Synthesis and conformational analysis of macrocyclic dilactones mimicking the pharmacophore of aplysiatoxin

Helvetica Chimica Acta Vol. 86 (2003)

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Synthesis and Conformational Analysis of Macrocyclic Dilactones

Mimicking the Pharmacophore of Aplysiatoxin

by Henner Knust and Reinhard W. Hoffmann*

Fachbereich Chemie der Philipps Universit‰t Marburg, D-35032 Marburg

(e-mail: rwho@chemie.uni-marburg.de; fax: 4964212825677)

A small number of macrocyclic dilactones of type 3, i.e., 9, 10, 11, and epi-11, comprising a 3,4-

dihydroxypentanoic acid unit, the pharmacophore of aplysiatoxin, and a conformationally preorganized w-

hydroxynonanoic acid unit were synthesized. Conformational analysis based on ²J and ³J NMR coupling

constants

of the dihydroxypentanoyl part of these macro-dilactones indicates the extent to which a

conformation induction across the macro-dilactone ring occurs from the stereogenic centres implemented in the

w-hydroxynonanoic acid part.

Introduction. Aplysiatoxin [1][2] (1) is a highly potent protein kinase C (PKC)

activator, in which the (3R,4R)-3,4-dihydroxypentanoyl unit constitutes [3] the

pharmacophore [1][2] (Fig. 1). This pharmacophore, the so-called recognition domain,

mimics a 1,2-di-O-acylglycerol unit 2, the physiological activator of PKC.

Fig. 1. Structure of Aplysiatoxin (1) and 1,2-Di-O-acylglycerol (2)

Aplysiatoxin (1) is ca. 50 times more active than di-O-oleoylglycerol 2 [4]. This has

been ascribed to a disposition of the flexible recognition domain in a specific

conformation of 1 optimal for binding to PKC. This disposition is realized by a

conformation-controlling unit (CCU) of 1 (cf. Fig. 1) which serves as a template to hold

the flexible recognition domain (RD) properly in space. Kishi and co-workers showed

[2] that the same conformation prevails in solution as well as in the solid state.

Therefore, the conformation found in the crystal structure of debromoaplysiatoxin [5]

(Fig. 2) might represent the biologically active conformation.¹)

1

)

Arbitrary numbering; for systematic names, see Exper. Part.

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Helvetica Chimica Acta Vol. 86 (2003)

Fig. 2. Pharmacophoric groups and their arrangement in space as seen from the crystal structure of the debromo-

aplysiatoxin core

From a chemical point of view, aplysiatoxin (1) is a macro-dilactone with a 12-

membered ring, in which the conformation of a flexible section (the RD) is being

controlled by the remaining, more rigid part of the ring. Transmission of conforma-

tional information across macrocyclic rings such as 14-membered macro-lactones has

been demonstrated by Still and co-workers [6] and Weiler and co-workers [7]. The

conformational transmission is aided by the fact that 14-membered rings have only few

low-energy conformations [8]. This suggested to us that the recognition domain, the

dihydroxypentanoyl unit of aplysiatoxin, could probably be conformationally con-

trolled as well by incorporation into a much simpler 14-membered macro-dilactone

such as 3, derived from 3,4-dihydroxypentanoic acid and an w-hydroxynonanoic acid

[4] (Fig. 3). The nature of such an w-hydroxynonanoic acid forms the object of this

study. In the context of our interest in the conformation control of flexible structures

[9], we wanted to find out which and how many rigidifying elements have to be

incorporated into an w-hydroxynonanoic acid to serve as a conformation-controlling

unit in aplysiatoxin analogues of type 3. The ability of the w-hydroxynonanoic acid in

macro-dilactones of type 3 to induce the dihydroxypentanoyl unit to adopt a

conformation similar to that found in aplysiatoxin could be monitored by determining

2

conformation-dependent J or ³J coupling constants in the NMR spectra.

Fig. 3. Macro-dilactone 3 and conformationally unconstrained dihydroxypentanoyl model 4

Aplysiatoxin itself shows a strong conformational preorganization at the

C(2)ÀC(3) bond¹) of the dihydroxypentanoyl unit. In contrast, the conformational

preorganization at the C(3)ÀC(4) bond is moderate only [5]. The conformational

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preferences of the dihydroxypentanoyl unit in the macro-dilactones 3 are then expected

to be in-between that of aplysiatoxin itself and that of 4, a model for a conformationally

unconstrained dihydroxypentanoyl unit.

The choice of the w-hydroxynonanoic acid 5 as a starting point for our study was

inspired by the macrocyclic ether 6, which populates a single low-energy conformation

to ca. 90% [10]. In the preferred conformation of 6, the gem-dimethyl moiety takes up

a corner position in the ring. Hence, the gem-dimethyl moiety of 5 would mark one

corner position of the macro-dilactone ring of 3 and should coincide with the gem-

dimethyl moiety present in aplysiatoxin itself. Furthermore, the placement of an O-

atom in position 7 of 5 would lessen any transannular interactions with CH₂(3), after

incorporation into a macro-dilactone. As a further refinement of 5, we considered the

−ring-fused× w-hydroxynonanoic acid derivative 7. Incorporation of one of the backbone

bonds into a six-membered ring should introduce a certain sense of folding into the

macro-dilactone derived from 7. As will be seen later, the −fused× cyclohexane ring in 7

takes up conformation 7a. With the intent to study the effect of the other chair

conformation 7b as well, i.e., of another folding pattern, a further Me group was placed

at the ring, such as in compound 8, which was also included in this study.

A different aspect comes into play as the components 7 and 8 are chiral. The sense

of folding induced by these components on the derived macro-dilactones 3 could be

reinforcing or counteracting the conformational preference resulting from the chiral

dihydroxypentanoyl unit. To learn about such effects, we included also ent-8 in this

study.

The set of compounds chosen for this study, therefore, comprises the macro-

dilactones 9, 10, 11, and 5,5',6-triepi-isomer¹) epi-11. Admittedly, this set is rather

limited. But the efforts involved in the synthesis of these macro-dilactones did not in

the end permit the inclusion of further dilactones [11] into this study. What could be

included, though, were the corresponding D^2,3-unsaturated systems¹), which were part

of the synthesis sequence.

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Synthesis. A convergent synthesis of the target molecules outlined above was

initiated. It turned out that the synthesis of the individual building blocks was not a

major problem. However, their assembly to the macro-dilactones met with consid-

erable difficulties: The Achilles heel was the b-(acyloxy)pentanoyl unit with its high

tendency towards base-induced elimination. This prevented macro-ring closure via a

WadsworthÀHornerÀEmmons reaction [11] at bonds C(2)ÀC(3) or interfered with

deprotection schemes to generate macrolactonization precursors. In the long run, it was

olefin metathesis to form a CC bond between position 2 and 3 which turned out to be

successful in closing the macro-dilactone rings.

Our standard building block for the dihydroxypentanoyl unit was the differentially

protected acid 15 (Scheme 1). It was derived from the protected (R)-lactaldehyde 12

[12] by tin(IV) chloride catalyzed reaction with an allylsilane [13] to give 13. Protection

as (tert-butyl)dimethylsilyl ether ( ! 14) was followed by oxidative cleavage of the

CC bond to furnish the acid 15.

Scheme 1

TBDMS ^tBuMe₂Si

The next intermediate in the synthesis of the macro-dilactone 9 was the building

block 19 (Scheme 2). Its elaboration started from the dioxolane 16 [14]. Alkylative ring

opening [15] with Me₃Al furnished the alkoxy alcohol 17 which was then esterified with

the dihydroxypentanoic acid 15 under Yamaguchi activation [16] of the acid function.

This resulted in 83% of the ester 18. The silyl protecting group was then removed from

18 with (Bu₄N)F to give 81% of the b-hydroxy ester 19.

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Scheme 2

TBDMS ^tBuMe₂Si, Bn PhCH₂, DBU 1,8-diazabicyclo[5.4.0]undec-7-ene, Mes MeSO₂, DDQ 4,5-

dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile

To prepare for ring-closing metathesis, we tried to esterify the hydroxy function of

19 with acryloyl chloride. This succeeded, if at all, in only low yield. Fortunately at that

time, the second generation of Grubbs catalysts [17][18] became available, which are

able to metathesize (2E)-but-2-enoates as well. With the intent to generate the (2E)-

but-2-enoate 21, we esterified 19 with (2E)-but-2-enoyl chloride and Et₃N. This

reaction furnished, however, the but-3-enoate 20, which fortunately could readily be

isomerized to an (E)/(Z) mixture of the desired but-2-enoates 21 in 73% overall yield.

Ring-closing metathesis of 21 with 0.02 equiv. of 22 as catalyst furnished 93% of the

protected macro-dilactone 23. The latter could be readily deprotected as indicated to

give either 9 (90%) or 2,3-didehydro-9 (48%).

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A similar approach to 10 then relied on the building block rac-26: The latter was

obtained from allylcyclohexanone 24 [19] via alkylative ring opening of the acetal 25

(Scheme 3). This led to 92% of a 2.2 :1 mixture of diastereoisomers rac-26 and rac-27.

