–3.70 (m, 4H), 5.30 ppm (s,

1H); ¹³C NMR (100 MHz, CDCl₃): d=ꢀ5.2, ꢀ5.3, 5.4 (3C), 7.2 (3C), 9.0

(3C), 13.7 (3C), 17.9, 18.4, 18.5, 22.0, 26.0 (3C), 26.3, 26.7, 27.3 (3C),

27.6, 29.2 (3C), 32.7, 34.9, 35.0, 39.7, 44.3, 60.4, 64.4, 73.8, 79.3, 130.7,

138.7 ppm; IR (neat): n˜ =2955, 1462, 1416, 1383, 1254, 1101, 1007, 961,

Compound 28: colorless viscous liquid; [a]²_D⁰= ꢀ4.8 (c=1.04 in CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=0.05 (s, 6H), 0.60 (q, J=8.2 Hz, 6H),

0.78 (s, 3H), 0.90 (s, 9H), 0.93–0.97 (m, 12H), 1.13 (dt, J=12.1, 2.9 Hz,

1H), 1.24–1.29 (m, 2H), 1.34–1.45 (m, 1H), 1.47–1.55 (m, 3H), 1.61–1.72

(m, 3H), 1.83–1.90 (m, 1H), 1.95–2.13 (m, 2H), 3.28 (s, 3H), 3.48–3.62

(m, 3H), 3.74 (s, 2H), 5.34 ppm (s, 1H); ¹³C NMR (100 MHz, CDCl₃):

d=ꢀ5.29, ꢀ5.28, 5.4 (3C), 7.2 (3C), 17.9, 18.35, 18.40, 21.9, 26.0 (3C),

26.3, 26.7, 27.7, 32.6, 34.9, 35.0, 39.7, 44.2, 57.4, 64.4, 73.8, 77.1, 130.4,

139.0 ppm; IR (neat): n˜ =2953, 2877, 2817, 1470, 1415, 1384, 1254, 1187,

1103, 1043, 1005, 960, 836, 775, 665 cm^ꢀ1; HRMS (EI): m/z: calcd for

C₂₉H₅₈O₃Si₂: 510.3924, found 510.3931 [M]⁺.

(1R,4aR,5S,6R,8aS)-5-(3-tert-Butyldimethylsiloxypropyl)-5,8a-dimethyl-

2-methylene-6-(triethylsiloxy)decahydronaphthalene-1-carbaldehyde (11):

Dess–Martin periodinane (366 mg, 0.86 mmol) was added in small por-

tions to a stirred solution of 12 (147 mg, 0.29 mmol) containing NaHCO₃

(244 mg, 2.90 mmol) in dry CH₂Cl₂(12 mL) at room temperature. After

1 h, the reaction was quenched with 10% aqueous Na₂S₂O₃(10 mL) at

08C, and the resulting mixture was extracted with CHCl₃(3ꢃ50 mL).

The combined extracts were washed with saturated aqueous NaHCO₃

(2ꢃ20 mL) and brine (2ꢃ20 mL), then dried over MgSO₄. Concentration

of the solvent in vacuo afforded a residue, which was purified by column

chromatography (hexane/EtOAc 50:1) to give 11 (143 mg, 98%) as a col-

837, 775, 739, 683, 596, 511 cm^ꢀ1

; HRMS (EI): m/z: calcd for

C₄₁H₈₄O₃Si₂Sn: 800.4981, found 800.4984 [M]⁺.

1

orless viscous liquid. [a]²_D⁰=ꢀ3.1 (c=1.22 in CHCl₃); H NMR (400 MHz,

(1R,4aR,5S,6R,8aS)-5-(3-tert-Butyldimethylsiloxypropyl)-5,8a-dimethyl-

2-methylene-6-(triethylsiloxy)decahydronaphthalen-1-methanol (12), its

(1S,4aR,5S,6R,8aS)-isomer (27), and (4aR,5S,6R,8aR)-5-(3-tert-butyldi-

methylsiloxypropyl)-2-methoxymethyl-5,8a-dimethyl-6-triethylsiloxy-

3,4,4a,5,6,7,8,8a-octahydronaphthalene (28): nBuLi in hexane (1.58m so-

lution, 0.91 mL, 1.4 mmol) was added dropwise to a stirred solution of 13

(116 mg, 0.14 mmol) in dry hexane (3 mL) at ꢀ508C under argon, and

the mixture was gradually warmed up to 08C over 4 h, and stirring was

continued for 1 h at 08C. The reaction was quenched with saturated

aqueous NH₄Cl (3 mL) at 08C, and the resulting mixture was extracted

with EtOAc (3ꢃ30 mL). The combined extracts were washed with brine

CDCl₃): d=0.05 (s, 6H), 0.57–0.64 (m, 6H), 0.80 (s, 3H), 0.90 (s, 9H),

0.96 (t, J=7.9 Hz, 9H), 0.98 (s, 3H), 1.09 (dt, J=12.9, 3.1 Hz, 1H), 1.24–

1.35 (m, 2H), 1.37–1.54 (m, 4H), 1.69–1.77 (m, 1H), 1.83–1.93 (m, 1H),

1.99–2.11 (m, 2H), 2.26–2.36 (m, 1H), 2.41–2.47 (m, 1H), 2.49 (d, J=

3.9 Hz, 1H), 3.48–3.55 (m, 1H), 3.56–3.66 (m, 2H), 4.73 (s, 1H), 4.89 (s,

1H), 10.03 ppm (d, J=3.9 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): d=

ꢀ5.2, ꢀ5.3, 5.4 (3C), 7.1 (3C), 18.4, 18.9, 22.2, 22.3, 25.8, 26.0 (3C), 26.7,

30.1, 33.7, 35.3, 38.9, 40.1, 42.2, 64.2, 71.4, 73.3, 113.1, 143.1, 203.4 ppm;

IR (neat): n˜ =2955, 2880, 2730, 1719, 1647, 1462, 1414, 1385, 1362, 1258,

1100, 1013, 966, 895, 837, 810, 777, 739 cm^ꢀ1; HRMS (EI): m/z: calcd for

C₂₉H₅₆O₃Si₂: 508.3768, found 508.3750 [M]⁺.

Chem. Eur. J. 2009, 15, 2826 – 2845

ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

2837

T. Katoh et al.

Methyl 4-methyl-3,5-dioxohexanoate (30): A solution of 3-methyl-2,4-

pentanedione (29; 7.40 mL, 63 mmol) in dry THF (50 mL) was added

231.9724 [M]⁺; elemental analysis calcd (%) for C₈H₉BrO₃: C 41.23, H

3.89; found C 41.32, H 3.95.

dropwise to a stirred solution of NaNACHTNUTRGNEUNG(SiMe₃)₂in THF (1.9m solution,

3-[(1R,4aR,5S,6R,8aS)-5-(3-tert-Butyldimethylsiloxypropyl)-5,8a-dimeth-

yl-2-methylene-6-(triethylsiloxy)decahydronaphthalen-1-yl]hydroxymeth-

yl-5,6-dimethyl-2-methoxy-4H-pyran-4-one (33): nBuLi in hexane (1.58m

solution, 0.66 mL, 1.0 mmol) was added dropwise to a stirred solution of

10 (254 mg, 1.1 mmol) in dry THF (8 mL) at ꢀ788C under argon. After

30 min, a solution of 11 (139 mg, 0.27 mmol) in dry THF (8 mL) was

added dropwise to the above mixture at ꢀ788C, and stirring was contin-

ued for 2 h at ꢀ308C. The reaction was quenched with saturated aqueous

NH₄Cl (8 mL) at ꢀ308C, and the resulting mixture was extracted with

EtOAc (3ꢃ60 mL). The combined extracts were washed with brine (2ꢃ

30 mL), then dried over MgSO₄. Concentration of the solvent in vacuo

100 mL, 190 mmol) in dry THF (100 mL) at ꢀ788C under argon, and the

reaction mixture was stirred for 4 h at room temperature. Dimethylcar-

bonate (5.4 mL, 64.0 mmol) was added dropwise to the mixture at

ꢀ788C, and the resulting solution was further stirred for 24 h at room

temperature. The reaction mixture was acidified with 2m HCl (150 mL)

at 08C. The resulting mixture was extracted with EtOAc (3ꢃ200 mL).

The combined extracts were washed with brine (2ꢃ100 mL), and dried

over MgSO₄. Concentration of the solvent in vacuo afforded a residue,

which was purified by column chromatography (hexane/EtOAc 10:1!

5:1) to give 30 (ca. 1:1 tautomeric mixture) (9.21 g, 85%) as a pale

1

3

afforded

a residue, which was purified by column chromatography

yellow oil. H NMR (400 MHz, CDCl₃): d=1.36 (d, J=7.3 Hz, = H), 1.85

2

3

(hexane/EtOAc 5:1) to give 33 (ca. 8:1 diastereomeric mixture) (172 mg,

95%) as a colorless viscous liquid. [a]²_D⁰=ꢀ17.7 (c=1.13 in CHCl₃). The

¹H and ¹³C NMR spectra described below represent the major isomer.

¹H NMR (400 MHz, CDCl₃): d=0.05 (s, 6H), 0.58–0.69 (m, 6H), 0.77 (s,

3H), 0.80–0.87 (m, 1H), 0.90 (s, 9H), 0.94 (s, 3H), 0.99 (t, J=7.9 Hz,

9H), 1.25–1.41 (m, 3H), 1.48–1.55 (m, 3H), 1.58–1.66 (m, 1H), 1.82–1.92

(m, 2H), 1.87 (s, 3H), 2.25 (s, 3H), 2.30–2.37 (m, 2H), 2.44 (dd, J=12.8,

2.9 Hz, 1H), 2.50–2.60 (m, 1H), 3.48–3.54 (m, 1H), 3.55–3.65 (m, 2H),

3.95 (s, 3H), 4.32 (s, 1H), 4.72 (s, 1H), 4.84 (d, J=9.9 Hz, 1H), 5.22 ppm

(dd, J=9.9, 4.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): d=ꢀ5.2, ꢀ5.3, 5.4

(3C), 7.2 (3C), 9.7, 16.9, 18.4, 19.6, 23.0, 23.2, 26.0 (3C), 26.5, 27.1, 28.9,

35.0, 35.6, 38.5, 40.2, 40.3, 55.7, 62.0, 64.5, 67.7, 74.2, 105.7, 111.6, 119.5,

148.7, 155.3, 161.0, 181.6 ppm; IR (neat): n˜ =3301, 2955, 2878, 1671, 1588,

1464, 1424, 1379, 1319, 1296, 1254, 1152, 1096, 1009, 937, 835, 802, 779,

741, 669 cm^ꢀ1; HRMS (EI): m/z: calcd for C₃₇H₆₆O₆Si₂: 662.4398, found

662.4383 [M]⁺.

(s, = H), 2.15 (s, = H), 2.23 (s, = H), 3.48 (s, 1H), 3.55 (s, 1H), 3.74 (s,

2

³= H), 3.75 (s, = H), 3.87 ppm (q, J=7.3 Hz, = H); ¹³C NMR (100 MHz,

3

1

2

CDCl₃): d=12.4 (¹= C), 12.6 (¹= C), 23.5 (¹= C), 28.5 (¹= C), 42.5 (¹= C),

2

47.5 (¹= C), 52.3 (¹= C), 60.7 (¹= C), 90.2 (¹= C), 105.4 (¹= C), 167.3 (¹= C),

2

168.1 (¹= C), 184.1 (¹= C), 191.8 (¹= C), 199.5 ppm; IR (neat): n˜ =3628,

2

3566, 3461, 3421, 2992, 2955, 1744, 1704, 1615, 1437, 1406, 1327, 1263,

1160, 1056, 1003, 887, 846, 816 cm^ꢀ1

; HRMS (EI): m/z: calcd for

C₈H₁₂O₄: 172.0736, found 172.0743 [M]⁺.

4-Hydroxy-5,6-dimethyl-2H-pyran-2-one

(31):

1,8-Diazabicyclo-

ACHTUNGTRENNUNG[5.4.0]undec-7-ene (DBU) (2.18 mL, 14 mmol) was added dropwise to a

stirred solution of 30 (5.00 g, 29 mmol) in benzene (250 mL) at room

temperature under argon, and the mixture was heated at reflux for 1 h.

After cooling, the reaction was quenched with 1m HCl (60 mL) at 08C,

and the resulting mixture was extracted with EtOAc (3ꢃ300 mL). The

combined extracts were washed with brine (2ꢃ200 mL), and dried over

Na₂SO₄. Concentration of the solvent in vacuo afforded a residue, which

was purified by column chromatography (EtOAc) to give 31 (3.46 g,

86%) as a yellow solid. Recrystallization from acetone afforded a pale

yellow solid. M.p. 209–2108C; ¹H NMR (400 MHz, CD₃OD): d=1.91 (s,

3H), 2.23 (s, 3H), 5.39 ppm (s, 1H); ¹³C NMR (100 MHz, CD₃OD): d=

9.4, 17.4, 89.5, 109.3, 160.5, 168.1, 173.3 ppm; IR (KBr): n˜ =3313, 2938,

2797, 2616, 1672, 1570, 1508, 1366, 1308, 1267, 1120, 916, 821, 758, 629,

461 cm^ꢀ1; HRMS (EI): m/z: calcd for C₇H₈O₃: 140.0473, found 140.0475

[M]⁺.