Assignment of the relative configuration rests on the chemical shift of the Me group,

the one of the major product rac-26 being equatorial (d(C) 23.7) and the one of the

other diastereoisomer rac-27 being axial (d(C) 18.3). The products were separated by

chromatography. Coupling of rac-26 with the enantiomerically pure building block 15

led in 77% (> 50%) yield by necessity to a mixture of diastereoisomeric coupling

products 28 and 29, although the spectra did not reveal that. After carrying the

diastereoisomer mixture 28/29 on through the subsequent steps (the same as in the

preparation of 9), it was only after ring-closing metathesis that the diastereoisomers, a

1.65 :1 mixture 30/31, could be differentiated and separated.

Scheme 3

The major diastereoisomer 30 was carried forward as before to give 10 and 2,3-

didehydro-10 (Scheme 4). As 10 turned out to be crystalline, an X-ray crystal-structure

secured its relative configuration as shown in Fig. 4. Moreover, the crystal structure

shows the cyclohexane ring in a conformation related to 7a. This conformation

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Scheme 4

Fig. 4. Comparison of the backbone conformation of the dihydroxypentanoyl part of the aplysiatoxin core and of

the macro-dilactone 10 as taken from the X-ray crystal structures¹)

apparently prevails also in solution, as the ¹³C-NMR spectrum of 10 (and of the

precursor molecules) shows a signal of an equatorial Me group (d(C) ca. 23).

The synthesis of the macro-dilactone 11 required compound 35 as a key building

block. Its synthesis started by addition of Me₂CuLi ¥ LiI to 2-allylcyclohexenone 32 [20]

followed by diastereoselective protonation [21] of the resulting enolate by methyl

salicylate to give 80% of rac-33 as a 96 :4 cis/trans mixture (Scheme 5). To avoid

epimerization to the trans compound during acetalization, we applied the Noyori

method [22] which furnished 34 as a 93 :7 cis/trans mixture. Reductive alkylation of 34

as before gave alkoxy alcohol 35 as a >10 :1 epimer mixture, from which pure 35 was

obtained by chromatography. To secure the relative configuration at the stereogenic

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Scheme 5

center formed in the reductive alkylation, the double bond of 35 was cleaved to furnish

carboxylic acid 36 in a two-step process. Treatment of 36 with Ac₂O led to the

formation of lactone 37, which displayed characteristic NOE contacts that established

the relative configuration of 35 as shown.

With the racemic building-block 35 in hand, the synthesis of 11 was attained in the

usual fashion: Coupling with the enantiomerically pure dihydroxypentanoyl unit 15

proceeded in 79% yield (Scheme 6). The resulting product 38 must be a diaster-

eoisomer mixture, without that being noticeable in the spectra. This mixture was then

subjected to a reaction sequence of desilylation (66%), butenoylation (90%), and ring-

closing metathesis (69%): This led to a 1.46 :1 diastereoisomer mixture 39/40 (relative

configuration not assigned) that could be separated by chromatography. Each isomer

was carried forward to give 11 and 2,3-didehydro-11 or epi-11 and 2,3-didehydro-epi-11

(Scheme 7).

The idea of having a Me group at C(5') in 35 was to favor the chair conformation

35b, rather than conformation 35a corresponding to 7a, the conformation prevailing in

10 and its precursors (Scheme 8). However, the ¹³C-NMR-signal positions of the Me

groups of 35 (tertiary Me at d 23.2 (i.e., an equatorial position), secondary Me at d 17.9

(i.e., an axial position)) indicate that conformer 35a prevails as contrary to our

expectations MeÀC(5') is not in a position to shift the conformer equilibrium from

35a to 35b. This holds also for all the compounds in this series up to the macro-

lactonization step and results in a downfield shift of the signal of the secondary Me

group (to d ca. 20), whereas the signal of the tertiary Me group remains essentially

constant. This indicates that the initially aspired chair conformation corresponding to

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Scheme 6

Scheme 7

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Scheme 8

35b is neither populated in the macro-dilactones 39 and 40, etc.; rather the twist-boat

conformation corresponding to 35c may come into play.

Finally, we wanted to study compound 4 as a model for a conformationally non-

preorganized dihydroxypentanoyl unit. The synthesis of 4 started also from the benzyl-

protected lactaldehyde 12 (Scheme 9). LiClO₄-Induced Mukaiyama aldol reaction

furnished b-hydroxy ester 41 [23] in diastereoisomerically pure form (56%). The

hydroxy group of 41 was acetylated to give 42. Subsequent hydrogenolytic benzyl

deprotection furnished the desired model compound 3.

Scheme 9

Conformational Analysis of the Dihydroxypentanoyl Unit. The (3R,4R)-3,4-

dihydroxypentanoyl unit comprises the pharmacophore of aplysiatoxin and of the

analogues discussed here (Fig. 5). The folding of the dihydroxypentanoyl unit may be

characterized by the dihedral angles of rotation about the three backbone bonds

C(1)ÀC(2), C(2)ÀC(3), and C(3) ÀC(4). When incorporated into aplysiatoxin or into

the macro-dilactones described here, bonds C(1)ÀC(2) and C(2)ÀC(3) are endocyclic,

bond C(3)ÀC(4) is exocyclic.

Fig. 5. (3R,4R)-Dihydroxypentanoyl unit comprising the pharmacophores of aplysiatoxin

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A detailed conformational analysis about individual conformationally flexible

2

bonds can be based on the determination of J or ³J NMR coupling constants. Murata

and co-workers have recently shown how powerful this method is for oxygenated

alkane chains [24] (cf. also [25]). Conformational analysis by this method of the

dihydroxypentanoyl part of the molecules of interest here is limited to an analysis of the

situation at bonds C(2)ÀC(3) and C(3) ÀC(4). Regarding these two bonds, a total of

nine diamond-lattice-type conformations are possible which are depicted in Fig. 6.

Fig. 6. Diamond-lattice-type conformations of the dihydroxypentanoyl unit

Conformational analysis of the situation at bond C(2)ÀC(3) looks simple at first, as

any coupling-constant pair of either ³J(H,H') and ²J(C,H) or ³J(C,H') across this bond

would suffice to identify a preferred conformation, provided that the individual signals

of the diastereotopic protons H_proRÀC(2) and H_proSÀC(2) can be assigned. Their

assignment is, however, not given a priori. We therefore resorted to an expanded set of

6 coupling constants characteristic for the situation at bond C(2)ÀC(3). These

comprise also ²J(C,H) coupling constants to C(3) which are diagnostic as C(3) bears an

electronegative atom [24][26]. As the compilation of the characteristic magnitudes of

these coupling constants in Table 1 shows, this leads to a self-consistent picture which

implies an assignment of the chemical shifts to H_proRÀC(2) and H_proSÀC(2).

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Table 1. Predicted [24][27] Magnitude of the Various Conformation-Characteristic Coupling Constants of the

Dihydroxypentanoyl Unit

Bond^a)

Coupling constant

Conformation

t

g

g^À

C(2)ÀC(3)

³J(H_proRÀC(2),HÀC(3))

³J(H_proSÀC(2),HÀC(3))

²J(C(3),H_proRÀC(2))

²J(C(3),H_proSÀC(2))

³J(C(4),H_proRÀC(2))

³J(C(4),H_proSÀC(2))

³J(HÀC(3),HÀC(4))

²J(C(4),HÀC(3))

large ^b)

small ^c)

large ^d)

small ^e)

small ^f)

small ^c)

small ^d)

small ^f)

small^c)

small^e)

large^d)

small^f)

large^g)

large^b)

large^e)

small^f)

small^c)

large^b)

large^d)

large^g)

small^f)

small^c)

large^e)

large^g)

C(3)ÀC(4)

²J(C(3),HÀC(4))

³J(C(5),HÀC(3))

³J(C(2),HÀC(4))

^a) Numbering of the dihydroxypentanoyl unit. ^b) Large: 9 12 Hz. ^c) Small: 2 4 Hz). ^d) Large: 5 7 Hz.

^e) Small: 0 2 Hz. ^f) Small: 1 3 Hz. ^g) Large: 6 8 Hz.

Regarding the conformational analysis of bond C(3)ÀC(4), the situation is

straightforward. Each backbone conformation leads to a different pattern (small/large)

3

of J(H,H) and J(C,H). Actually, any combination of J(H,H) and one of the J(C,H)

would suffice to identify a given conformation, provided it is populated to a large

extent. When the ²J(C,H) to C(4) are considered as well, we have an overdetermined

system as the compilation in Table 1 shows.

Experimentally, the ³J(H,H) coupling constants for the macrocyclic dilactones were

1

2

3

directly taken from the H-NMR spectra, and the J(C,H) and J(C,H) coupling

constants were determined by HETLOC experiments [28]. The data are summarized in

Table 2. A good criterion [29] for the extent of conformational preorganization at the

C(2)ÀC(3) bond is the difference (alternation) between the ³J(H,H) coupling

constants to the two diastereotopic protons at C(2). This difference is also listed in

Table 2.

As outlined above, the assignment of the chemical shifts to the diastereotopic

protons H_proRÀC(2) and H_proSÀC(2) was not given a priori. It could be derived from the

total set of 6 coupling constants characteristic for the situation at bond C(2)ÀC(3).

When this assignment was done for each of the compounds studied, a common picture

emerged, in that H_proRÀC(2) generally resonated downfield from H_proSÀC(2) (Fig. 7).

Fig. 7. Chemical shifts of the diastereotopic protons at C(2) of the dihydroxy-

pentanoyl unit

The experimental coupling constants listed in Table 2 may then be compared with

the predicted ones in Table 1. Two extremes can be noted: Aplysiatoxin (1) itself shows

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Table 2. Coupling Constants [Hz] for the Dihydroxypentanoyl Part in 4, the Macrocyclic Dilactones 9, 10, 11, and

epi-11, and Aplysiatoxin (1) [2][5]^a)

Bond¹)

Coupling constant

1

4

9

10

11

epi-11

C(2)ÀC(3)

³J(H_proRÀC(2),HÀC(3)) 12.0 (l)

5.5 (m) 3.2 (s) 7.8 (l)

2.0 (s) 7.5 (m) 7.5 (m) 3.8 (s) 2.3 (s) 8.1 (l)

9.2 (l)

3.4 (s)

³J(H_proSÀC(2),HÀC(3))

D³J(HÀC(2),HÀC(3)

²J(C(3),H_proRÀC(2))

²J(C(3),H_proSÀC(2))

³J(C(4),H_proRÀC(2))

³J(C(4),H_proSÀC(2))

³J(HÀC(3),HÀC(4))

²J(C(4),HÀC(3))

10.0

2.0

3.4 (m) 1.9 (s) 4.6 (l)

4.4 (l) 5.1 (l)

3.2 (m) 2.9 (s) 3.4 (s) 2.7 (s) 1.0 (s)

3.2 (m) 7.1 (l) n.d. 3.1 (s) 2.9 (s)

4.9

4.0

6.9

6.1 (l)

4.7

2.2 (s)

1.7 (s) 2.1 (s) 4.9 (l)

C(3)ÀC(4)

4.2 (m) 4.0 (m) 5.0 (m) 5.0 (m) 4.5 (m) 5.0 (m)

1.4 (s) 2.9 (s) 1.8 (s) 2.2 (s) 0.5 (s)

0.4 (s) 1.9 (s) 0.3 (s) 2.2 (s) 2.1 (s)

2.2 (s) 1.9 (s) 2.2 (s) 2.0 (s) 2.6 (s)

²J(C(3),HÀC(4))

³J(C(5),HÀC(3))

³J(C(2),HÀC(4))

0.9 (s) 1.2 (s) 2.2 (s) n.d.

0.5 (s)

Preferred conformation

tt

g t

tt

g t

^a) m medium, s small, l large, n.d. not determined.

a very strong conformational preorganization at the C(2)ÀC(3) bond, whereas the

conformational preorganization at the C(3)ÀC(4) bond is moderate only. The

preferred conformation of the dihydroxypentanoyl unit was established as tt. On the

other extreme is the open-chain dihydroxypentanoyl model compound 4 which shows a

conformational mix (vic. the −middle× values of the coupling constants) with a slight

preference for the g t conformer.

The values for the simple macro-dilactone 9 indicate a preference for the g t

conformation which is only marginally more marked than that for the model compound

4. The fused macro-dilactone 10 shows a preference for the tt conformation of the

dihydroxypentanoyl unit, albeit much smaller than that seen in 1 itself. In compound 11,

the preference for the tt conformation is substantial. Any interpretation, though, is

hampered by the fact that we do not know the relative configuration of 11 and epi-11.

The similarity of the coupling constants between 10 and 11 suggests that 11 may have

the same relative configuration at the stereogenic centres as the structurally established

10. But this remains an ill-founded speculation.

If it is the chirality of the w-hydroxynonanoic unit in 11 that induces a strong

preference for the tt conformation in the dihydroxypentanoyl part, it is not astonishing

that the opposite chirality in the w-hydroxynonanoic tether of epi-11 should induce

another conformational preference in the dihydroxypentanoyl unit. The latter prefers

in epi-11 a g t conformation and, as the difference of the ³J(H,H) coupling constants to

the diastereotopic protons at C(2) shows, even to a larger extent than in 11.

In summary it becomes clear, that conformational induction across the macro-

dilactone ring from the w-hydroxynonanoic part to the dihydroxypentanoyl pharma-

cophore is substantial, especially in compounds 11, despite the fact that the inducing

stereogenic centers are few and remote. However, none of the compounds studied

reached a level of conformational preorganization in the dihydroxypentanoyl unit as

that displayed by aplysiatoxin (1) itself.

Increasing rigidity in the macro-dilactone ring should lead to enhanced conforma-

tional induction across the ring from the conformation-controlling w-hydroxynonanoic

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part to the dihydroxypentanoyl unit. For this reason, the data of the 2,3-didehydro

derivatives are of interest, which are compiled in Table 3. Introduction of a CC bond

into compound 11, which already has a significant conformational preorganization of

the dihydroxypentanoyl part, to give 2,3-didehydro-11 turned out to be without

consequence. In the macro-dilactone 10, however, introduction of the CC bond (i.e.,

going to 2,3-didehydro-10) brings a substantial increase in the population of the tt

conformer as evidenced by the D³J value of 7.5 Hz, approaching that of aplysiatoxin (1)

itself. Apparently rigidification of the ring by the CC bond favors the tt arrangement

of the dihydroxypentanoyl unit. Thus, 2,3-didehydro-9 and 2,3-didehydro-epi-11 now

also adopt the tt conformation, rather than the g t one recorded for 9 and epi-11. It is,

therefore, evident that remote conformational control of the dihydroxypentanoyl

pharmacophore unit in simple aplysiatoxin analogues of the type 3 is principally

possible.

Table 3. Coupling Constants [Hz] for the Dihydroxypentanoyl Part in 3, the Macrocyclic Unsaturated Dilactones 2,3-

Didehdro-9, 2,3-Didehydro-10, 2,3-Didehydro-11, 2,3-Didehydro-epi-11, and Aplysiatoxin (1)^a)

Bond^b)

Coupling constant

1

3

2,3-dide- 2,3-dide-

2,3-dide-

hydro-9¹) hydro-10¹) hydro-11¹) hydro-11¹)

C(2)ÀC(3)

³J(H_proRÀC(2),HÀC(3)) 12.0 (l) 5.5 (m) 8.8 (l)

³J(H_proSÀC(2),HÀC(3)) 12.0 (s) 7.5 (m) 3.9 (s)

10.5 (l)

3.0 (s)

7.5

n.d.

5.0 (m)

n.d.

8.9 (l)

3.7 (s)

5.2

6.8 (l)

1.8 (s)

n.d.

9.3 (s)

3.5 (s)

5.8

6.1 (l)

2.3 (l)

2.1 (s)

n.d.

5.3 (m)

0.5 (s)

1.2 (s)

n.d.

D³J(HÀC(2),HÀC(3))

²J(C(3),H_proRÀC(2))

²J(C(3),H_proSÀC(2))

³J(C(4),H_proRÀC(2))

³J(C(4),H_proSÀC(2))

³J(HÀC(3),HÀC(4))

²J(C(4),HÀC(3))

10.0

2.0

4.9

3.4 (m) 5.4 (l)

4.4 (l) 2.1 (s)

3.2 (m) 1.9 (s)

3.2 (m) 2.0 (s)

4.0 (m) 5.2 (m)

1.4 (s) 1.7 (s)

0.4 (s) 1.4 (s)

2.2 (s) 1.7 (s)

0.9 (s) 1.2 (s)

n.d.

C(3)ÀC(4)

5.2 (m)

2.1 (s)

n.d.

1.4 (s)

n.d.

²J(C(3),HÀC(4))

³J(C(5),HÀC(3))

n.d.

tt

³J(C(2),HÀC(4))

Preferred conformation

tt

b

^a) m medium, s small, l large, n.d. not determined. ) Numbering of the dihydroxypentanoyl unit¹).

But a shadow fell on this picture when the crystal structure of compound 10 became

available: In line with the NMR studies, the dihydroxypentanoyl unit has the desired

conformation at bonds C(2)ÀC(3) and C(3) ÀC(4) in the solid state, but another

conformation at bond C(1)ÀC(2) than that in aplysiatoxin (1). An overlay of these

structures in Fig. 4 (see above) illustrates this point.

Regarding the conformation at the C(1)ÀC(2) bond in solution, we have no

experimental information other than the crystal structure for the solid state. Force-field

(Macromodel) calculations [11] for 11 suggest that the desired conformation at the

C(1)ÀC(2) bond is not likely to be populated in excess of 10%. Hence, further

improvement of the conformation induction in macro-dilactones of type 3 could be

guided by force-field calculations. This approach indicated [30] distinct modifications

of the macro-dilactones studied here, which should permit to master the problems of

conformation control of the pharmacophore moiety in aplysiatoxin analogues of type 3.