3-[(1R,4aR,5S,6R,8aR)-5-(3-tert-Butyldimethylsiloxypropyl)-5,8a-dimeth-

yl-2-methylene-6-(triethylsiloxy)decahydronaphthalen-1-yl]methyl-5,6-di-

methyl-2-methoxy-4H-pyran-4-one (8): NaNACHTUNRTGENUNG(SiMe₃)₂in THF (1.0m solu-

tion, 0.31 mL, 0.31 mmol) was added dropwise to a stirred solution of 33

(172 mg, 0.26 mmol) in dry THF (5 mL) containing CS₂(0.31 mL,

5.2 mmol) at ꢀ788C under argon. After 1 h, MeI (0.20 mL, 2.6 mmol)

was added dropwise to the mixture at ꢀ788C, and the resulting solution

was further stirred for 1 h at same temperature. The reaction was

quenched with saturated aqueous NH₄Cl (4 mL), and resulting mixture

was extracted with EtOAc (3ꢃ40 mL). The combined extracts were

washed with brine (2ꢃ30 mL), then dried over MgSO₄. Concentration of

the solvent in vacuo afforded crude methyl xanthate 34 (182 mg, 93%),

which was used for the next reaction without purification.

3-Bromo-5,6-dimethyl-2-methoxy-4H-pyran-4-one (10): Methyl fluorosul-

fonate (3.40 mL, 42 mmol) was added dropwise to a stirred solution of 31

(1.00 g, 7.1 mmol) in CH₂Cl₂(60 mL) at room temperature. After 24 h,

the reaction mixture was concentrated in vacuo taking great care to

avoid exposure to the volatile and highly toxic methyl fluorosulfonate. In

order to remove an excess of methyl fluorosulfonate, the residue was di-

luted with CH₂Cl₂(40 mL), and the resulting mixture was concentrated

in vacuo. This operation was repeated three times, affording crude me-

thoxy-g-pyrone (32; 978 mg, 89%) as a pale yellow solid, which was used

for the next reaction without purification. ¹H NMR (400 MHz, CDCl₃):

d=1.91 (s, 3H), 2.26 (s, 3H), 3.83 (s, 3H), 5.49 ppm (s, 1H); ¹³C NMR

(100 MHz, CDCl₃): d=9.6, 16.9, 55.8, 88.3, 118.7, 156.8, 167.1, 181.3 ppm;

IR (KBr): n˜ =3448, 2962, 2854, 1671, 1599, 1420, 1376, 1254, 1123, 1064,

938, 841 cm^ꢀ1; HRMS (EI): m/z: calcd for C₈H₁₀O₃: 154.0630, found

154.0627 [M]⁺.

nBu₃SnH (0.13 mL, 0.48 mmol) and 2,2’-azobisisobutyronitrile (AIBN)

(7.9 mg, 48 mmol) were added to

a stirred solution of 34 (182 mg,

0.24 mmol) in dry toluene (8 mL) at room temperature. For the deaera-

tion of the reaction mixture, it was frozen using liquid nitrogen, and the

reaction vessel was evacuated in vacuo for 30 min followed by filled with

dry argon. The mixture was then heated at reflux for 1 h under argon.

After cooling, the reaction mixture was concentrated in vacuo to afford-

ed a residue, which was purified by column chromatography (benzene/

EtOAc 30:1) to give 8 (129 mg, 77%) as a colorless viscous liquid. [a]_D²⁰

=

ꢀ43.7 (c=0.41 in CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=0.05 (s, 6H),

0.58–0.66 (m, 6H), 0.77 (s, 3H), 0.90 (s, 9H), 0.94–1.00 (m, 1H), 0.95 (s,

3H), 0.97 (t, J=7.9 Hz, 9H), 1.24–1.38 (m, 3H), 1.45–1.55 (m, 4H), 1.84–

1.95 (m, 3H), 1.90 (s, 3H), 2.07–2.18 (m, 1H), 2.23 (s, 3H), 2.28–2.43 (m,

2H), 2.48 (t, J=12.8 Hz, 1H), 2.75 (dd, J=12.8, 3.4 Hz, 1H), 3.45–3.55

(m, 1H), 3.56–3.63 (m, 2H), 3.84 (s, 3H), 4.14 (t, J=2.4 Hz, 1H),

4.47 ppm (t, J=2.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): d=ꢀ5.2,

ꢀ5.3, 5.5 (3C), 7.2 (3C), 10.0, 17.0, 18.4, 19.1, 19.8, 22.9, 23.1, 26.0 (3C),

26.2, 26.9, 28.6, 31.5, 35.4, 37.8, 39.2, 39.9, 55.3, 56.3, 64.5, 74.0, 103.8,

108.8, 118.6, 124.9, 149.6, 154.8, 180.4 ppm; IR (neat): n˜ =2955, 2282,

1736, 1672, 1605, 1460, 1414, 1375, 1318, 1256, 1163, 1100, 1009, 835, 810,

779, 725 cm^ꢀ1; HRMS (EI): m/z: calcd for C₃₇H₆₆O₅Si₂: 646.4449, found

646.4454 [M]⁺.

N-Bromosuccinimide (NBS) (1.95 g, 11 mmol) was added in small por-

tions to a stirred solution of 32 (978 mg, 6.4 mmol) in THF (70 mL) at

08C. After 2 h, the reaction mixture was quenched with 1m NaOH

(40 mL) at 08C, and the resulting mixture was extracted with EtOAc (3ꢃ

120 mL). The combined extracts were washed with brine (2ꢃ80 mL), and

dried over MgSO₄. Concentration of the solvent in vacuo to afforded a

residue, which was purified by column chromatography (hexane/EtOAc

2:1!1:1) to give 10 (1.04 g, 71%) as a white solid. Recrystallization from

acetone afforded white needles. M.p. 110–1118C; ¹H NMR (400 MHz,

CDCl₃): d=1.99 (s, 3H), 2.31 (s, 3H), 4.06 ppm (s, 3H); ¹³C NMR

(100 MHz, CDCl₃): d=10.7, 16.8, 56.3, 89.2, 118.8, 155.1, 161.8,

175.3 ppm; IR (KBr): n˜ =2961, 2930, 2866, 1665, 1626, 1584, 1460, 1393,

1368, 1327, 1217, 1013, 1179, 1138, 1065, 990, 955, 924, 804, 752, 664, 608,

586, 469 cm^ꢀ1; HRMS (EI): m/z: calcd for C₈H₉BrO₃: 231.9735, found

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

6-(triethylsiloxy)decahydronaphthalen-1-yl]methyl-5,6-dimethyl-2-me-

thoxy-4H-pyran-4-one (35):

A solution of 8 (120 mg, 0.19 mmol) in

2838

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Chem. Eur. J. 2009, 15, 2826 – 2845

Immunosuppressive Agents

FULL PAPER

AcOH/THF/H₂O 3:2:2 (20 mL) was stirred for 2 h at room temperature.

The reaction mixture was basified with 1m NaOH (7 mL) and saturated

aqueous NaHCO₃(10 mL) at 08C. The resulting mixture was extracted

with EtOAc (3ꢃ50 mL). The combined extracts were washed with satu-

rated aqueous NH₄Cl (2ꢃ30 mL) and brine (30 mL), and dried over

MgSO₄. Concentration of the solvent in vacuo afforded a residue, which

was purified by column chromatography (hexane/EtOAc 2:1) to give 35

(82.9 mg, 84%) as a colorless viscous liquid. [a]²_D⁰=ꢀ45.6 (c=0.80 in

CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=0.59–0.67 (m, 6H), 0.78 (s,

3H), 0.94–1.01 (m, 1H), 0.95 (s, 3H), 0.98 (t, J=7.9 Hz, 9H), 1.15–1.22

(m, 1H), 1.24–1.36 (m, 3H), 1.40–1.48 (m, 1H), 1.54–1.62 (m, 3H), 1.83–

1.94 (m, 1H), 1.90 (s, 3H), 2.07–2.14 (m, 1H), 2.23 (s, 3H), 2.29–2.44 (m,

2H), 2.48 (t, J=12.8 Hz, 1H), 2.75 (dd, J=12.8, 3.5 Hz, 1H), 3.55–3.68

(m, 3H), 3.85 (s, 3H), 4.14 (t, J=2.4 Hz, 1H), 4.48 ppm (t, J=2.4 Hz,

1H); ¹³C NMR (100 MHz, CDCl₃): d=5.5 (3C), 7.2 (3C), 10.0, 17.0, 19.2,

19.7, 22.9, 23.1, 26.2, 26.8, 28.6, 31.5, 35.4, 37.8, 39.2, 39.9, 55.3, 56.2, 64.3,

74.0, 103.7, 108.9, 118.6, 149.4, 154.8, 163.0, 180.4 ppm; IR (neat): n˜ =

3409, 3065, 2955, 2878, 1726, 1671, 1589, 1462, 1420, 1377, 1319, 1258,

1182, 1148, 1078, 1011, 885, 810, 750, 478 cm^ꢀ1; HRMS (EI): m/z: calcd

for C₃₁H₅₂O₅Si: 532.3584, found 532.3555 [M]⁺.

802, 754 cm^ꢀ1; HRMS (EI): m/z: calcd for C₂₅H₃₄O₄: 398.2457, found

398.2447 [M-H₂O]⁺.

3-[(4aR,6aR,7R,10aR,10bR)-6a,10b-Dimethyl-8-methylene-

4a,5,6,6a,7,8,9,10,10a,10b-perhydro-1H-benzo[f]chromen-7-yl]methyl-5,6-

dimethyl-2-methoxy-4H-pyran-4-one (candelalide A) (1): MsCl (70.0 mL,

90 mmol) was added to a stirred solution of 37 (15.0 mg, 35 mmol) in dry

THF (3 mL) containing Et₃N (40 mL, 0.29 mmol) at 08C under argon,

and stirring was continued at room temperature for 1 h. The reaction was

quenched with saturated aqueous NH₄Cl (1.0 mL) at 08C, and the result-

ing mixture was extracted with EtOAc (3ꢃ20 mL). The combined ex-

tracts were washed with saturated aqueous NaHCO₃(3ꢃ15 mL) and

brine (2ꢃ15 mL), then dried over MgSO₄. Concentration of the solvent

in vacuo afforded a residue, which was purified by column chromatogra-

phy (hexane/EtOAc 1:1) to give 1 (12.2 mg, 87%) as a colorless amor-

phous powder. [a]_D²²=ꢀ25.1 (c=0.35 in CH₃OH) {lit.^[1][a]²_D²=ꢀ23.1 (c=

1

0.26 in CH₃OH)}. The H and ¹³C NMR, IR, and MS spectra (see below)

are identical to those of natural (ꢀ)-candelalide A. ¹H NMR (600 MHz,

CDCl₃): d=0.90 (s, 3H), 0.99 (s, 3H), 1.04 (dt, J=13.2, 3.2 Hz, 1H), 1.36

(dq, J=13.2, 4.8 Hz, 1H), 1.54–1.55 (m, 1H), 1.59 (dt, J=17.9, 2.5 Hz,

1H), 1.73–1.77 (m, 1H), 1.86 (dd, J=11.6, 3.3 Hz, 1H), 1.89 (s, 3H),

1.95–1.96 (m, 1H), 1.98 (dd, J=12.8, 9.9 Hz, 1H), 2.08–2.14 (m, 2H),

2.23 (s, 3H), 2.37 (dd, J=13.2, 4.1 Hz, 1H), 2.40–2.49 (m, 2H), 2.70 (dd,

J=13.2, 3.3 Hz, 1H), 3.71 (s, 1H), 3.84 (s, 3H), 4.17 (t, J=2.6 Hz, 1H),

4.49 (t, J=2.6 Hz, 1H), 4.54 (dt, J=6.0, 2.2 Hz, 1H), 6.38 ppm (dd, J=

6.1, 2.2 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃): d=10.1, 16.9, 19.7, 22.8,

23.4, 23.5, 23.9, 28.7, 31.3, 32.5, 33.6, 34.4, 37.4, 55.3, 56.6, 78.9, 97.6,

103.5, 108.9, 118.5, 142.6, 149.2, 154.7, 162.8, 180.3 ppm; IR (KBr): n˜ =

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

(triethylsiloxy)decahydronaphthalen-1-yl]-methyl-5,6-dimethyl-2-me-

thoxy-4H-pyran-4-one

(36):