Helvetica Chimica Acta Vol. 86 (2003)

1885

We are grateful to the Fonds der Chemischen Industrie for providing a fellowship to H. K. and for additional

funds. We would like to thank the Volkswagen Stiftung for continued support. Special thanks go to Prof. A.

F¸rstner, M¸lheim, for providing us with samples of metathesis catalysts.

Experimental Part

General. Boiling range of petroleum ether: 40 608. pH 7 Buffer: NaH₂PO₄¥ 2H₂O (56.2 g) and Na₂HPO₄¥

4H₂O (213.6 g) filled up to 1 l with H₂O. All temperatures quoted are uncorrected. Flash chromatography (FC):

Silica gel SI 60 (E. Merck KGaA, Darmstadt), 40 63 mm. NMR Spectra: Bruker ARX-200, AC-300, WH-400,

and AMX-500; d in ppm rel. to Me₄Si, J in Hz.

1. (2R,3R)-2-(Benzyloxy)hex-5-en-3-ol (13). To a soln. of (2R)-2-(benzyloxy)propanal (12; 3.458 g,

21.06 mmol) in CH₂Cl₂(100 ml) at À788, SnCl₄(2.46 ml, 21.1 mmol) was added dropwise, and stirring was

continued for 15 min. Allyltrimethylsilane (3.67 ml, 23.1 mmol) was added. After stirring for 2 h at À788, the

reaction was quenched by addition of H₂O (50 ml). After reaching r.t., the aq. layer was extracted with CH₂Cl₂

(5 Â 30 ml). The combined extract was dried (Na₂SO₄) and evaporated and the residue submitted to FC

(^tBuOMe/pentane 1:9): 13 (3.497 g, 81%). Colorless liquid. [a]²_D⁰ À54.1 (c 2.2, CHCl₃). ¹H-NMR

(200 MHz, CDCl₃): 1.17 (d, J 6.0, 3 H); 2.09 2.24 (m, 1 H); 2.24 2.42 (m, 1 H); 2.52 (br. s, 1 H); 3.35

3.58 (m, 2 H); 4.41 (d, J 11.5, 1 H); 4.65 (d, J 11.5, 1 H); 5.00 5.14 (m, 2 H); 5.74 5.98 (m, 1 H); 7.19 7.38

(m, 5 H). ¹³C-NMR (50 MHz, CDCl₃): 15.3; 37.4; 70.9; 74.1; 77.4; 117.1; 127.6; 127.7 (2 C); 128.4 (2 C); 134.7;

138.2. The spectral data correspond to those given in [13].

2. (4R,5R)-5-(Benzyloxy)-4-{[(tert-butyl)dimethylsilyl]oxy}pent-1-ene (14). At r.t., 1H-imidazole (4.09 g,

60.0 mmol) and N,N-dimethylpyridin-4-amine (DMAP; 611 mg, 5.00 mmol) were added to a soln. of 13 (2.06 g,

10.0 mmol) in DMF (120 ml). Then a soln. of (tert-butyl)chlorodimethylsilane (50% (w/w) in toluene; 9.04 g,

30.0 mmol) was added within 20 min. After heating 4.5 h to 408, the mixture was poured into H₂O ( 1 l). The

t

resulting soln. was extracted with BuOMe (4 Â 150 ml), the combined extract washed with H₂O (150 ml) and

brine (150 ml), dried (MgSO₄), and evaporated, and the residue submitted to FC (^tBuOMe/pentane 1 :49): 14

1

(3.16 g, 99%). Colorless liquid. [a]²_D⁰ 0.04 (c 16.4, CHCl₃). H-NMR (200 MHz, CDCl₃): À0.04 (s, 3 H);

0.00 (s, 3 H); 0.85 (s, 9 H); 1.12 (d, J 6.3, 3 H); 2.01 2.20 (m, 1 H); 2.29 2.46 (m, 1 H); 3.50 (dq, J 4.8, 6.4,

1 H); 3.66 3.77 (m, 1 H); 4.48 (d, J 12.0, 1 H); 4.58 (d, J 12.0, 1 H); 4.94 5.10 (m, 2 H); 5.68 5.94

(m, 1 H); 7.23 7.35 (m, 5 H). ¹³C-NMR (50 MHz, CDCl₃): À4.54; À4.50; 14.0; 18.1; 25.8 (3 C); 36.3; 71.0; 73.8;

77.3; 116.5; 127.4; 127.5 (2 C); 128.3 (2 C); 136.1; 139.0. Anal. calc. for C₁₉H₃₂O₂Si (320.5): C 71.19, H 10.06;

found: C 71.23, H 10.04.

3. (3R,4R)-4-(Benzyloxy)-3-{[(tert-butyl)dimethylsilyl]oxy}pentanoic Acid (15). A stream of ozone was

introduced at À788 into a soln. of 14 (5.12 g, 16.0 mmol) in CH₂Cl₂(100 ml) until the blue color persisted.

Triphenylphosphine (6.28 g, 24.0 mmol) was added, and stirring was continued for 1.5 h at À788. After warming

to r.t., the mixture was adsorbed on silica gel (ca. 5 g) which was placed on top of a chromatography column.

Elution with ^tBuOMe/pentane 1:19 furnished the aldehyde (4.78 g, 93%). Colorless oil. [a]²_D⁰ À5.97 (c 12.4,

CHCl₃). ¹H-NMR (200 MHz, CDCl₃): À0.02 (s, 3 H); 0.03 (s, 3 H); 0.85 (s, 9 H); 1.14 (d, J 6.4, 3 H); 2.49

(ddd, J 15.9, 7.6, 3.0, 1 H); 2.69 (ddd, J 15.9, 4.4, 1.8, 1 H); 3.56 (dq, J 4.5, 6.4, 1 H); 4.33 (dt, J 7.6, 4.4,

1 H); 4.47 (d, J 12.0, 1 H); 4.57 (d, J 12.0, 1 H); 7.24 7.37 (m, 5 H); 9.78 (dd, J 3.0, 1.8, 1 H). ¹³C-NMR

(50 MHz, CDCl₃): À4.9; À4.7; 13.4; 17.9; 25.7 (3 C); 45.9; 68.9; 70.9; 76.5; 127.6 (3 C); 128.3 (2 C); 138.4; 201.7.

The aldehyde obtained was taken up in ^tBuOH (175 ml), and 2-methylbut-2-ene (92.0 ml, 868 mmol) was

added. After stirring for 15 min at r.t., a soln. of NaClO₂(14.3 g, 158 mmol) and NaH₂PO₄¥ H₂O (13.5 g,

86.3 mmol) in H₂O (140 ml) was added dropwise. Upon stirring for 30 min, the initial yellow color disappeared.

t

Sat. aq. NH₄Cl soln. (200 ml) was added, and the mixture was extracted with BuOMe (4 Â 150 ml). The

combined extract was washed with brine (200 ml), dried (MgSO₄), and evaporated, the residue taken up in

pentane (5 ml), the soln. evaporated again, and the co-evaporation repeated (5 Â): 15 (5.00 g, 99%). Colorless

oil. [a]²_D⁰ 17.6 (c 12.3, CHCl₃). ¹H-NMR (200 MHz, CDCl₃): 0.01 (s, 3 H); 0.03 (s, 3 H); 0.85 (s, 9 H); 1.15

(d, J 6.4, 3 H); 2.42 (dd, J 15.3, 8.3, 1 H); 2.71 (dd, J 15.3, 3.8, 1 H); 3.58 (dq, J 4.6, 6.4, 1 H); 4.22 4.33

(m, 1 H); 4.54 (d, J 11.8, 1 H); 4.58 (d, J 11.8, 1 H); 7.27 7.37 (m, 5 H). ¹³C-NMR (50 MHz, CDCl₃): À5.0;

À4.8; 13.3; 17.9; 25.7 (3 C); 36.8; 70.1; 71.0; 76.3; 127.6 (3 C); 128.3 (2 C); 138.4; 178.5. Anal. calc. for

C₁₈H₃₀O₄Si (338.5): C 63.87, H 8.93; found: C 63.74, H 8.80.

4. 2-[(1,1-Dimethylpent-4-enyl)oxy]ethanol (17). At 08, 2m Me₃Al in heptane (10.0 ml, 20.0 mmol) was

added to a precooled soln. of acetal 16 [14] (1.42 g, 10.0 mmol) in CH₂Cl₂(30 ml). After stirring for 4 h at 08, the

mixture was heated to reflux for 6 h. The clear and colorless soln. was added in small portions to sat. aq.

1886

Helvetica Chimica Acta Vol. 86 (2003)

potassium sodium tartrate soln. (150 ml). The aq. layer was extracted with Et₂O ( 3Â 100 ml) and the combined

org. phase washed with brine (150 ml), dried (MgSO₄), and evaporated: 17 (1.51 g, 96%). Colorless liquid.