Dess–Martin

periodinane

(191 mg,

0.42 mmol) was added in small portions to a stirred solution of 35

(80.0 mg, 0.14 mmol) in dry CH₂Cl₂(8 mL) containing NaHCO₃(120 mg,

1.4 mmol) at room temperature. After 30 min, the reaction was quenched

with 20% aqueous Na₂S₂O₃(8 mL) at 08C, and the resulting mixture was

extracted with Et₂O (3ꢃ50 mL). The combined extracts were washed

with saturated aqueous NaHCO₃(2ꢃ30 mL) and brine (2ꢃ30 mL), then

dried over MgSO₄. Concentration of the solvent in vacuo afforded a resi-

due, which was purified by column chromatography (hexane/EtOAc 4:1)

to give 36 (76.7 mg, 96%) as a colorless viscous liquid. [a]²_D⁰=ꢀ46.7 (c=

0.65 in CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=0.58–0.67 (m, 6H), 0.78

(s, 3H), 0.94–0.99 (m, 12H), 0.99–1.05 (m, 1H), 1.20–1.39 (m, 2H), 1.55–

1.66 (m, 2H), 1.69–1.78 (m, 1H), 1.84–1.98 (m, 3H), 1.91 (s, 3H), 2.08–

2.15 (m, 1H), 2.24 (s, 3H), 2.28–2.37 (m, 1H), 2.38–2.51 (m, 4H), 2.76

(dd, J=12.9, 3.5 Hz, 1H), 3.58 (brs, 1H), 3.85 (s, 3H), 4.15 (t, J=2.3 Hz,

1H), 4.49 (t, J=2.3 Hz, 1H), 9.80 ppm (d, J=1.6 Hz, 1H); ¹³C NMR

(100 MHz, CDCl₃): d=5.4 (3C), 7.2 (3C), 10.0, 17.0, 19.4, 19.8, 23.0, 26.1,

28.5, 29.7, 31.4, 31.5, 37.7, 38.8, 39.1, 39.7, 55.3, 56.0, 74.3, 103.5, 109.2,

118.6, 149.1, 154.8, 163.0, 180.4, 203.6 ppm; IR (neat): n˜ =2953, 1726,

1672, 1603, 1460, 1414, 1383, 1318, 1256, 1090, 802, 741, 567, 476,

2935, 2361, 1783, 1670, 1591, 1462, 1255, 1145, 1060, 985, 952, 754 cm^ꢀ1

;

HRMS (EI): m/z: calcd for C₂₅H₃₄O₄: 398.2457, found 398.2447 [M]⁺.

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

enyl)-6-(triethylsiloxy)decahydronaphthalen-1-yl]methyl-2-methoxy-5,6-

dimethyl-4H-pyran-4-one (38): nBuLi in hexane (1.56m, 0.17 mL,

0.26 mmol) was added dropwise to a stirred suspension of isopropyltri-

phenylphosphonium iodide (127 mg, 0.30 mmol) in dry THF (10 mL) at

ꢀ208C under argon, and stirring was continued for 30 min at the same

temperature. A solution of 36 (52.0 mg, 98 mmol) in dry THF (3 mL) was

added dropwise to the above mixture at ꢀ208C, and the mixture was

warmed up to ꢀ58C over 1 h. The reaction was quenched with saturated

aqueous NH₄Cl (8 mL), and the resulting mixture was extracted with

EtOAc (3ꢃ50 mL). The combined extracts were washed with brine (2ꢃ

40 mL), and dried over MgSO₄. Concentration of the solvent in vacuo af-

forded

a residue, which was purified by column chromatography

403 cm^ꢀ1

; HRMS (EI): m/z: calcd for C₃₁H₅₀O₅Si: 530.3428, found

(hexane/EtOAc 10:1!5:1) to give 38 (44.8 mg, 82%) as a colorless amor-

phous powder. [a]²_D⁰=ꢀ43.4 (c=0.93 in CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=0.60–0.66 (m, 6H), 0.80 (s, 3H), 0.94–1.00 (m, 12H), 1.18–

1.35 (m, 2H), 1.44–1.59 (m, 4H), 1.62 (s, 3H), 1.69 (s, 3H), 1.85–1.98 (m,

5H), 1.92 (s, 3H), 2.09 (dd, J=13.2, 3.4 Hz, 1H), 2.23 (s, 3H), 2.32–2.38

(m, 2H), 2.45–2.50 (m, 1H), 2.76 (dd, J=12.7, 3.4 Hz, 1H), 3.64 (s, 1H),

3.84 (s, 3H), 4.14 (s, 1H), 4.47 (s, 1H), 5.08 ppm (t, J=6.8 Hz, 1H);

¹³C NMR (100 MHz, CDCl₃): d=5.4 (3C), 7.2 (3C), 10.0, 16.9, 17.7, 19.0,

19.7, 21.8, 22.9, 23.1, 25.7, 26.2, 28.5, 31.5, 37.7, 39.2, 39.6, 40.1, 55.3, 56.1,

73.7, 103.7, 108.8, 118.6, 125.8, 130.5, 149.5, 154.8, 162.9, 180.4 ppm; IR

(KBr): n˜ =2952, 2932, 2876, 1729, 1672, 1604, 1460, 1415, 1374, 1316,

1254, 1084, 1005, 885, 812, 782, 723 cm^ꢀ1; HRMS (EI): m/z: calcd for

C₃₄H₅₆O₄Si: 556.3948, found 556.3937 [M]⁺.

530.3447 [M]⁺.

3-[(4aR,6aR,7R,10aR,10bR)-6a,10b-Dimethyl-3-hydroxy-8-(methylene)-

perhydro-1H-benzo[f]chromen-7-yl]-methyl-5,6-dimethyl-2-methoxy-4H-

pyran-4-one (37): Tetrabutylammonium fluoride (TBAF) in THF (1.0m

solution, 0.45 mL, 0.45 mmol) was added dropwise to a stirred solution of

36 (23.7 mg, 45 mmol) in THF (3 mL) at 08C under argon, and stirring

was continued for 40 min at room temperature. The reaction was

quenched with saturated aqueous NH₄Cl (2 mL) at 08C, and the resulting

mixture was extracted with EtOAc (3ꢃ30 mL). The combined extracts

were washed with saturated aqueous NaHCO₃(3ꢃ20 mL) and brine (2ꢃ

20 mL), then dried over MgSO₄. Concentration of the solvent in vacuo

afforded

a residue, which was purified by column chromatography

(hexane/EtOAc 2:1!1:1) to give 37 (1:1 diastereomeric mixture)

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

an-2-yl)ethyl-6-(triethylsiloxy)decahydronaphthalen-1-yl]methyl-2-me-

thoxy-5,6-dimethyl-4H-pyran-4-one (39): 3-Chloroperoxybenzoic acid

(mCPBA) (17.1 mg, 64 mmol) was added in small portions to a stirred so-

lution of 38 (36.0 mg, 63 mmol) in CH₂Cl₂(4 mL) containing NaHCO₃

(10.8 mg, 0.13 mmol) at 08C, and stirring was continued for 2 h at the

same temperature. The reaction was quenched with 20% aqueous

Na₂S₂O₃(2 mL) at 08C, and the resulting mixture was extracted with

CHCl₃(3ꢃ30 mL). The combined extracts were washed with saturated

aqueous NaHCO₃(2ꢃ20 mL) and brine (2ꢃ20 mL), then dried over

MgSO₄. Concentration of the solvent in vacuo afforded a residue, which

was purified by column chromatography (hexane/EtOAc 5:1) to give 39

(ca. 1:1 diastereomeric mixture) (36.3 mg, 98%) as a colorless amorphous

1

(18.8 mg, 99%) as a colorless viscous liquid. H NMR (400 MHz, CDCl₃):

3

1

d=0.80 (s, = H), 0.84 (s, = H), 0.97 (s, 3H), 0.98–1.03 (m, = H), 1.28–

2

5

1.36 (m, 3H), 1.41–1.52 (m, 2H), 1.59–1.72 (m, = H), 1.88–2.04 (m, 3H),

1.90 (s, 3H), 2.08–2.14 (m, = H), 2.15–2.20 (m, = H), 2.24 (s, 3H), 2.26–

2

1

2

1

2.38 (m, 2H), 2.39–2.46 (m, = H), 2.54–2.63 (m, 1H), 2.68–2.74 (m, = H),

2

2.81 (dd, J=13.2, 4.7 Hz, ¹= H), 3.05–3.12 (m, ¹= H), 3.35 (t, J=2.7 Hz,

2

¹= H), 3.80–3.84 (m, ¹= H), 3.86 (s, ³= H), 3.87 (s, ³= H), 4.17–4.20 (m,

2

¹= H), 4.22–4.25 (m, = H), 4.44–4.56 (m, 1H), 4.71 (brs, = H), 5.33 ppm

1

2

(brs, = H); ¹³C NMR (100 MHz, CDCl₃): d=10.1, 14.1, 16.9, 19.8, 22.6,

1

2

22.9, 23.3, 24.4, 29.1, 31.4, 33.8, 34.5, 35.1, 37.5, 55.3, 56.0, 80.3, 96.9,

103.5, 109.0, 120.1, 149.3, 154.7, 162.7, 180.4 ppm; IR (neat): n˜ =3403,

2930, 2292, 1726, 1671, 1589, 1462, 1422, 1377, 1321, 1260, 1019, 951, 885,

Chem. Eur. J. 2009, 15, 2826 – 2845

ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

2839

T. Katoh et al.

powder. ¹H NMR (400 MHz, CDCl₃): d=0.60–0.67 (m, 6H), 0.77 (s,

³= H), 0.78 (s, ³= H), 0.95–1.00 (m, 12H), 1.19–1.36 (m, 2H), 1.27 (s,

(3C), 7.1 (3C), 19.1, 19.2, 20.1, 25.2, 25.8, 25.9, 37.5, 41.6, 44.2, 45.8, 48.7,

73.3, 117.1, 135.9, 215.5 ppm; IR (neat): n˜ =3399, 3073, 2954, 2876, 1712,

1636, 1455, 1382, 1239, 1084, 999, 909, 823, 789, 724 cm^ꢀ1; HRMS (EI):

m/z: calcd for C₂₁H₃₈O₂Si: 350.2641, found 350.2643 [M]⁺.

2

³= H), 1.29 (s, = H), 1.31 (s, = H), 1.32 (s, = H), 1.43–1.71 (m, 6H), 1.85–

3

2

1.95 (m, 3H), 1.91 (s, 3H), 2.08–2.13 (m, 1H), 2.24 (s, 3H), 2.30–2.40 (m,

2H), 2.44–2.52 (m, 1H), 2.64–2.69 (m, 1H), 2.73–2.78 (m, 1H), 3.59–3.61

(m, 1H), 3.85 (s, 3H), 4.14–4.56 (m, 1H), 4.48–4.49 ppm (m, 1H);

¹³C NMR (100 MHz, CDCl₃): d=5.4 (3C), 7.2 (3C), 10.0, 17.0, 18.6, 18.9

(¹= C), 19.0 (¹= C), 19.4 (¹= C), 19.7 (¹= C), 22.88 (¹= C), 22.94 (¹= C), 22.98

(Z)-(4aS,5S,6R,8aS)-5-Allyl-5,8a-dimethyl-2-hydroxymethylene-6-(tri-

AHCTUNGERTGeNNUN thylsiloxy)decahydronaphthalen-1-one (49): A solution of 48 (7.71 g,

22 mmol) in dry THF (50 mL) containing ethyl formate (26.7 mL,

0.33 mol) was added to a stirred suspension of NaH (60% dispersion in

mineral oil) (13.2 g, 0.33 mol) in dry THF (300 mL) at 08C under argon,

and stirring was continued for 1 h at room temperature. The reaction was

quenched with saturated aqueous NH₄Cl (50 mL) at 08C, and the result-

ing mixture was extracted with EtOAc (3ꢃ300 mL). The combined ex-

tracts were washed with brine (2ꢃ200 mL), then dried over MgSO₄. Con-

centration of the solvent in vacuo afforded a residue, which was purified

by column chromatography (hexane/EtOAc 30:1) to give 49 (7.66 g,

92%) as a pale yellow viscous liquid. [a]²_D⁰=+4.3 (c=1.02 in CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=0.62 (q, J=7.8 Hz, 6H), 0.82 (s, 3H),

0.96 (t, J=7.8 Hz, 9H), 1.21 (s, 3H), 1.47 (ddd, J=24.4, 13.2, 6.8 Hz,

1H), 1.57–1.63 (m, 2H), 1.71–1.79 (m, 3H), 1.83–1.91 (m, 1H), 2.01 (dd,

J=13.2, 8.3 Hz, 1H), 2.20 (dd, J=13.2, 5.9 Hz, 1H), 2.28–2.36 (m, 1H),

2.41–2.46 (m, 1H), 3.57 (brs, 1H), 4.99–5.05 (m, 2H), 5.86–5.97 (m, 1H),

8.42 (d, J=4.4 Hz, 1H), 14.67 ppm (d, J=4.4 Hz, 1H); ¹³C NMR

(100 MHz, CDCl₃): d=5.3 (3C), 7.1 (3C), 17.7, 19.1, 20.6, 23.0, 25.5, 26.6,

41.0, 41.4, 42.0, 44.0, 73.3, 106.0, 117.2, 136.0, 184.8, 195.1 ppm; IR (neat):

n˜ =3073, 2953, 2876, 1704, 1635, 1584, 1455, 1414, 1383, 1361, 1283, 1079,

2

(¹= C), 23.07 (¹= C), 23.09 (¹= C), 23.11 (¹= C), 24.9 (¹= C), 25.0 (¹= C), 26.1

2

(¹= C), 26.2 (¹= C), 28.48 (¹= C), 28.53 (¹= C), 31.4 (¹= C), 31.5 (¹= C), 35.6

2

(¹= C), 36.5 (¹= C), 37.6, 39.0 (¹= C), 39.3 (¹= C), 39.98 (¹= C), 40.0 (¹= C),

2

55.3, 56.09 (¹= C), 56.13 (¹= C), 58.1 (¹= C), 58.4 (¹= C), 65.3 (¹= C), 65.5

2

(¹= C), 73.6 (¹= C), 74.3 (¹= C), 103.6 (¹= C), 103.7 (¹= C), 109.0, 118.6,

2

149.3 (¹= C), 149.4, (¹= C), 154.8, 162.9 (¹= C), 163.0 (¹= C), 180.4 ppm; IR

2

(KBr): n˜ =2954, 2876, 1672, 1603, 1460, 1415, 1375, 1317, 1254, 1075,

1004, 928, 887, 812, 783, 732, 673 cm^ꢀ1; HRMS (EI): m/z: calcd for

C₃₄H₅₆O₅Si: 572.3897, found 572.3887 [M]⁺.

3-[(3R,4aR,6aR,7R,10aR,10bR)-6a,10b-Dimethyl-3-(1-hydroxy-1-methyl-

ethyl)-(8-methylene)perhydor-1H-benzo[f]chromen-7-yl]methyl-5,6-di-

methyl-2-methoxy-4H-4-one (candelalide C) (3): TBAF in THF (1.0m so-

lution, 0.24 mL, 0.24 mmol) was added dropwise to a stirred solution of

39 (ca. 1:1 diastereomeric mixture) (13.8 mg, 24 mmol) in THF (3 mL) at

08C under argon, and stirring was continued for 1 h at room temperature.

The reaction was quenched with saturated aqueous NH₄Cl (2 mL) at

08C, and the resulting mixture was extracted with EtOAc (3ꢃ40 mL).

The combined extracts were washed with saturated aqueous NaHCO₃

(2ꢃ20 mL) and brine (2ꢃ20 mL), then dried over MgSO₄. Concentration

of the solvent in vacuo afforded a residue, which was purified by column

chromatography (hexane/EtOAc 2:1!1:1) to give 3 (4.8 mg, 43%) as a

1009, 969, 910, 823, 795, 723 cm^ꢀ1

; HRMS (EI): m/z: calcd for

C₂₂H₃₈O₃Si: 378.2590, found 378.2589 [M]⁺.

(Z)-(4aS,5S,6R,8aS)-5-Allyl-2-(ethoxyethan-1-yl)oxymethylene-5,8a-di-

methyl-6-(triethylsiloxy)decahydronaphthalen-1-one (50): PPTS (485 mg,

1.9 mmol) was added to a stirred solution of 49 (7.31 g, 19 mmol) in dry

THF (200 mL) containing ethyl vinyl ether (37.0 mL, 39 mmol) at room

temperature. After 1.5 h, the reaction was quenched with saturated aque-

ous NaHCO₃, 80 mL) at 08C, and the resulting mixture was extracted

with EtOAc (2ꢃ300 mL). The combined extracts were washed with brine

(2ꢃ200 mL), then dried over MgSO₄. Concentration of solvent in vacuo

[1]

colorless amorphous powder. [a]²_D²=ꢀ68.8 (c=0.98 in CH₃OH) {lit.

[a]²_D²=ꢀ67.0 (c=1.03 in CH₃OH)}. The ¹H and ¹³C NMR, IR, and MS

spectra (see below) are identical to those of natural (ꢀ)-candelalide C.

¹H NMR (400 MHz, CDCl₃): d=0.80 (s, 3H), 0.96 (s, 3H), 0.99–1.07 (m,

2H), 1.17 (s, 3H), 1.20 (s, 3H), 1.30–1.36 (m, 2H), 1.49–1.54 (m, 1H),

1.63–1.69 (m, 2H), 1.86 (dd, J=11.7, 2.9 Hz, 1H), 1.90 (s, 3H), 1.92–2.00

(m, 2H), 2.11–2.16 (m, 1H), 2.19 (dd, 1H, J=13.2, 2.9 Hz), 2.24 (s, 3H),

2.34–2.49 (m, 3H), 2.77 (dd, J=13.2, 3.4 Hz, 1H), 3.16 (dd, J=11.7,

2.4 Hz, 1H), 3.24 (t, J=2.9 Hz, 1H), 3.85 (s, 3H), 4.19–4.20 (m, 1H),

4.49–4.51 ppm (m, 1H); ¹³C NMR (100 MHz, CDCl₃): d=10.0, 17.0, 19.8,

22.0, 22.4, 22.9, 23.3, 23.8, 24.6, 25.7, 29.2, 31.3, 33.7, 34.7, 36.1, 37.5, 55.3,

56.7, 72.0, 81.7, 83.9, 103.7, 108.9, 118.6, 149.4, 154.8, 162.9, 180.3 ppm;

IR (KBr): n˜ =3419, 2937, 2857, 1725, 1670, 1591, 1461, 1418, 1376, 1318,

1255, 1149, 1097, 1071, 986, 887, 753 cm^ꢀ1; HRMS (EI): m/z: calcd for

C₂₈H₄₂O₅: 458.3032, found 458.3026 [M]⁺.

afforded

a residue, which was purified by column chromatography

(hexane/EtOAc 10:1) to give 50 (1:1 diastereomeric mixture caused by

the EE group) (8.35 g, 96%) as a pale yellow viscous liquid. ¹H NMR

(400 MHz, CDCl₃): d=0.58–0.64 (m, 6H), 0.84 (s, 3H), 0.95 (t, J=

3

7.8 Hz, 9H), 1.12 (s, 3H), 1.211 (t, J=6.8 Hz, = H), 1.213 (t, J=6.8 Hz,

2

³= H), 1.42–1.44 (m, 3H), 1.53–1.65 (m, 3H), 1.71–1.91 (m, 4H), 2.00–

2

2.06 (m, 1H), 2.21–2.29 (m, 2H), 2.64–2.70 (m, 1H), 3.45–3.53 (m, 1H),

3.55 (s, 1H), 3.68–3.76 (m, 1H), 4.98–5.09 (m, 3H), 5.86–5.97 (m, 1H),

7.43 ppm (brs, 1H); ¹³C NMR (100 MHz, CDCl₃): d=5.3 (3C), 7.1 (3C),

14.9 (¹= C), 15.0 (¹= C), 17.7, 19.48, 19.52 (¹= C), 19.54 (¹= C), 21.1, 22.16

(4aS,5S,6R,8aS)-5-Allyl-5,8a-dimethyl-6-(triethylsiloxy)decahydronaph-

thalen-1-one (48): PPTS (1.11 g, 4.4 mmol) was added to a stirred solu-

tion of 16 (6.16 g, 22 mmol) in acetone (200 mL) containing water

(40 mL) at room temperature. The mixture was heated at reflux for 4 h.

After cooling, the reaction was diluted with saturated aqueous NaHCO₃

(100 mL) at 08C, and the resulting mixture was extracted with EtOAc

(2ꢃ300 mL). The combined extracts were washed with brine (2ꢃ

100 mL), then dried over MgSO₄. Concentration of the solvent in vacuo

afforded crude keto alcohol 47 (5.38 g), which was used for the next reac-

tion without purification.

2

(¹= C), 22.19 (¹= C), 25.5, 26.8, 41.4, 41.60 (¹= C), 41.63 (¹= C), 44.0, 46.3,

2

63.6 (¹= C), 63.7 (¹= C), 73.4, 103.5 (¹= C), 103.7 (¹= C), 117.0, 136.1, 151.4,

2

206.39 (¹= C), 206.41 ppm (¹= C); IR (neat): n˜ =3073, 2953, 2914, 2877,

2

1681, 1600, 1455, 1383, 1344, 1284, 1211, 1001, 821, 725 cm^ꢀ1; HRMS

(EI): m/z: calcd for C₂₆H₄₆O₄Si: 450.3165, found 450.3177 [M]⁺.

(Z)-(4aR,5S,6R,8aS)-5-Allyl-2-(ethoxyethan-1-yl)oxymethylene-5,8a-di-

methyl-6-(triethylsiloxy)decahydronaphthalen-1-ol (51): NaBH₄(2.24 g,

59 mmol) was added in small portions to a stirred solution of 50 (5.33 g,

12 mmol) in THF (120 mL) containing water (12 mL) at 08C, and stirring

was continued for 4 h at room temperature. The reaction was quenched

with saturated aqueous NH₄Cl (60 mL) at 08C, and the resulting mixture

was extracted with EtOAc (3ꢃ200 mL). The combined extracts were

washed with brine (2ꢃ100 mL), then dried over MgSO₄. Concentration

of the solvent in vacuo afforded a residue, which was purified by column

chromatography (hexane/EtOAc 10:1) to give 51 (1:1 diastereomeric

mixture caused by the EE group) (5.25 g, 98%) as a colorless viscous

liquid. ¹H NMR (400 MHz, CDCl₃): d=0.63 (q, J=7.8 Hz, 6H), 0.77 (s,

3H), 0.78 (s, 3H), 0.98 (t, J=7.8 Hz, 9H), 1.16–1.18 (m, 1H), 1.20 (t, J=

TESOTf (10.3 mL, 46 mmol) was added dropwise to a stirred solution of

47 (5.38 g, 23 mmol) in dry CH₂Cl₂(200 mL) containing iPr₂NEt

(19.4 mL, 0.11 mol) at 08C under argon. After 30 min, the reaction was

quenched with saturated aqueous NH₄Cl (50 mL) at 08C, and the result-

ing mixture was extracted with Et₂O (3ꢃ300 mL). The combined extracts

were washed with brine (2ꢃ200 mL), then dried over MgSO₄. Concentra-

tion of the solvent in vacuo afforded a residue, which was purified by

column chromatography (hexane/EtOAc 10:1) to give 48 (7.71 g, 97%, 2

steps) as a colorless viscous liquid; [a]²_D⁰=ꢀ48.5 (c=1.01 in CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=0.59–0.65 (m, 6H), 0.87 (s, 3H), 0.96 (t,

J=8.0 Hz, 9H), 1.15 (s, 3H), 1.29 (dt, J=13.7, 3.4 Hz, 1H), 1.54–1.63 (m,

3H), 1.65–1.71 (m, 2H), 1.76–1.84 (m, 1H), 1.94–2.07 (m, 3H), 2.16–2.23

(m, 2H), 2.56 (td, J=13.7, 7.3 Hz, 1H), 3.54 (t, J=2.9 Hz, 1H), 4.97–5.04

(m, 2H), 5.83–5.93 ppm (m, 1H); ¹³C NMR (100 MHz, CDCl₃): d=5.3

3

6.8 Hz, = H), 1.21 (t, J=6.8 Hz, = H), 1.37 (d, J=5.4 Hz, 3H), 1.41–1.54

2

(m, 5H), 1.60–1.66 (m, 2H), 1.78–1.85 (m, 1H), 1.96 (dd, J=13.2, 8.8 Hz,

1H), 2.19 (dd, J=13.2, 5.9 Hz, 1H), 2.90 (dd, J=13.9, 2.9 Hz, 1H), 3.44–

3.54 (m, 1H), 3.57 (brs, 1H), 3.69–3.78 (m, 2H), 4.87–4.93 (m, 1H), 4.96–

5.02 (m, 2H), 5.84–5.95 (m, 1H), 6.24–6.25 ppm (m, 1H); ¹³C NMR

2840

www.chemeurj.org

ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 2826 – 2845

Immunosuppressive Agents

FULL PAPER

(100 MHz, CDCl₃): d=5.4 (3C), 7.2 (3C), 12.9, 15.1 (¹= C), 15.2 (¹= C),

(100 MHz, CDCl₃): d=5.4 (3C), 7.1 (3C), 9.0 (3C), 13.7 (3C), 18.0, 18.4,

21.9, 26.2, 27.3 (3C), 27.5, 29.2 (3C), 32.7, 35.1, 40.6, 43.8, 43.9, 60.5, 74.1,

79.3, 116.7, 130.8, 136.6, 138.5 ppm; IR (neat): n˜ =3073, 2955, 2921, 2874,

2

19.0, 20.47 (¹= C), 20.55 (¹= C), 20.90 (¹= C), 20.93 (¹= C), 24.2, 25.8, 30.11

2

(¹= C), 30.14 (¹= C), 40.5, 40.57 (¹= C), 40.60 (¹= C), 44.2, 45.0, 62.2 (¹= C),

2

1636, 1463, 1380, 1237, 1128, 1076, 1004, 960, 909, 799, 775, 726 cm^ꢀ1

;

62.4 (¹= C), 73.6, 80.7, 100.8, 116.9, 119.0 (¹= C), 119.1 (¹= C), 133.4 (¹= C),

2

133.7 (¹= C), 136.3 ppm; IR (neat): n˜ =3478, 3073, 2952, 2912, 2876, 1683,

HRMS (EI): m/z: calcd for C₃₅H₆₈O₂SiSn: 668.4011, found 668.3988

[M]⁺.