¹H-NMR (200 MHz, CDCl₃): 1.17 (s, 6 H); 1.51 1.63 (m, 2 H); 1.99 2.16 (m, 2 H); 2.01 (br. s, 1 H); 3.43

(br. t, J 4.6, 2 H); 3.68 (br. t, J 4.5, 2 H); 4.95 (br. d, J 10.0, 1 H); 5.04 (br. d, J 17.1, 1 H); 5.73 5.91

(m, 1 H). ¹³C-NMR (50 MHz, CDCl₃): 25.4 (2 C); 28.1; 39.3; 62.1; 62.2; 74.5; 113.9; 138.9. Anal. calc. for

C₉H₁₈O₂(158.2): C 68.31, H 11.47; found: C 68.09, H 11.59.

5. 2-[(1,1-Dimethylpent-4-enyl)oxy]ethyl (3R,4R)-4-(Benzyloxy)-3-{[(tert-butyl)dimethylsilyl]oxy}penta-

noate (18). DMAP (488 mg, 4.00 mmol) and Et₃N (558 ml, 4.00 mmol) were added at 08 to a soln. of 15 (676 mg,

2.00 mmol) and 17 (316 mg, 2.00 mmol) in toluene (50 ml). After stirring for 15 min at 0 8, 2,4,6-trichlorobenzoyl

chloride (625 ml, 4.00 mmol) was added dropwise within 20 s resulting in the formation of a white precipitate.

After stirring vigorously for 10 min, sat. aq. NaHCO₃soln. (80 ml) was added. The aq. layer was extracted with

^tBuOMe (4 Â 100 ml) and the combined org. phase washed with brine (200 ml), dried (MgSO₄), and

evaporated. FC (^tBuOMe/pentane 1:9) furnished 18 (796 mg, 83%). Colorless liquid. [a]²_D⁰ 13.7 (c 11.8,

CHCl₃). ¹H-NMR (200 MHz, CDCl₃): 0.00 (s, 3 H); 0.01 (s, 3 H); 0.84 (s, 9 H); 1.12 (d, J 6.4, 3 H); 1.16

(s, 6 H); 1.50 1.59 (m, 2 H); 2.03 2.15 (m, 2 H); 2.40 (dd, J 15.1, 8.8, 1 H); 2.66 (dd, J 15.1, 3.5, 1 H); 3.46

3.58 (m, 1 H); 3.50 (br. t, J 5.3, 2 H); 4.14 (dt, J 5.3, 2.0, 2 H); 4.30 4.40 (m, 1 H); 4.52 (d, J 12.0, 1 H);

4.57 (d, J 12.0, 1 H); 4.93 (br. d, J 10.3, 1 H); 5.01 (br. d, J 17.1, 1 H); 5.83 (ddt, J 17.1, 10.3, 6.7, 1 H);

7.27 7.36 (m, 5 H). ¹³C-NMR (50 MHz, CDCl₃): À5.0; À4.8; 13.3; 17.9; 25.5 (2 C); 25.7 (3 C); 28.1; 36.8; 39.1;

59.4; 64.2; 70.1; 70.9; 74.6; 76.4; 114.0; 127.4; 127.5 (2 C); 128.3 (2 C); 138.6; 139.0; 172.3. Anal. calc. for

C₂₇H₄₆O₅Si (478.7): C 67.74, H 9.68; found: C 67.44, H 9.92.

6. 2-[(1,1-Dimethylpent-4-enyl)oxy]ethyl (3R,4R)-4-(Benzyloxy)-3-hydroxypentanoate (19). At 08, 1m

Bu₄NF in THF (1.20 ml, 1.21 mmol) was added over 15 min to a soln. of 18 (482 mg, 1.01 mmol) in THF

(40 ml). After stirring for 1 h at 08 and 6.5 h at r.t., the mixture was evaporated and the residue submitted to FC

(^tBuOMe/pentane 1:4): 19 (297 mg, 81%). Colorless liquid. [a]²_D⁰ 7.50 (c 8.36, CHCl₃). ¹H-NMR

(200 MHz, CDCl₃): 1.16 (s, 6 H); 1.22 (d, J 6.3, 3 H); 1.47 1.61 (m, 2 H); 2.00 2.16 (m, 2 H); 2.54 (d, J

6.2, 1 H); 2.57 2.62 (m, 1 H); 2.95 (br. d, J 5.0, 1 H); 3.51 (br. t, J 5.1, 2 H); 3.54 (dq, J 4.8, 6.3, 1 H); 4.01

(ddd, J 11.1, 6.3, 4.9, 1 H); 4.19 (br. t, J 5.0, 2 H); 4.48 (d, J 11.8, 1 H); 4.68 (d, J 11.8, 1 H); 4.87 5.07

(m, 2 H); 5.82 (ddt, J 17.0, 10.3, 6.6, 1 H); 7.22 7.37 (m, 5 H). ¹³C-NMR (50 MHz, CDCl₃): 15.1; 25.4 (2 C);

28.1; 37.9; 39.1; 59.3; 64.4; 71.0 (2 C); 74.8; 76.5; 114.1; 127.66; 127.73 (2 C); 128.4 (2 C); 138.3; 139.0; 172.3.

Anal. calc. for C₂₁H₃₂O₅(364.5): C 69.20, H 8.85; found: C 68.84, H 9.14.

7. 2-[(1,1-Dimethylpent-4-enyl)oxy]ethyl (3R,4R)-4-(Benzyloxy)-3-(but-2-enoyloxy)pentanoate (21). Et₃N

(486 ml, 3.48 mmol) and directly afterwards (2E)-but-2-enoyl chloride (technical grade, 90%; 204 ml, 1.92 mmol)

were added at 08 to a soln. of 19 (635 mg, 1.74 mmol) in Et₂O (50 ml). After stirring for 1 h at 08 and 1 h at r.t.;

Et₃N (486 ml, 3.48 mmol) and directly afterwards (2E)-but-2-enoyl chloride (technical grade, 90%; 204 ml,

1.92 mmol) were added again. Stirring was continued for 1.5 h, then H₂O (100 ml) was added. The aq. layer was

extracted with Et₂O ( 3Â 100 ml) and the combined org. layer washed with brine (200 ml), dried (Na₂SO₄), and

evaporated. FC (^tBuOMe/pentane 3 :17) furnished 20/(E)-21/(Z)-21 (672 mg, 1.55 mmol, 89%). The mixture

was taken up in Et₂O (30 ml). DBU (255 ml, 1.71 mmol) was added, and the suspension was stirred for 13.5 h.

H₂O (50 ml) was added, the aq. layer extracted with Et₂O ( 3Â 50 ml), and the combined org. phase dried

(Na₂SO₄) and evaporated. FC (^tBuOMe/pentane 1:4) furnished (E)-21 (415 mg, 62%) and (Z)-21 (137 mg,

20%).

Data of (E)-21: [a]²_D⁰ 2.39 (c 4.59, CHCl₃). ¹H-NMR (300 MHz, CDCl₃): 1.12 (s, 6 H); 1.13 (d, J 6.5,

3 H); 1.46 1.55 (m, 2 H); 1.83 (dd, J 7.0, 1.6, 3 H); 1.99 2.08 (m, 2 H); 2.63 (dd, J 16.1, 8.3, 1 H); 2.74

(dd, J 16.1, 5.0, 1 H); 3.44 (br. t, J 5.0, 2 H); 3.75 (dq, J 3.7, 6.5, 1 H); 4.10 (br. t, J 5.3, 2 H); 4.49 (d, J

11.7, 1 H); 4.59 (d, J 11.7, 1 H); 4.90 (br. d, J 10.3, 1 H); 5.01 (br. d, J 16.9, 1 H); 5.42 (ddd, J 4.6, 8.3, 3.9,

1 H); 5.73 5.87 (m, 2 H); 6.95 (dq, J 15.1, 7.0, 1 H); 7.24 7.34 (m, 5 H). ¹³C-NMR (75 MHz, CDCl₃): 14.8;

17.9; 25.4 (2 C); 28.1; 34.6; 39.1; 59.3; 64.4; 71.0; 71.1; 73.7; 74.6; 114.0; 122.4; 127.6; 127.7 (2 C); 128.3 (2 C);

138.2; 139.0; 145.2; 165.5; 170.7. HR-MS (ESI): 455.2459 ([C ₂₅H₃₆O₆ Na] ; calc. 455.2410).

Data of (Z)-21: [a]²_D⁰ 2.08 (c 2.41, CHCl₃). ¹H-NMR (300 MHz, CDCl₃): 1.15 (s, 6 H); 1.17 (d, J 6.5,

3 H); 1.50 1.58 (m, 2 H); 2.02 2.11 (m, 2 H); 2.14 (dd, J 7.3, 2.0, 3 H); 2.66 (dd, J 16.1, 8.3, 1 H); 2.78

(dd, J 16.1, 5.0, 1 H); 3.48 (br. t, J 5.1, 2 H); 3.79 (dq, J 4.0, 6.5, 1 H); 4.14 (br. t, J 5.3, 2 H); 4.53 (d, J

11.7, 1 H); 4.63 (d, J 11.7, 1 H); 4.93 (br. d, J 10.3, 1 H); 5.00 (br. d, J 17.1, 1 H); 5.46 (ddd, J 5.0, 8.3, 4.0,

1 H); 5.80 (dq, J 11.6, 2.0, 1 H); 5.76 5.90 (m, 1 H); 6.35 (dq, J 11.6, 7.3, 1 H); 7.30 7.37 (m, 5 H).

¹³C-NMR (75 MHz, CDCl₃): 14.8; 14.9; 25.4 (2 C); 28.1; 34.6; 39.1; 59.3; 64.5; 70.7; 71.2; 73.8; 74.7; 114.1; 120.3;

127.6; 127.7 (2 C); 128.3 (2 C); 138.2; 139.0; 145.9; 165.4; 170.7. HR-MS (ESI): 455.2377 ([C₂₅H₃₆O₆ Na] ; calc.