2

1636, 1455, 1381, 1340, 1239, 1149, 1081, 1008, 933, 910, 806, 726 cm^ꢀ1

;

HRMS (EI): m/z: calcd for C₂₆H₄₈O₄Si: 452.3322, found 452.3333 [M]⁺.

(1R,4aS,5S,6R,8aS)-5-Allyl-5,8a-dimethyl-2-methylene-6-(triethylsiloxy)-

decahydronaphthalene-1-methanol (45) and its (1S,4aR,5S,6R,8aS)-

isomer (54): nBuLi in hexane (1.55m solution, 33.8 mL, 52 mmol) was

added dropwise to a stirred solution 46 (7.00 g, 10 mmol) in dry hexane

(500 mL) at ꢀ508C under argon, and the mixture was gradually warmed

up to 08C over 4 h, and stirring was continued for 5 h at 08C. The reac-

tion was quenched with saturated aqueous NH₄Cl (100 mL) at 08C, and

the resulting mixture was extracted with EtOAc (3ꢃ250 mL). The com-

bined extracts were washed with brine (2ꢃ200 mL), then dried over

MgSO₄. Concentration of the solvent in vacuo afforded a residue, which

was purified by column chromatography (hexane/EtOAc 20:1!10:1) to

give 45 (3.01 g, 76%), 54 (673 mg, 17%), and 53 (198 mg, 5%).

(4aR,5S,6R,8aR)-5-Allyl-5,8a-dimethyl-6-triethylsiloxy-3,4,4a,5,6,7,8,8a-

octahydronaphthalene-2-carbaldehyde (52): MsCl (11.0 mL, 0.14 mol)

was added dropwise to a stirred solution of 51 (6.44 g, 14 mmol) in dry

CH₂Cl₂(140 mL) containing Et₃N (23.8 mL, 0.17 mmol) at 08C under

argon. After 30 min, the reaction was quenched with saturated aqueous

NH₄Cl (60 mL) at 08C, and the resulting mixture was extracted with

CHCl₃(3ꢃ250 mL). The combined extracts were washed with brine (2ꢃ

200 mL), then dried over MgSO₄. Concentration of the solvent in vacuo

afforded

a residue, which was purified by column chromatography

(hexane/EtOAc, 100:1!50:1) to give 52 (4.94 g, 96%) as a colorless vis-

1

cous liquid. [a]²_D⁰=+3.7 (c=1.01 in CHCl₃); H NMR (400 MHz, CDCl₃):

d=0.62 (q, J=7.8 Hz, 6H), 0.82 (s, 3H), 0.96 (t, J=7.1 Hz, 9H), 1.06 (s,

3H), 1.31 (dt, J=12.7, 2.9 Hz, 1H), 1.35–1.42 (m, 1H), 1.61 (q, J=

3.4 Hz, 1H), 1.70 (dd, J=12.7, 2.0 Hz, 1H), 1.74–1.79 (m, 1H), 1.83–1.87

(m, 1H), 1.91–1.96 (m, 1H), 1.98–2.03 (m, 1H), 2.06–2.15 (m, 1H), 2.19

(dd, J=13.4, 6.3 Hz, 1H), 2.38 (dd, J=18.5, 6.3 Hz, 1H), 3.60–3.61 (m,

1H), 5.00–5.05 (m, 2H), 5.85–5.95 (m, 1H), 6.40 (s, 1H), 9.40 ppm (s,

1H); ¹³C NMR (100 MHz, CDCl₃): d=5.3 (3C), 7.1 (3C), 16.9, 18.5, 20.7,

22.9, 25.9, 31.4, 36.5, 40.8, 43.3, 43.8, 73.7, 117.1, 135.9, 137.5, 162.4,

194.9 ppm; IR (neat): n˜ =3354, 3073, 2953, 2913, 2876, 2804, 2711, 1690,

1642, 1456, 1382, 1237, 1185, 1079, 1005, 909, 823, 796, 723 cm^ꢀ1; HRMS

(EI): m/z: calcd for C₂₂H₃₈O₂Si: 362.2641, found 362.2639 [M]⁺.

Compound 45: white crystals (recrystallization from Et₂O); M.p. 102–

1038C; [a]²_D⁰=ꢀ39.0 (c=1.03 in CHCl₃); ¹H NMR (400 MHz, CDCl₃):

d=0.62 (q, J=7.8 Hz, 6H), 0.76 (s, 3H), 0.90 (dt, J=12.2, 2.9 Hz, 1H),

0.96–1.00 (m, 12H), 1.25–1.39 (m, 2H), 1.51 (dq, J=13.9, 3.4 Hz, 1H),

1.58–1.61 (m, 1H), 1.77 (dd, J=13.2, 2.9 Hz, 1H), 1.84–1.92 (m, 2H),

1.95–2.04 (m, 2H), 2.10–2.20 (m, 2H), 2.27–2.29 (m, 1H), 3.56 (d, J=

2.0 Hz, 1H), 3.66 (dd, J=10.7, 10.2 Hz, 1H), 3.79–3.85 (m, 1H), 4.74 (t,

J=2.0 Hz, 1H), 4.92 (t, J=2.0 Hz, 1H), 4.95–5.02 (m, 2H), 5.84–

5.94 ppm (m, 1H); ¹³C NMR (100 MHz, CDCl₃): d=5.4 (3C), 7.1 (3C),

19.2, 22.4, 23.1, 25.8, 29.0, 31.4, 37.4, 39.9, 40.8, 44.4, 59.0, 60.7, 74.0,

112.7, 116.9, 136.2, 147.2 ppm; IR (KBr): n˜ =3323, 3067, 2962, 2913, 2879,

1653, 1459, 1382, 1234, 1084, 1003, 911, 815, 737 cm^ꢀ1; HRMS (EI): m/z:

calcd for C₂₃H₄₂O₂Si: 378.2954, found 378.2964 [M]⁺.

(4aR,5S,6R,8aR)-5-Allyl-5,8a-dimethyl-6-triethylsiloxy-3,4,4a,5,6,7,8,8a-

octahydronaphthalene-2-methanol (53): NaBH₄(773 mg, 20 mmol) was

added in small portions to a stirred solution of 52 (4.94 g, 14 mmol) in

THF (140 mL) containing water (14 mL) at 08C, and stirring was contin-

ued for 30 min at room temperature. The reaction was quenched with sa-

turated aqueous NH₄Cl (80 mL) at 08C, and the resulting mixture was

extracted with EtOAc (3ꢃ200 mL). The combined extracts were washed

with brine (2ꢃ80 mL), then dried over MgSO₄. Concentration of the sol-

vent in vacuo afforded a residue, which was purified by column chroma-

tography (hexane/EtOAc 10:1!8:1) to give 53 (4.85 g, 98%) as a color-

less viscous liquid. [a]²_D⁰=ꢀ15.9 (c=1.01 in CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=0.59–0.65 (m, 6H), 0.78 (s, 3H), 0.94–0.98 (m, 12H), 1.15 (dt,

J=12.2, 3.4 Hz, 1H), 1.36–1.45 (m, 2H), 1.52 (dq, J=14.1, 3.4 Hz, 1H),

1.64–1.73 (m, 3H), 1.83–1.92 (m, 1H), 1.96–2.09 (m, 3H), 2.19 (dd, J=

13.2, 5.9 Hz, 1H), 3.57–3.58 (m, 1H), 3.95 (s, 2H), 4.97–5.03 (m, 2H),

5.34 (s, 1H), 5.87–5.97 ppm (m, 1H); ¹³C NMR (100 MHz, CDCl₃): d=

5.4 (3C), 7.1 (3C), 17.9, 18.5, 21.8, 26.2, 27.3, 32.6, 34.9, 40.6, 43.8, 43.9,

67.2, 74.1, 116.8, 133.4, 136.6, 136.7 ppm; IR (neat): n˜ =3303, 3072, 2953,

2876, 1823, 1636, 1457, 1382, 1238, 1184, 1078, 1004, 909, 859, 796,

Compound 54: white crystals (recrystallization from Et₂O); M.p. 96–

978C; [a]²_D⁰=ꢀ41.6 (c=1.00 in CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=

0.60–0.67 (m, 6H), 0.74 (s, 3H), 0.75 (s, 3H), 0.99 (t, J=7.8 Hz, 9H),

1.29–1.33 (m, 2H), 1.41 (dd, J=8.8, 2.9 Hz, 1H), 1.53–1.56 (m, 1H),

1.65–1.69 (m, 2H), 1.77–1.81 (m, 1H), 1.94 (dd, J=13.7, 8.3 Hz, 1H),

2.00–2.07 (m, 2H), 2.17 (dd, J=13.2, 5.9 Hz, 1H), 2.41 (dq, J=12.7,

2.0 Hz, 1H), 3.74–3.88 (m, 2H), 4.64 (s, 1H), 4.93–5.03 (m, 3H), 5.85–

5.96 ppm (m, 1H); ¹³C NMR (100 MHz, CDCl₃): d=5.4 (3C), 7.1 (3C),

15.8, 18.9, 23.4, 26.1, 31.5, 37.6, 38.8, 40.9, 44.4, 47.7, 58.7, 59.0, 73.5,

106.2, 116.9, 136.3, 147.8 ppm; IR (KBr): n˜ =3323, 3254, 3078, 2953, 2876,

1638, 1459, 1438, 1383, 1238, 1088, 1005, 909, 884, 737 cm^ꢀ1; HRMS (EI):

m/z: calcd for C₂₃H₄₂O₂Si: 378.2954, found 378.2964 [M]⁺.

(1R,4aR,5S,6R,8aS)-5-Allyl-5,8a-dimethyl-2-methylene-6-(triethylsiloxy)-

decahydronaphthalene-1-carbaldehyde (44): Dess–Martin periodinane

(1.74 g, 4.1 mmol) was added in small portions to a stirred solution of 45

(1.04 g, 2.7 mmol) containing NaHCO₃(2.30 g, 27 mmol) in dry CH₂Cl₂

(280 mL) at room temperature. After 1 h, the reaction was quenched

with 10% aqueous Na₂S₂O₃(50 mL) at 08C, and the resulting mixture

was extracted with CHCl₃(3ꢃ100 mL). The combined extracts were

washed with saturated aqueous NaHCO₃(50 mL) and brine (50 mL),

then dried over MgSO₄. Concentration of the solvent in vacuo afforded a

residue, which was purified by column chromatography (hexane/EtOAc

50:1) to give 44 (941 mg, 91%) as a colorless viscous liquid. [a]²_D⁰=ꢀ29.1

(c=1.01 in CHCl₃); ¹H NMR (400 MHz, CDCl₃): d=0.61 (q, J=7.7 Hz,

6H), 0.79 (s, 3H), 0.94–0.99 (m, 12H), 1.10 (dt, J=13.0, 3.4 Hz, 1H), 1.42

(dq, J=13.0, 4.8 Hz, 1H), 1.51–1.55 (m, 1H), 1.70–1.75 (m, 1H), 1.84–

1.93 (m, 1H), 1.97–2.08 (m, 2H), 2.12 (dd, J=12.6, 2.9 Hz, 1H), 2.23 (dd,

J=13.5, 6.3 Hz, 1H), 2.26–2.34 (m, 1H), 2.41–2.46 (m, 1H), 2.50 (d, J=

3.9 Hz, 1H), 3.59–3.60 (m, 1H), 4.74 (t, J=1.9 Hz, 1H), 4.89 (t, J=

1.9 Hz, 1H), 4.98–5.05 (m, 2H), 5.85–5.95 (m, 1H), 10.0 ppm (d, J=

3.9 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): d=5.3 (3C), 7.1 (3C), 19.0,

22.0, 22.2, 25.7, 30.0, 33.5, 38.8, 40.9, 41.5, 44.2, 71.3, 73.7, 113.2, 117.2,

135.9, 143.0, 203.3 ppm; IR (neat): n˜ =3073, 2952, 2877, 2725, 1717, 1645,

1457, 1385, 1239, 1082, 1004, 967, 909, 811, 725 cm^ꢀ1; HRMS (EI): m/z:

calcd for C₂₃H₄₀O₂Si: 376.2798, found 376.2789 [M]⁺.

724 cm^ꢀ1

; HRMS (EI): m/z: calcd for C₂₂H₄₀O₂Si: 364.2798, found

364.2806 [M]⁺.

(4aR,5S,6R,8aR)-5-Allyl-5,8a-dimethyl-2-(tri-n-butylstannylmethoxy-

methyl)-6-triethylsiloxy-3,4,4a,5,6,7,8,8a-octahydronaphthalene (46): KH

(30% dispersion in mineral oil) (5.34 g, 13 mmol), [18]crown-6 (10.6 g,

40 mmol), and iodomethyl tri-n-butyltin (8.0 mL, 26 mmol) were added

successively to a stirred solution of 53 (4.85 g, 13 mmol) in dry THF

(260 mL) at 08C under argon, and stirring was continued for 3 h at room

temperature. The reaction was quenched with saturated aqueous NH₄Cl

(80 mL) at 08C, and resulting mixture was extracted with EtOAc (3ꢃ

150 mL). The combined extracts were washed with brine (2ꢃ100 mL),

then dried over MgSO₄. Concentration of the solvent in vacuo afforded a

residue, which was purified by column chromatography [hexane/EtOAc

100:1 (containing 0.2% Et₃N)] to give 46 (7.39 g, 83%) as a colorless vis-

1

cous liquid. [a]²_D⁰=ꢀ8.5 (c=1.01 in CHCl₃); H NMR (400 MHz, CDCl₃):

d=0.58–0.62 (m, 6H), 0.77 (s, 3H), 0.87–0.92 (m, 16H), 0.94–0.98 (m,

12H), 1.12–1.17 (m, 1H), 1.26–1.35 (m, 6H), 1.36–1.45 (m, 1H), 1.47–

1.55 (m, 6H), 1.63–1.74 (m, 3H), 1.83–1.86 (m, 1H), 1.87–2.08 (m, 3H),

2.19 (dd, J=13.2, 5.9 Hz, 1H), 3.56–3.58 (m, 1H), 3.63–3.69 (m, 4H),

4.97–5.02 (m, 2H), 5.31 (brs, 1H), 5.86–5.97 ppm (m, 1H); ¹³C NMR

3-[(1R,4aR,5S,6R,8aS)-5-Allyl-5,8a-dimethyl-2-methylene-6-(triethylsil-

AHCTUNGTERGoNNUN xy)decahydronaphthalen-1-yl]hydroxymethyl-5,6-dimethyl-2-methoxy-

Chem. Eur. J. 2009, 15, 2826 – 2845

ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

2841

T. Katoh et al.

4H-pyran-4-one (55): nBuLi in hexane (1.55m solution, 3.48 mL,

5.4 mmol) was added dropwise to stirred solution of 10 (1.26 g,

(3ꢃ30 mL), then dried over MgSO₄. Concentration of the solvent in

vacuo afforded a residue, which was purified by column chromatography

(hexane/EtOAc 5:1) to give 42 (226 mg, 85%) as a white amorphous

powder. [a]²_D⁰=ꢀ72.7 (c=1.07 in CHCl₃); ¹H NMR (400 MHz, CDCl₃):

d=0.63 (q, J=7.8 Hz, 6H), 0.94–0.99 (m, 15H), 1.06 (dt, J=13.2, 3.4 Hz,

1H), 1.40 (qd, J=12.9, 4.9 Hz, 1H), 1.48–1.52 (m, 1H), 1.62–1.66 (m,

1H), 1.91 (s, 3H), 1.93–1.99 (m, 2H), 2.10–2.21 (m, 3H), 2.24 (s, 3H),

2.33–2.46 (m, 4H), 2.77 (dd, J=12.7, 3.4 Hz, 1H), 3.77 (brs, 1H), 3.85 (s,

3H), 4.17 (t, J=2.4 Hz, 1H), 4.51 (t, J=2.4 Hz, 1H), 9.94–9.95 ppm (m,

1H); ¹³C NMR (100 MHz, CDCl₃): d=5.1 (3C), 7.0 (3C), 9.9, 16.9, 19.7,

21.3, 22.8, 23.0, 25.8, 28.3, 31.1, 37.5, 37.8, 42.8, 53.7, 55.3, 55.8, 75.8,

103.3, 109.5, 118.5, 148.7, 154.8, 162.9, 180.3, 204.0 ppm; IR (KBr): n˜ =

2952, 2876, 1714, 1671, 1602, 1462, 1415, 1375, 1317, 1254, 1163, 1146,

1085, 1004, 886, 812, 742 cm^ꢀ1; HRMS (EI): m/z: calcd for C₃₀H₄₈O₅Si:

516.3271, found 516.3254 [M]⁺.

a

5.4 mmol) in dry THF (120 mL) at ꢀ788C under argon. After 20 min, a

solution of 44 (507 mg, 1.4 mmol) in dry THF (20 mL) was added to the

above mixture at ꢀ788C, and stirring was continued for 1 h at ꢀ408C.

The reaction was quenched with saturated aqueous NH₄Cl (50 mL) at

ꢀ408C, and the resulting mixture was extracted with EtOAc (3ꢃ

100 mL). The combined extracts were washed brine (2ꢃ50 mL), then

dried over MgSO₄. Concentration of the solvent in vacuo afforded a resi-

due, which was purified by column chromatography (hexane/EtOAc 4:1)

to give 55 (ca. 8:1 diastereomeric mixture) (615 mg, 86%) as a white

solid. Recrystallization from hexane/Et₂O 10:1 afforded single major

isomer of 55 as colorless needles. M.p. 167–1688C; ¹H NMR (400 MHz,

CDCl₃): d=0.62–0.68 (m, 6H), 0.76 (s, 3H), 0.85 (dt, J=12.2, 3.4 Hz,

1H), 0.90 (s, 3H), 0.97–1.02 (m, 9H), 1.30 (qd, J=12.9, 4.9 Hz, 1H), 1.53

(dq, J=14.1, 3.4 Hz, 1H), 1.63–1.67 (m, 1H), 1.84–1.92 (m, 2H), 1.87 (s,

3H), 2.00 (dd, J=13.2, 8.3 Hz, 1H), 2.23–2.28 (m, 1H), 2.26 (s, 3H),

2.33–2.40 (m, 2H), 2.48–2.58 (m, 2H), 3.56 (brs, 1H), 3.95 (s, 3H), 4.32

(t, J=2.4 Hz, 1H), 4.72 (t, J=2.4 Hz, 1H), 4.94–5.01 (m, 2H), 5.21 (brs,

1H), 5.91–6.04 ppm (m, 1H); ¹³C NMR (100 MHz, CDCl₃): d=5.4 (3C),

7.1 (3C), 9.7, 16.9, 19.6, 22.9, 23.0, 26.4, 28.9, 34.9, 38.5, 39.8, 41.0, 44.6,

55.7, 61.8, 67.8, 74.5, 105.6, 111.6, 116.3, 119.4, 137.1, 148.6, 155.3, 161.0,

181.6 ppm; IR (KBr): n˜ =3448, 3244, 2939, 2876, 1663, 1597, 1573, 1458,

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

methylpent-3-enyl]-6-(triethylsiloxy)decahydronaphthalen-1-yl]methyl-2-

methoxy-5,6-dimethyl-4H-pyran-4-one (57) and its 5-[(S)]-isomer (58): 2-

Methyl-1-propenyl magnesium bromide in THF (0.5m solution, 2.40 mL,

1.2 mmol) was added dropwise to a stirred solution of 42 (209 mg,

0.40 mmol) in dry THF (20 mL) at room temperature under argon. After

1 h, the reaction mixture was quenched with saturated aqueous NH₄Cl

(10 mL) at 08C, and the resulting mixture was extracted with EtOAc (3ꢃ

60 mL). The combined extracts were washed with brine (2ꢃ30 mL), then

dried over MgSO₄. Concentration of the solvent in vacuo afforded a resi-

due, which was purified by column chromatography (hexane/EtOAc 4:1)

to give 57 (97.3 mg, 42%) and 58 (92.7 mg, 40%).

1421, 1376, 1321, 1241, 1153, 1077, 1007, 913, 883, 802, 780, 739, 474 cm^ꢀ1

;

HRMS (EI): m/z: calcd for C₃₁H₅₀O₅Si: 530.3428, found 530.3416 [M]⁺.

3-[(1R,4aR,5S,6R,8aR)-5-Allyl-5,8a-dimethyl-2-methylene-6-(triethylsil-

ACHTUNGTRENNUNG

Compound 57: white amorphous powder. [a]²_D⁰=ꢀ43.6 (c=1.01 in

ACHTUNGTRENNUNG

1

dropwise to a stirred solution of 55 (431 mg, 0.81 mmol) in dry THF

(30 mL) containing CS₂(0.24 mL, 4.1 mmol) at ꢀ788C under argon.

After 1 h, MeI (0.51 mL, 8.1 mmol) was added dropwise to the mixture

at ꢀ788C, and the resulting solution was further stirred for 1 h at the

same temperature. The reaction was quenched with saturated aqueous

NH₄Cl (10 mL), and the resulting mixture was extracted with EtOAc (3ꢃ

50 mL). The combined extracts were washed with brine (2ꢃ30 mL), then

dried over MgSO₄. Concentration of the solvent in vacuo afforded crude

methyl xanthate 56 (350 mg), which was used for the next reaction with-

out purification.

CHCl₃); H NMR (400 MHz, CDCl₃): d=0.70 (q, J=7.8 Hz, 6H), 0.87 (s,

3H), 0.95 (s, 3H), 1.01 (t, J=7.8 Hz, 9H), 1.30 (qd, J=13.2, 4.4 Hz, 1H),

1.51–1.63 (m, 2H), 1.66–1.74 (m, 1H), 1.69 (s, 3H), 1.71 (s, 3H), 1.79–

1.84 (m, 2H), 1.87–1.94 (m, 2H), 1.90 (s, 3H), 2.07–2.12 (m, 1H), 2.20–

2.24 (m, 4H), 2.27–2.43 (m, 2H), 2.47 (t, J=12.7 Hz, 1H), 2.74 (dd, J=

12.7, 3.4 Hz, 1H), 3.85 (s, 3H), 3.89–3.90 (m, 1H), 4.15 (s, 1H), 4.47–4.53

(m, 2H), 5.22 ppm (td, J=8.8, 1.5 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃):

d=5.4 (3C), 7.1 (3C), 9.9, 16.9, 18.1, 19.1, 19.8, 23.1, 23.4, 25.7, 25.9, 28.7,

31.4, 37.8, 40.0, 40.7, 46.6, 55.3, 56.1, 65.0, 75.0, 103.5, 109.0, 118.5, 130.4,

132.5, 149.1, 154.8, 162.9, 180.3 ppm; IR (KBr): n˜ =3434, 2952, 2876,

1671, 1593, 1463, 1417, 1376, 1318, 1255, 1086, 1005, 886, 813, 751 cm^ꢀ1

;

nBu₃SnH (0.46 mL, 1.7 mmol) and 2,2’-azobisisobutyronitrile (AIBN)

(18.6 mg, 0.11 mmol) were added successively to a stirred solution of 56

(351 mg, 0.57 mmol) in dry toluene (15 mL) at room temperature. For

the deaeration of the reaction mixture, it was frozen using liquid nitro-

gen, and the reaction vessel was evacuated in vacuo for 30 min followed

by filled with dry argon. The mixture was heated at reflux for 1 h under

argon. After cooling, the reaction mixture was concentrated in vacuo to

afford a residue, which was purified by column chromatography (ben-

zene/EtOAc 30:1!20:1) to give 43 (284 mg, 68%, 2 steps) as a pale

yellow amorphous powder. [a]²_D⁰=ꢀ63.3 (c=1.03 in CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=0.60–0.67 (m, 6H), 0.76 (s, 3H), 0.94 (s, 3H), 0.98

(t, J=7.8 Hz, 9H), 1.24–1.41 (m, 2H), 1.53–1.65 (m, 2H), 1.85–1.96 (m,

3H), 1.91 (s, 3H), 1.98–2.01 (m, 1H), 2.07–2.11 (m, 1H), 2.21–2.28 (m,

1H), 2.24 (s, 3H), 2.32–2.44 (m, 2H), 2.49 (t, J=12.7 Hz, 1H), 2.76 (dd,

J=12.7, 3.4 Hz, 1H), 3.58 (d, J=2.0 Hz, 1H), 3.85 (s, 3H), 4.14 (t, J=

2.4 Hz, 1H), 4.48 (t, J=2.4 Hz, 1H), 4.96–5.03 (m, 2H), 5.88–5.98 ppm

(m, 1H); ¹³C NMR (100 MHz, CDCl₃): d=5.4 (3C), 7.2, (3C), 10.0, 16.9,

19.1, 19.7, 22.8, 22.9, 26.1, 28.6, 31.4, 37.8, 38.8, 40.8, 44.3, 55.3, 56.1, 74.3,

103.7, 108.9, 116.5, 118.5, 136.7, 149.4, 154.7, 162.9, 180.4 ppm; IR (KBr):

n˜ =3069, 2952, 2876, 1672, 1604, 1461, 1415, 1375, 1316, 1254, 1148, 1079,

1004, 885, 813, 782, 741 cm^ꢀ1; HRMS (EI): m/z: calcd for C₃₁H₅₀O₄Si:

514.3478, found 514.3465 [M]⁺.

HRMS (EI): m/z: calcd for C₃₄H₅₆O₅Si: 572.3897, found 572.3889 [M]⁺.