455.2410).

Helvetica Chimica Acta Vol. 86 (2003)

1887

8. (7R,10E)-7-[(1R)-1-(Benzyloxy)ethyl]-14,14-dimethyl-1,4,8-trioxacyclotetradec-10-ene-5,9-dione (23).

Ruthenium complex 22 [18] (22 mg, 26 mmol) was added to a soln. of (E)- and (Z)-21 (552 mg, 1.28 mmol)

in CH₂Cl₂(320 ml). After heating to reflux for 1 d, the mixture was evaporated and the residue submitted to FC

(^tBuOMe/pentane 3 :17 ! 3 :7): 23 (348 mg, 93%). Colorless oil. [a]²_D⁰ 17.5 (c 2.03, CHCl₃). ¹H-NMR

(300 MHz, CDCl₃): 1.13 (s, 3 H); 1.19 (d, J 6.4, 3 H); 1.21 (s, 3 H); 1.66 (ddd, J 14.4, 8.4, 4.6, 1 H); 1.74

(ddd, J 14.4, 7.6, 4.7, 1 H); 2.19 2.43 (m, 2 H); 2.58 (dd, J 13.7, 2.9, 1 H); 2.79 (dd, J 13.7, 10.4, 1 H); 3.38

3.46 (m, 2 H); 3.81 (dq, J 4.8, 6.4, 1 H); 4.00 (ddd, J 11.8, 3.8, 5.6, 1 H); 4.32 (ddd, J 11.8, 4.2, 3.0, 1 H); 4.55

(d, J 11.9, 1 H); 4.64 (d, J 11.9, 1 H); 5.31 (ddd, J 10.3, 4.5, 3.0, 1 H); 5.67 (dd, J 15.6, 0.7, 1 H); 7.20 7.30

(m, 1 H); 7.31 7.35 (m, 5 H). ¹³C-NMR (75 MHz, CDCl₃): 14.8; 24.2; 25.5; 28.5; 35.3; 39.3; 59.1; 65.2; 71.2;

72.0; 74.1; 75.2; 119.5; 127.5; 127.7 (2 C); 128.3 (2 C); 138.2; 152.2; 165.7; 171.6. HR-MS (EI): 390.2034

(C₂₂H₃₀O₆; calc. 390.2042).

9. (7R)-7-[(1R)-1-Hydroxyethyl]-14,14-dimethyl-1,4,8-trioxacyclotetradecane-5,9-dione (9). Pd/C (10%;

ca. 5 mg) was added to a soln. of 23 (30 mg, 77 mmol) in THF (3 ml). The suspension was stirred for 1.5 h under

1 bar of H₂. The mixture was filtered through a pad of silica gel and evaporated. FC (^tBuOMe/pentane 1 :1 !

1:0) furnished 9 (21 mg, 90%). Colorless oil. [a]²_D⁰ À29.5 (c 2.15, CHCl₃). ¹H-NMR (200 MHz, CDCl₃): 1.14

(s, 3 H); 1.16 (s, 3 H); 1.19 (d, J 6.8, 3 H); 1.27 1.49 (m, 4 H); 1.54 1.71 (m, 2 H); 2.30 2.47 (m, 2 H); 2.35

(br. s, 1 H); 2.69 (dd, J 16.0, 7.0, 1 H); 2.79 (dd, J 16.0, 4.0, 1 H); 3.39 3.53 (m, 2 H); 3.92 4.08 (m, 1 H);

4.16 (ddd, J 11.8, 3.3, 5.5, 1 H); 4.38 (ddd, J 11.8, 5.1, 3.1, 1 H); 5.14 (ddd, J 6.8, 5.0, 4.0, 1 H). ¹³C-NMR

(75 MHz, CDCl₃): 19.0; 21.6; 25.2; 26.0; 26.5; 34.3; 36.0; 37.5; 59.7; 64.8; 68.4; 74.1; 74.2; 171.1; 171.3. HR-MS

(EI): 302.1709 (C₁₅H₂₆O₆; calc. 302.1729).

10. (7R,10E)-7-[(1R)-1-Hydroxyethyl]-14,14-dimethyl-1,4,8-trioxacyclotetradec-10-ene-5,9-dione (2,3-di-

dehydro-9¹)). Molecular sieves (freshly powdered, 153 mg) and 2,3-dichloro-5,6-dicyanobenzoquinone (4,5-

dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile; DDQ; 173 mg, 768 mmol) were added to a soln. of 23

(30 mg, 77 mmol) in CH₂Cl₂(12 ml). After refluxing the suspension for 1 d, sat. aq. NaHCO₃soln. (20 ml) was

added. The aq. layer was extracted with CH₂Cl₂(4 Â 10 ml), the combined extract washed with brine (25 ml),

dried (Na₂SO₄), and evaporated, and the residue submitted to FC (^tBuOMe/pentane 1 :1): 2,3-didehydro-9¹)

(11 mg, 48%). Colorless oil. [a]²_D⁰ 10.7 (c 1.68, CHCl₃). ¹H-NMR (200 MHz, CDCl₃): 1.14 (s, 3 H); 1.21

(s, 3 H); 1.24 (d, J 6.5, 3 H); 1.59 1.82 (m, 2 H); 2.24 2.42 (m, 3 H); 2.68 (dd, J 13.8, 4.0, 1 H); 2.77

(dd, J 13.8, 8.8, 1 H); 3.45 (br. dd, J 5.1, 3.4, 2 H); 3.95 (br. q, J 6.0, 1 H); 4.07 (ddd, J 11.9, 5.3, 4.2, 1 H);

4.28 (ddd, J 11.9, 4.1, 3.1, 1 H); 5.07 (ddd, J 8.8, 5.2, 3.8, 1 H); 5.70 (dt, J 15.5, 1.1, 1 H); 7.27 (ddd, J 15.5,

9.8, 5.8, 1 H). ¹³C-NMR (50 MHz, CDCl₃): 19.3; 24.1; 25.5; 28.6; 36.5; 39.5; 59.2; 65.5; 69.0; 74.8; 75.3; 119.3;

152.9; 166.3; 171.2. HR-MS (ESI): 323.1481 ([C₁₅H₂₄O₆ Na] ; calc. 323.1471).

11. (6RS)-6-Allyl-1,4-dioxaspiro[4.5]decane (25). Ethylene glycol (5.01 g, 80.7 mmol) and TsOH (ca.

100 mg) were added to a soln. of rac-2-allylcyclohexanone [19] (24, 9.32 g, 67.4 mmol) in toluene (80 ml). The

soln. was heated to reflux for 20 h with azeotropic removal of the H₂O formed. The soln. was washed with sat. aq.

NaHCO₃soln. (50 ml) and H₂O (50 ml), dried (MgSO₄), and evaporated. Distillation (918/106 mbar) [31]

afforded 25 (9.69 g, 70%). Colorless liquid. ¹H-NMR (200 MHz, CDCl₃): 1.08 1.45 (m, 3 H); 1.48 1.90

(m, 7 H); 2.30 2.46 (m, 1 H); 3.85 3.99 (m, 4 H); 4.88 5.04 (m, 2 H); 5.62 5.86 (m, 1 H). ¹³C-NMR

(50 MHz, CDCl₃): 23.9; 24.6; 28.8; 32.9; 34.8; 44.3; 64.6; 64.8; 110.5; 115.3; 137.9. HR-MS (EI): 182.1306

(C₁₁H₁₈O₂; calc. 182.1307).

12. 2-{[(1RS,2RS)- and (1RS,2SR)-2-Allyl-1-methylcyclohexyl]oxy}ethanol (rac-26 and rac-27, resp.). At

À788, 2m Me₃Al in toluene (31.5 ml, 63.0 mmol) was added dropwise over 1.5 h to a precooled soln. of 25

(5.75 g, 31.6 mmol) in CH₂Cl₂(50 ml). The mixture was allowed to reach r.t. over 12 h and was carefully stirred

into sat. aq. potassium sodium tartrate soln. (400 ml). The aq. layer was extracted with CH₂Cl₂(4 Â 100 ml), the

combined extract dried (Na₂SO₄) and evaporated, and the residue submitted to FC (^tBuOMe/pentane 1 :4): rac-

26 (3.93 g, 63%) and rac-27 (1.84 g, 29%) as colorless liquids.