Compound 58: white amorphous powder. [a]²_D⁰=ꢀ29.6 (c=1.00 in

1

CHCl₃), H NMR (400 MHz, CDCl₃): d=0.67–0.73 (m, 6H), 0.87 (s, 3H),

0.96–1.01 (m, 12H), 1.08 (dt, J=13.2, 3.4 Hz, 1H), 1.41–1.51 (m, 2H),

1.54–1.57 (m, 1H), 1.707 (s, 3H), 1.711 (s, 3H), 1.91 (s, 3H), 1.96–1.99

(m, 2H), 2.13–2.16 (m, 2H), 2.24 (s, 3H), 2.27–2.36 (m, 1H), 2.42–2.50

(m, 2H), 2.80 (dd, J=12.9, 3.4 Hz, 1H), 3.60 (brs, 1H), 3.83 (s, 3H), 4.17

(s, 1H), 4.26 (brs, 1H), 4.49–4.55 (m, 2H), 5.20 ppm (d, J=8.3 Hz, 1H);

¹³C NMR (100 MHz, CDCl₃): d=4.9 (3C), 7.0 (3C), 9.9, 16.9, 18.1, 19.9,

23.2, 24.1, 24.4, 25.8, 26.5, 28.7, 31.3, 36.4, 37.6, 41.6, 48.9, 55.3, 55.8, 64.4,

77.4, 103.6, 109.6, 118.6, 130.2, 132.2, 149.2, 154.8, 163.1, 180.4 ppm; IR

(neat): n˜ =3329, 2952, 2876, 1669, 1586, 1463, 1422, 1376, 1320, 1257,

1147, 1080, 1005, 986, 885, 783, 753 cm^ꢀ1; HRMS (EI): m/z: calcd for

C₃₄H₅₆O₅Si: 572.3897, found 572. 572.3897 [M]⁺.

3-[(1R,4aR,5S,6R,8aR)-5-[(R)-2[(S)-3,3-Dimethyloxiran-2-yl]-2-hydroxy-

AHCTUNGTERGeNNUN thyl]-5,8a-dimethyl-2-methylene-6-(triethylsiloxy)decanaphthlen-1-yl]-

methyl-5,6-dimethyl-2-methoxy-4H-pyran-4-one (59): tert-Butylhydroper-

oxide (TBHP) in decane (5.0–6.0m solution, 33.0 mL, 0.18 mmol) was

added dropwise to a stirred solution of 57 (69.1 mg, 0.12 mmol) in ben-

zene (7 mL) containing vanadyl acetylacetonate [VOACTHNUGTRENUNG(acac)₂] (6.40 mg,

24 mmol) at 08C, and stirring was continued for 1 h at room temperature.

The reaction was quenched with 10% aqueous Na₂S₂O₃(5 mL), and the

resulting mixture was extracted with EtOAc (3ꢃ40 mL). The combined

extracts were washed with brine (3ꢃ20 mL), then dried over MgSO₄.

Concentration of the solvent in vacuo afforded a residue, which was puri-

fied by column chromatography (hexane/EtOAc 3:1) to give 59 (59.6 mg,

84%) as a white amorphous powder. [a]²_D⁰=ꢀ35.9 (c=1.02 in CHCl₃);

¹H NMR (400 MHz, CDCl₃): d=0.68 (q, J=7.8 Hz, 6H), 0.87 (s, 3H),

0.97–1.01 (m, 12H), 1.26–1.39 (m, 1H), 1.32 (s, 3H), 1.33 (s, 3H), 1.47–

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

(triethylsiloxy)decahydronaphthalen-1-yl]methyl-5,6-dimethyl-2-methoxy-

4H-pyran-4-one (42): 4% Aqueous OsO₄(0.32 mL, 50 mmol) and NaIO₄

(438.4 mg, 2.1 mmol) was added slowly to

a stirred solution of 43

(264 mg, 0.51 mmol) in dioxane/water 3:1 (8 mL) containing 2,6-lutidine

(0.12 mL, 1.0 mmol) at room temperature. After 1 h, the reaction mixture

was diluted with water (10 mL), and the resulting mixture was extracted

with EtOAc (3ꢃ50 mL). The combined extracts were washed with brine

2842

www.chemeurj.org

ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2009, 15, 2826 – 2845

Immunosuppressive Agents

FULL PAPER

1

1.57 (m, 2H), 1.61–1.66 (m, 1H), 1.84–1.98 (m, 4H), 1.91 (s, 3H), 2.12

(dd, J=13.7, 3.4 Hz, 1H), 2.24 (s, 3H), 2.32 (dd, J=12.9, 3.4 Hz, 1H),

2.36–2.43 (m, 1H), 2.47–2.55 (m, 2H), 2.70–2.74 (m, 2H), 3.58–3.63 (m,

1H), 3.86 (s, 3H), 3.88–3.89 (m, 1H), 4.16 (s, 1H), 4.49 ppm (t, J=

2.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): d=5.3 (3C), 7.1 (3C), 10.0,

16.9, 18.9, 19.5, 19.7, 23.2, 23.4, 24.8, 25.9, 28.5, 31.4, 37.8, 39.6, 40.6, 42.0,

55.3, 56.2, 59.4, 67.5, 69.1, 74.9, 103.5, 109.1, 118.5, 149.0, 154.8, 162.8,

180.3 ppm; IR (KBr): n˜ =3435, 2952, 2875, 1671, 1595, 1462, 1417, 1376,

1317, 1254, 1096, 1079, 1006, 888, 815, 751 cm^ꢀ1; HRMS (EI): m/z: calcd

for C₃₄H₅₆O₆Si: 588.3846, found 588.3829 [M]⁺.

CHCl₃); H NMR (400 MHz, CDCl₃): d=0.84 (s, 3H), 0.91 (s, 3H), 0.94–

1.03 (m, 2H), 1.29–1.38 (m, 1H), 1.32 (s, 3H), 1.33 (s, 3H), 1.62–1.71 (m,

2H), 1.85–1.93 (m, 2H), 1.90 (s, 3H), 2.05 (dd, J=12.7, 2.9 Hz, 1H), 2.15

(dd, J=14.4, 4.4 Hz, 1H), 2.22–2.29 (m, 1H), 2.24 (s, 3H), 2.30 (dd, J=

13.7, 3.4 Hz, 1H), 2.35–2.42 (m, 2H), 2.73 (dd, J=12.7, 2.9 Hz, 1H), 2.96

(d, J=3.0 Hz, 1H), 3.23 (s, 1H), 3.85 (s, 3H), 4.00 (ddd, J=11.2, 9.3,

4.4 Hz, 1H), 4.17 (s, 1H), 4.50 ppm (s, 1H); ¹³C NMR (100 MHz,

CDCl₃): d=10.0, 16.9, 19.6, 22.58, 22.62, 23.1, 24.0, 24.1, 28.3, 29.1, 31.2,

35.6, 37.5, 38.1, 45.0, 55.3, 56.3, 64.7, 74.1, 81.5, 85.8, 103.5, 109.1, 118.5,

149.0, 154.9, 163.0, 180.4 ppm; IR (neat): n˜ =3346, 2970, 2933, 2860, 1668,

1584, 1463, 1422, 1376, 1321, 1257, 1164, 1097, 1051, 984, 888, 754 cm^ꢀ1

;

3-[(1R,4aR,5S,6R,8aR)-5-[(S)-2[(R)-3,3-Dimethyloxiran-2-yl]-2-hydroxy-

ACHTUNGTRENNUNGethyl]-5,8a-dimethyl-2-methylene-6-(triethylsiloxy)decanaphthlen-1-yl]-

HRMS (EI): m/z: calcd for C₂₈H₄₂O₆: 474.2981, found 474. 2998 [M]⁺.

methyl-5,6-dimethyl-2-methoxy-4H-pyran-4-one (60): tert-Butylhydroper-

oxide (TBHP) in decane (5.0–6.0m solution, 30.0 mL, 0.17 mmol) was

added dropwise to a stirred solution of 58 (62.5 mg, 0.11 mmol) in ben-

(3S,4aR,6aR,7R,10aR,1bR)-6a,1b-Dimethyl-3-(1-hydroxy-1-methylethyl)-

7-[(4-oxo-5,6-dimethyl-2-methoxy-4H-pyran-3-yl)methyl]-(8-methylene)-

perhydro-1H-benzo[f]chromen-2(3H)-one (62): Tetra-n-propylammoni-

um perruthenate (TPAP) (1.34 mg, 3.7 mmol) was added to a stirred solu-

tion of 61 (17.6 mg, 37 mmol) in CH₂Cl₂(3 mL) containing N-methylmor-

pholine N-oxide (6.72 mg, 56 mmol) and 4 ꢂ molecular sieves (20 mg,

zene (5 mL) containing [VOACTHNUTRGNEUNG(acac)₂] (5.80 mg, 21 mmol) at 08C, and stir-

ring was continued for 1 h at room temperature. The reaction was

quenched with 10% aqueous Na₂S₂O₃(5 mL), and the resulting mixture

was extracted with EtOAc (3ꢃ40 mL). The combined extracts were

washed with brine (3ꢃ30 mL), then dried over MgSO₄. Concentration of

the solvent in vacuo afforded a residue, which was purified by column

chromatography (hexane/EtOAc 3:1) to give 60 (51.4 mg, 80%) as a

white amorphous powder. [a]²_D⁰=ꢀ26.2 (c=0.81 in CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=0.69–0.77 (m, 6H), 0.93 (s, 3H), 0.97–1.02 (m,

12H), 1.11 (dt, J=13.5, 3.4 Hz, 1H), 1.33 (s, 3H), 1.34 (s, 3H), 1.45 (dd,

J=12.6, 3.9 Hz, 1H), 1.52 (dd, J=14.9, 2.0 Hz, 1H), 1.63–1.70 (m, 2H),

1.81–2.01 (m, 3H), 1.90 (s, 3H), 2.08–2.12 (m, 2H), 2.24 (s, 3H), 2.28–

2.32 (m, 1H), 2.36–2.46 (m, 2H), 2.67 (d, J=7.2 Hz, 1H), 2.78 (dd, J=

12.6, 3.0 Hz, 1H), 3.55–3.63 (m, 2H), 3.83 (s, 3H), 4.16 (s, 1H), 4.51 (s,

1H), 4.88 ppm (s, 1H); ¹³C NMR (100 MHz, CDCl₃): d=4.9 (3C), 7.0

(3C), 9.9, 16.9, 19.4, 19.7, 23.1, 24.37, 24.4, 24.9, 26.5, 28.7, 31.1, 36.5,

37.5, 41.5, 45.3, 55.2, 55.8, 58.1, 66.4, 68.9, 77.4, 103.3, 109.6, 118.5, 148.9,

154.9, 163.2, 180.4 ppm; IR (KBr): n˜ =3376, 2954, 2877, 1671, 1595, 1460,

1417, 1376, 1318, 1255, 1146, 1082, 1005, 887, 783, 747 cm^ꢀ1; HRMS (EI):

m/z: calcd for C₃₄H₅₆O₆Si: 588.3846, found 588.3829 [M]⁺.

0.5 gmmol^ꢀ1

) at room temperature. After 30 min, the reaction was

quenched with 10% aqueous Na₂S₂O₃(3 mL), and the resulting mixture

was extracted with EtOAc (3ꢃ20 mL). The combined extracts were

washed with brine (3ꢃ20 mL), then dried over MgSO₄. Concentration of

the solvent in vacuo afforded a residue, which was purified column chro-

matography (hexane/EtOAc 2:1) to give 62 (14.4 mg, 82%) as a colorless

viscous liquid. [a]²_D⁰=ꢀ71.2 (c=0.96 in CHCl₃); ¹H NMR (400 MHz,

CDCl₃): d=0.94 (s, 3H), 0.95 (s, 3H), 1.12 (dt, J=13.2, 3.4 Hz, 1H), 1.26

(s, 3H), 1.32 (s, 3H), 1.35–1.42 (m, 1H), 1.52–1.57 (m, 1H), 1.84–1.93 (m,

3H), 1.90 (s, 3H), 1.94 ꢀ2.02 (m, 1H), 2.05 (d, J=15.1 Hz, 1H), 2.15 (dd,

J=13.7, 2.9 Hz, 1H), 2.24 (s, 3H), 2.30 (dd, J=12.7, 11.7 Hz, 1H), 2.34–

2.46 (m, 2H), 2.66 (d, J=15.1 Hz, 1H), 2.77 (dd, J=12.7, 2.9 Hz, 1H),

3.47 (brs, 1H), 3.60–3.61 (m, 1H), 3.66 (s, 1H), 3.83 (s, 3H), 4.20 (t, J=

2.0 Hz, 1H), 4.52 ppm (t, J=2.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃):

d=9.9, 16.9, 19.8, 22.4, 22.5, 22.7, 23.8, 24.9, 26.1, 28.9, 30.9, 37.7, 38.8,

42.5, 53.2, 55.3, 56.0, 71.8, 80.8, 86.7, 103.2, 109.5, 118.6, 148.4, 154.9,

163.0, 180.3, 211.5 ppm; IR (neat): n˜ =3442, 2972, 2934, 2877, 1715, 1670,

1593, 1462, 1418, 1376, 1318, 1255, 1167, 1093, 986, 889, 753 cm^ꢀ1; HRMS

(EI): m/z: calcd for C₂₈H₄₀O₆: 472.2825, found 472.2824 [M]⁺.