1

Data of rac-26: H-NMR (200 MHz, CDCl₃): 1.16 (s, 3 H); 1.21 1.64 (m, 8 H); 1.81 2.02 (m, 2 H); 2.12

(br. s, 1 H); 2.29 2.41 (m, 1 H); 3.33 3.38 (m, 2 H); 3.64 3.69 (m, 2 H); 4.90 5.01 (m, 2 H); 5.76 (dddd, J

16.9, 10.2, 8.3, 5.9, 1 H). ¹³C-NMR (50 MHz, CDCl₃): 21.8; 23.7; 25.5; 26.6; 33.9; 34.6; 46.6; 61.0; 62.4; 74.8;

115.0; 138.8. Anal. calc. for C₁₂H₂₂O₂(198.3): C 72.68, H 11.18; found: C 72.53, H 1.16.

Data of rac-27: ¹H-NMR (200 MHz, CDCl₃): 1.06 (s, 3 H); 1.15 1.75 (m, 9 H); 2.32 2.48 (m, 2 H); 3.38

3.46 (m, 2 H); 3.62 3.69 (m, 2 H); 4.89 5.01 (m, 2 H); 5.74 (dddd, J 16.6, 10.5, 7.8, 6.0, 1 H). ¹³C-NMR

(50 MHz, CDCl₃): 18.3; 23.5; 25.0; 28.1; 34.1; 36.3; 44.1; 60.9; 62.3; 76.9; 115.1; 138.5. HR-MS (EI): 198.1576

(C₁₂H₂₂O₂; calc. 198.1619).

13. 2-{[(1R,2R)- and (1S,2S)-2-Allyl-1-methylcyclohexyl]oxy}ethyl (3R,4R)-4-(Benzyloxy)-3-{[(tert-

butyl)dimethylsilyl]oxy}pentanoate (28 and 29, resp.). As described in Exper. 5, with 15 (338 mg, 1.00 mmol)

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Helvetica Chimica Acta Vol. 86 (2003)

and rac-26 (198 mg, 1.00 mmol). FC (^tBuOMe/pentane 1 :19) furnished 28/29 (400 mg, 77%). Colorless oil.

¹H-NMR (200 MHz, CDCl₃): 0.01 (s, 3 H); 0.02 (s, 3 H); 0.84 (s, 9 H); 1.14 (d, J 6.3, 3 H); 1.15 (s, 3 H); 1.23

1.52 (m, 7 H); 1.58 1.68 (m, 1 H); 1.79 1.99 (m, 2 H); 2.30 2.37 (m, 1 H); 2.39 (dd, J 14.9, 8.8, 1 H); 2.66

(dd, J 14.9, 3.7, 1 H); 3.40 3.49 (m, 2 H); 3.55 (qd, J 6.3, 4.8, 1 H); 4.15 (br. t, J 5.3, 2 H); 4.34 (ddd, J

8.6, 4.2, 4.2, 1 H); 4.52 (d, J 11.9, 1 H); 4.57 (d, J 11.9, 1 H); 4.91 5.00 (m, 2 H); 5.76 (dddd, J 17.0, 10.1,

8.0, 6.6, 1 H); 7.29 7.35 (m, 5 H). ¹³C-NMR (50 MHz, CDCl₃): À5.0; À4.8; 13.4; 17.9; 21.7; 23.5; 25.5; 25.7

(3 C); 26.4; 33.6; 34.5; 36.9; 46.6; 58.4; 64.2; 70.1; 70.9; 74.7; 76.4; 115.0; 127.4; 127.5 (2 C); 128.2 (2 C); 138.6;

138.9; 172.3. HR-MS (ESI): 541.3315 ([C₃₀H₅₀O₅Si Na] ; calc. 541.3325).

14. {[(1R,2R)- and (1S,2S)-2-Allyl-1-methylcyclohexyl]oxy}ethyl (3R,4R)-4-(Benzyloxy)-3-hydroxypentan-

oate. The mixture 28/29 (170 mg, 328 mmol) was treated as described in Exper. 6. FC (^tBuOMe/pentane 1 :4 !

1:0) furnished the product (80 mg, 60%). Colorless oil. ¹H-NMR (200 MHz, CDCl₃): 1.15 (s, 3 H); 1.09 1.32

(m, 3 H); 1.23 (d, J 6.4, 3 H); 1.33 1.51 (m, 3 H); 1.54 1.72 (m, 2 H); 1.75 2.03 (m, 2 H); 2.28 2.43

(m, 1 H); 2.53 (br. d, J 6.3, 1 H); 2.55 (br. d, J 6.3, 1 H); 3.89 (br. s, 1 H); 3.46 (br. t, J 5.0, 2 H); 3.55

(dq, J 4.8, 6.4, 1 H); 3.95 4.08 (m, 1 H); 4.21 (br. t, J 5.1, 2 H); 4.46 (d, J 11.8, 1 H); 4.66 (d, J 11.8, 1 H);

4.90 5.04 (m, 2 H); 5.65 5.87 (m, 1 H); 7.22 7.41 (m, 5 H). ¹³C-NMR (50 MHz, CDCl₃): 15.0; 21.7; 23.4; 25.4;

26.4; 33.6; 34.5; 37.8; 46.5; 58.4; 64.4; 70.9 (2 C); 74.8; 76.5; 115.0; 127.6; 127.7 (2 C); 128.3 (2 C); 138.2; 138.8;

172.2. HR-MS (ESI): 427.2419 ([C₂₄H₃₆O₅ Na] ; calc. 427.2460).

15. 2-{[(1R,2R)- and (1S,2S)-2-Allyl-1-methylcyclohexyl]oxy}ethyl (3R,4R)-4-(Benzyloxy)-3-(but-2-eno-

yloxy)pentanoate. The alcohol obtained in Exper. 14 (400 mg, 988 mmol) was esterified with (2E)-but-2-enoyl

chloride and isomerized as described in Exper. 7. FC (^tBuOMe/pentane 1 :19 ! 1:9) furnished the (2E)-

(285 mg, 68%) and (2Z)-but-2-enoyl derivatives (100 mg, 22%) as colorless oils.

Data of (2E)-But-2-enoyl Derivative: ¹H-NMR (200 MHz, CDCl₃): 1.13 (s, 3 H); 1.16 (d, J 6.5, 3 H);

1.08 1.30 (m, 3 H); 1.31 1.49 (m, 4 H); 1.52 1.70 (m, 1 H); 1.75 1.99 (m, 2 H); 1.86 (dd, J 6.9, 1.6, 3 H);

2.26 2.42 (m, 1 H); 2.65 (dd, J 16.2, 8.0, 1 H); 2.78 (dd, J 16.2, 5.0, 1 H); 3.42 (br. t, J 5.1, 2 H); 3.78

(dq, J 4.0, 6.5, 1 H); 4.14 (br. t, J 5.1, 2 H); 4.52 (d, J 12.0, 1 H); 4.63 (d, J 12.0, 1 H); 4.88 5.04

(m, 2 H); 5.40 5.51 (m, 1 H); 5.65 5.86 (m, 1 H); 5.90 (dq, J 15.4, 1.5, 1 H); 6.99 (dq, J 15.5, 6.9, 1 H);

7.24 7.37 (m, 5 H). ¹³C-NMR (50 MHz, CDCl₃): 15.1; 18.2; 22.0; 23.7; 25.7; 26.6; 33.9; 34.7; 34.8; 46.8; 58.6;

64.7; 71.4 (2 C); 73.9; 75.0; 115.2; 122.6; 127.8; 127.9 (2 C); 128.5 (2 C); 138.4; 139.1; 145.5; 165.8; 170.9. Anal.

calc. for C₂₈H₄₀O₆(472.6): C 71.16, H 8.53; found: C 70.97, H 8.62.

Data of (2Z)-But-2-enoyl Derivative: ¹H-NMR (200 MHz, CDCl₃): 1.14 (s, 3 H); 1.18 (d, J 6.3, 3 H);

1.07 1.31 (m, 3 H); 1.32 1.51 (m, 4 H); 1.53 1.70 (m, 1 H); 1.75 2.00 (m, 2 H); 2.14 (dd, J 7.3, 1.8, 3 H);

2.27 2.42 (m, 1 H); 2.65 (dd, J 16.0, 8.0, 1 H); 2.79 (dd, J 16.0, 5.1, 1 H); 3.43 (br. t, J 5.3, 2 H); 3.79

(dq, J 3.9, 6.3, 1 H); 4.15 (br. t, J 5.1, 2 H); 4.53 (d, J 11.8, 1 H); 4.64 (d, J 11.8, 1 H); 4.89 5.03 (m, 2 H);

5.46 (ddd, J 8.0, 5.1, 3.9, 1 H); 5.64 5.86 (m, 1 H); 5.84 (dq, J 11.5, 1.8, 1 H); 6.35 (dq, J 11.5, 7.3, 1 H);

7.23 7.39 (m, 5 H). ¹³C-NMR (50 MHz, CDCl₃): 14.9; 15.4; 21.7; 23.5; 25.5; 26.4; 33.6; 34.5; 34.6; 46.5; 58.3;

64.4; 70.7; 71.1; 73.7; 74.8; 115.0; 120.3; 127.6; 127.7 (2 C); 128.3 (2 C); 138.2; 138.9; 145.9; 165.4; 170.7. Anal.

calc. for C₂₈H₄₀O₆(472.6): C 71.16, H 8.53; found: C 70.83, H 8.36.