3-[(1R,4aR,5S,6R,8aR)-5-[(R)-2[(S)-3,3-Dimethyloxiran-2-yl]-2-hydroxy-

ACHTUNGTRENNUNGethyl]-5,8a-dimethyl-2-methylene-(6-hydroxy)decanaphthlen-1-yl]methyl-

5,6-dimethyl-2-methoxy-4H-pyran-4-one (41): TBAF in THF (1.0m solu-

tion, 0.18 mL, 0.18 mmol) was added dropwise to a stirred solution of 59

(52.5 mg, 89 mmol) in THF (5 mL) at 08C under argon, and stirring was

continued for 1.5 h at room temperature. The reaction was quenched

with saturated aqueous NH₄Cl (3 mL) at 08C, and the resulting mixture

was extracted with EtOAc (3ꢃ30 mL). The combined extracts were

washed with brine (2ꢃ20 mL), then dried over MgSO₄. Concentration of

the solvent in vacuo afforded a residue, which was purified by column

chromatography (hexane/EtOAc 1:4) to give 41 (42.3 mg, 100%) as a

white amorphous powder. [a]²_D⁰=ꢀ27.2 (c=1.05 in CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=0.84 (s, 3H), 0.97 (s, 3H), 1.04 (dt, J=13.2,

3.4 Hz, 1H), 1.26–1.39 (m, 2H), 1.31 (s, 3H), 1.34 (s, 3H), 1.49–1.55 (m,

1H), 1.71–1.83 (m, 2H), 1.90 (s, 3H), 1.94–2.01 (m, 3H), 2.13 (dd, J=

14.1, 3.4 Hz, 1H), 2.24 (s, 3H), 2.35 (dd, J=13.7, 3.4 Hz, 1H), 2.40–2.49

(m, 1H), 2.56 (dd, J=12.7, 11.7 Hz, 1H), 2.76–2.80 (m, 2H), 3.67 (t, J=

8.8 Hz, 1H), 3.73 (s, 1H), 3.85 (s, 3H), 4.20 (s, 1H), 4.50–4.51 ppm (m,

1H); ¹³C NMR (100 MHz, CDCl₃): d=10.0, 16.9, 19.2, 19.5, 20.1, 22.6,

22.9, 24.8, 25.0, 28.5, 31.4, 37.9, 40.18, 40.23, 43.6, 55.3, 55.9, 59.3, 67.1,

68.4, 71.8, 103.6, 108.9, 118.5, 149.1, 154.8, 162.8, 180.4 ppm; IR (KBr):

n˜ =3330, 2929, 1668, 1584, 1462, 1422, 1377, 1320, 1257, 1147, 1058, 1030,

984, 886, 753 cm^ꢀ1; HRMS (EI): m/z: calcd for C₂₈H₄₂O₆: 474.2981, found

474.2963 [M]⁺.

3-[(2S,3R,4aR,6aR,7R,10aR,10bR)-6a,10b-Dimethyl-2-hydroxy-3-(1-hy-

droxy-1-methylethyl)-(8-methylene)perhydro-1H-benzo[f]chromen-7-yl]-

methyl-5,6-dimethyl-2-methoxy-4H-pyran-4-one (candelalide B) (2):

NaBH₄(1.51 mg, 40 mmol) in water (0.2 mL) was added dropwise to a

stirred solution of 62 (9.4 mg, 20 mmol) in THF (2 mL) at ꢀ308C. After

1 h, the reaction was quenched with saturated aqueous NH₄Cl (1 mL),

and the resulting mixture was extracted with EtOAc (3ꢃ15 mL). The

combined extracts were washed with brine (2ꢃ10 mL), then dried over

MgSO₄. Concentration of the solvent in vacuo to afforded a residue,

which was purified by column chromatography (hexane/EtOAc 2:1) to

give 2 (8.3 mg, 88%) as a white amorphous powder. [a]²_D⁰=ꢀ56.3 (c=

0.75 in CH₃OH) {lit.^[1][a]_D²²=ꢀ50.9 (c=0.49 in CH₃OH)}. The ¹H and

¹³C NMR, IR, and MS spectra (see below) are identical to those of natu-

ral (ꢀ)-candelalide B. ¹H NMR (400 MHz, CDCl₃): d=0.76 (s, 3H),

0.85–0.89 (m, 1H), 0.92 (s, 3H), 0.95–0.96 (m, 1H), 1.23–1.31 (m, 2H),

1.33 (s, 3H), 1.38 (s, 3H), 1.65–1.75 (m, 2H), 1.83–1.93 (m, 2H), 1.90 (s,

3H), 2.10–2.16 (m, 2H), 2.24 (s, 3H), 2.26–2.40 (m, 3H), 2.96–3.05 (m,

3H), 3.26–3.27 (m, 1H), 3.85 (s, 3H), 4.06 (s, 1H), 4.31 (s, 1H), 4.52 ppm

(t, J=2.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): d=10.1, 16.9, 21.3, 22.7,

23.1 (2C), 24.0, 24.5, 28.1, 29.2, 31.5, 34.7, 35.0, 37.6, 42.0, 55.2, 57.4, 67.2,

73.7, 81.8, 83.0, 104.5, 107.6, 118.6, 151.2, 154.7, 163.1, 179.9 ppm; IR

(neat): n˜ =3357, 2971, 2931, 2860, 1668, 1586, 1463, 1420, 1376, 1320,

1260, 1171, 1146, 1102, 1077, 985, 884, 554 cm^ꢀ1; HRMS (EI): m/z: calcd

for C₂₈H₄₂O₆: 474.2981, found 474.2975 [M]⁺.

3-[(2R,3R,4aR,6aR,7R,10aR,10bR)-6a,10b-Dimethyl-2-hydroxy-3-(1-hy-

droxy-1-methylethyl)-(8-methylene)perhydro-1H-benzo[f]chromen-7-yl]-

methyl-5,6-dimethyl-2-methoxy-4H-pyran-4-one (61): PPTS (12.4 mg,

50 mmol) was added to a stirred solution of 41 (46.8 mg, 98 mmol) in

CH₂Cl₂(10 mL) at 08C, and stirring was continued for 4 h at room tem-

perature. The reaction was quenched with Et₃N (30 mL) at 08C, and the

resulting mixture was concentrated in vacuo to afford a residue, which

was purified by column chromatography (hexane/EtOAc 3:1) to give 61

(37.2 mg, 79%) as a white amorphous powder. [a]²_D⁰=ꢀ37.6 (c=1.00 in

3-[(1R,4aR,5S,6R,8aR)-5-[(S)-2[(R)-3,3-Dimethyloxiran-2-yl]-2-hydroxy-

AHCTUNGTERGeNNUN thyl]-5,8a-dimethyl-2-methylene-(6-hydroxy)decanaphthlen-1-yl]methyl-

5,6-dimethyl-2-methoxy-4H-pyran-4-one (63): TBAF in THF (1.0m solu-

tion, 0.17 mL, 0.17 mmol) was added dropwise to a stirred solution of 60

(49.1 mg, 84 mmol) in THF (4 mL) at 08C under argon, and stirring was

continued for 1 h at room temperature. The reaction was quenched with

saturated aqueous NH₄Cl (3 mL) at 08C, and the resulting mixture was

Chem. Eur. J. 2009, 15, 2826 – 2845

ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

2843

T. Katoh et al.

extracted with EtOAc (3ꢃ20 mL). The combined extracts were washed

with brine (2ꢃ15 mL), then dried over MgSO₄. Concentration of the sol-

vent in vacuo afforded a residue, which was purified by column chroma-

tography (hexane/EtOAc 1:4) to give 63 (39.5 mg, 100%) as a white

amorphous powder. [a]_D²⁰=ꢀ37.0 (c=0.99 in CHCl₃); ¹H NMR

(400 MHz, CDCl₃): d=0.91 (s, 3H), 0.96 (s, 3H), 1.03 (dt, J=13.2,

2.9 Hz, 1H), 1.24–1.28 (m, 1H), 1.34 (s, 3H), 1.36 (s, 3H), 1.39–1.41 (m,

2H), 1.58–1.65 (m, 1H), 1.69–1.74 (m, 1H), 1.90 (s, 3H), 1.92–1.97 (m,

2H), 2.04–2.11 (m, 2H), 2.24 (s, 3H), 2.32–2.41 (m, 2H), 2.49 (dd, J=

12.7, 11.7 Hz, 1H), 2.74–2.79 (m, 2H), 3.55 (s, 1H), 3.71 (t, J=8.8 Hz,

1H), 3.84 (s, 3H), 4.20 (s, 1H), 4.50 ppm (s, 1H); ¹³C NMR (100 MHz,

CDCl₃): d=10.0, 16.9, 19.6, 20.1, 23.1, 23.2, 23.3, 25.0, 26.2, 28.3, 31.1,

36.0, 37.8, 40.7, 45.5, 55.3, 56.2, 59.5, 66.5, 68.6, 74.4, 103.5, 109.3, 118.6,

149.0, 155.0, 163.0, 180.5 ppm; IR (KBr): n˜ =3278, 2927, 1668, 1584, 1464,

1320, 1257, 1147, 1067, 985, 885, 819, 753 cm^ꢀ1; HRMS (EI): m/z: calcd

for C₂₈H₄₂O₆: 474.2981, found 474.2972 [M]⁺.

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gianesi, R. S. Slaughter, G. J. Kaczorowski, M. L. Garcia, S. N. Ha,

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3-{(2S,3R,5aR,7aS,8R,11aS,11bS)-2,3-Dihydroxy-9-methylene-4,4,7a-(tri-

methyl)perhydro[b]oxepin-8-yl}methyl}-5,6-dimethyl-2-methoxy-4H-

pyran-4-one (64): PPTS (1.90 mg, 7.7 mmol) was added to a stirred solu-

tion of 63 (18.3 mg, 39 mmol) in CH₂Cl₂(3 mL) at 08C, and stirring was

continued for 3 h at room temperature. The reaction was quenched with

Et₃N (20 mL) at 08C, and the resulting mixture was concentrated in

vacuo to afford a residue, which was purified by column chromatography

(hexane/EtOAc 3:1) to give 64 (15.8 mg, 86%) as a white amorphous

powder. [a]²_D⁰=ꢀ26.5 (c=1.02 in CHCl₃); ¹H NMR (400 MHz, CDCl₃):

d=0.90 (s, 3H), 0.91 (s, 3H), 1.00 (dt, J=12.7, 2.9 Hz, 1H), 1.20 (s, 3H),

1.24–1.28 (m, 2H), 1.30 (s, 3H), 1.32–1.40 (m, 1H), 1.42–1.51 (m, 2H),

1.55–1.61 (m, 1H), 1.68–1.71 (m, 1H), 1.78 (dd, J=12.7, 2.9 Hz, 1H),

1.83–1.88 (m, 2H), 1.90 (s, 3H), 2.01–2.13 (m, 1H), 2.24 (s, 3H), 2.27–

2.36 (m, 1H), 2.39–2.44 (m, 1H), 2.47–2.53 (m, 1H), 2.73 (dd, J=13.2,

3.4 Hz, 1H), 3.16 (d, J=9.3 Hz, 1H), 3.31 (dd, J=2.9, 2.4 Hz, 1H), 3.67

(dd, J=9.8, 9.3 Hz, 1H), 3.85 (s, 3H), 4.16 (t, J=2.4 Hz, 1H), 4.50 ppm

(t, J=2.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): d=10.1, 16.9, 18.7, 19.8,

21.2, 21.5, 23.1, 26.4, 28.9, 30.9, 31.5, 37.5, 37.9, 42.9, 49.3, 55.3, 55.9, 68.4,

73.3, 75.3, 84.7, 103.7, 109.1, 118.6, 149.4, 154.8, 162.9, 180.5 ppm; IR

(KBr): n˜ =3376, 2932, 2873, 1728, 1669, 1583, 1464, 1422, 1377, 1320,

1258, 1207, 1186, 1149, 1077, 1037, 986, 885, 754 cm^ꢀ1; HRMS (EI): m/z:

calcd for C₂₈H₄₂O₆: 474.2981, found 474.2985 [M]⁺.

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Acknowledgements

We are especially grateful to Dr. Sheo B. Singh, Merck Research Labora-

tories, for providing us with copies of the ¹H and ¹³C NMR spectra of nat-

ural candelalides A (1), B (2) and C (3). This work was supported in part

by a Grant-in-Aid for Scientific Research on Priority Area “Creation of

Biologically Functional Molecules” (No. 17035073), a Grant-in-Aid for

Scientific Research (C) (No. 18590013), and a Grant-in-Aid for High

Technology Research Program from the Ministry of Education, Culture,

Sports, Science and Technology of Japan (MEXT).

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Received: October 14, 2008

Revised: November 25, 2008

Published online: February 3, 2009

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Article Doi

Enantioselective total synthesis of (-)-candelalides A, B and C: Potential Kvl.3 blocking immunosuppressive agents

DOI: 10.1002/chem.200802122

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