16. (7R,10E,12aR,16aR)-7-[(1R)-1-(Benzyloxy)ethyl]-2,3,6,7,12a,13,14,15,16,16a-decahydro-16a-methyl-

5H-1,4,8-benzotrioxacyclotetradecine-5,9(12H)-dione (30) and (7R,10E,12aS,16aS)-7-[(1R)-1-(Benzyloxy)eth-

yl]-2,3,6,7,12a,13,14,15,16,16a-decahydro-16a-methyl-5H-1,4,8-benzotrioxacyclotetradecine-5,9(12H)-dione

(31). The mixture of the butenoyl derivatives (285 mg, 638 mmol) obtained in Exper. 15 was cyclized as

described in Exper. 8 in the presence of 5 mol-% of the catalyst. FC (^tBuOMe/pentane 1 :9 ! 1:4 ! 3 :7)

furnished 30 (120 mg, 33%) and 31 (72 mg, 20%) as colorless oils.

Data of 30: [a]²_D⁰ 27.5 (c 9.93, CHCl₃). ¹H-NMR (200 MHz, CDCl₃): 1.13 1.17 (m, 3 H); 1.18 (d, J

6.4, 3 H); 1.25 (s, 3 H); 1.35 1.46 (m, 2 H); 1.49 1.57 (m, 1 H); 1.65 1.79 (m, 2 H); 1.85 2.00 (m, 2 H); 2.54

(dd, J 13.2, 2.2, 1 H); 2.64 2.74 (m, 1 H); 2.77 (dd, J 13.3, 11.4, 1 H); 3.34 (br. d, J 10.5, 1 H); 3.57

(br. t, J 10.4, 1 H); 3.87 (qd, J 6.3, 4.5, 1 H); 3.94 (br. d, J 11.7, 1 H); 4.39 (br. t, J 11.0, 1 H); 4.57 (d, J

12.0, 1 H); 4.65 (d, J 12.0, 1 H); 5.30 (ddd, J 11.4, 3.2, 3.2, 1 H); 5.36 (d, J 15.6, 1 H); 7.23 7.37 (m, 6 H).

¹³C-NMR (50 MHz, CDCl₃): 14.6; 21.4; 23.4; 26.3; 26.9; 34.0; 34.7; 35.2; 47.0; 57.9; 65.2; 71.2; 72.0; 73.8; 75.1;

119.4; 127.6; 127.8 (2 C); 128.3 (2 C); 138.2; 150.6; 165.9; 172.1. HR-MS (EI): 430.2384 (C₂₅H₃₄O₆; calc.

430.2355).

Data of 31: [a]²_D⁰ 1.26 (c 3.96, CHCl₃). ¹H-NMR (200 MHz, CDCl₃): 1.09 (s, 3 H); 1.23 (d, J 6.4,

3 H); 1.07 1.31 (m, 3 H); 1.32 1.48 (m, 3 H); 1.49 1.63 (m, 1 H); 1.74 1.94 (m, 1 H); 1.95 2.19 (m, 2 H);

2.58 2.82 (m, 3 H); 3.29 (br. dt, J 11.1, 2.9, 1 H); 3.41 (ddd, J 11.0, 7.3, 3.6, 1 H); 3.82 (dq, J 5.3, 6.4, 1 H);

4.06 4.20 (m, 2 H); 4.55 (d, J 11.9, 1 H); 4.66 (d, J 11.9, 1 H); 5.26 (br. ddd, J 8.4, 4.4, 4.4, 1 H); 5.59

(br. dd, J 15.5, 2.0, 1 H); 7.22 7.39 (m, 6 H). ¹³C-NMR (50 MHz, CDCl₃): 15.2; 21.6; 22.7; 26.5; 27.2; 34.5;

Helvetica Chimica Acta Vol. 86 (2003)

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35.2; 35.5; 46.4; 57.8; 65.4; 71.2; 72.0; 74.4; 75.4; 118.3; 127.5; 127.7 (2 C); 128.3 (2 C); 138.4; 151.4; 166.0; 171.5.

HR-MS (EI): 430.2391 (C₂₅H₃₄O₆; calc. 430.2355).

17. (7R,12aR,16aR)-2,3,6,7,11,12,12a,13,14,15,16,16a-Dodecahydro-7-[(1R)-1-hydroxyethyl]-16a-methyl-

5H-1,4,8-benzotrioxacyclotetradecine-5,9(10H)-dione (10). As described in Exper. 9, with 30 (30 mg, 70 mmol):

10 (15 mg, 63%). Colorless oil. [a]²_D⁰ 11.1 (c 2.07, CHCl₃). ¹H-NMR (200 MHz, CDCl₃): 1.14 (s, 3 H); 1.18

(d, J 6.4, 3 H); 1.22 1.29 (m, 4 H); 1.31 1.42 (m, 3 H); 1.43 1.50 (m, 1 H); 1.50 1.59 (m, 3 H); 1.62 1.72

(m, 2 H); 2.23 2.29 (m, 1 H); 2.31 2.39 (m, 1 H); 2.65 2.74 (m, 3 H); 3.41 (dt, J 10.6, 2.1, 1 H); 3.48 (td, J

10.3, 1.8, 1 H); 3.89 (br. d, J 11.8, 1 H); 3.95 (qd, J 6.3, 5.0, 1 H); 4.69 (br. t, J 10.4, 1 H); 5.25 (ddd, J 7.8,

4.9, 3.8, 1 H). ¹³C-NMR (50 MHz, CDCl₃): 19.1; 22.0; 23.4; 24.1; 24.3; 27.0; 28.2; 34.4; 35.77; 35.81; 45.2; 58.8;

64.0; 68.5; 73.7; 75.2; 170.6; 173.5. HR-MS (EI): 342.2046 (C₁₈H₃₀O₆; calc. 342.2042).

Crystallographic data (excluding structure factors) of 10 have been deposited with the Cambridge

Crystallographic Data Centre as private communication no. CCDC-196858 (Klaus Harms, University of

Marburg, 2002). Copies of the data can be obtained free of charge via www.cdcc.cam.ac.uk/conts/retrieving.html

or on application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax: (44)1233 336-033; e-mail:

deposit@ccdc.cam.ac.uk).

18. (7R,10E,12aR,16aR)-6,7,12a,13,14,15,16,16a-Decahydro-7-[(1R)-1-hydroxyethyl]-16a-methyl-2,3,5H-

1,4,8-trioxabenzocyclotetradecine-5,9(12H)-dione (2,3-didehydro-10¹)). As described in Exper. 10, with 30

(30 mg, 70 mmol): didehydro-10¹) (14 mg, 56%). Colorless oil. [a]²_D⁰ 33.2 (c 1.34, CHCl₃). ¹H-NMR

(200 MHz, CDCl₃): 1.22 (d, J 6.5, 3 H); 1.25 (s, 3 H); 1.27 1.45 (m, 3 H); 1.47 1.61 (m, 2 H); 1.64 1.79

(m, 3 H); 1.86 (br. s, 1 H); 1.90 2.03 (m, 2 H); 2.56 (dd, J 13.3, 3.0, 1 H); 2.62 2.76 (m, 1 H); 2.78 (dd, J

13.4, 10.5, 1 H); 3.36 (ddd, J 10.6, 2.9, 1.6, 1 H); 3.57 (ddd, J 10.6, 9.9, 1.0, 1 H); 3.90 4.10 (m, 2 H); 4.43

(ddd, J 11.8, 10.0, 1.8, 1 H); 5.08 (ddd, J 10.5, 5.0, 3.0, 1 H); 5.59 (d, J 15.5, 1 H); 7.29 (ddd, J 15.6, 9.8,

6.9, 1 H). ¹³C-NMR (50 MHz, CDCl₃): 14.1; 19.2; 21.5; 23.5; 26.3; 34.0; 34.8; 36.7; 47.0; 58.0; 65.4; 69.1; 75.1;

79.2; 119.2; 151.3; 166.7; 171.6. HR-MS (EI): 340.1908 (C₁₈H₂₈O₆; calc. 340.1886).

19. (2RS,3RS)-2-Allyl-3-methylcyclohexanone (rac-33). To a suspension of CuI (286 mg, 1.5 mmol) in Et₂O

(10 ml), 1.6m MeLi in hexane (1.88 ml, 3.0 mmol) was added. After cooling the clear soln. to À788, 2-

allylcyclohex-2-en-1-one [20] (32; 136 mg, 1.0 mmol) was added. After stirring for 1 h at this temp., the

suspension was added dropwise into a precooled (À 788) soln. of methyl 2-hydroxybenzoate (0.52 ml, 4.0 mmol)

in Et₂O (40 ml). After the formation of a white precipitate, the mixture was allowed to reach r.t. AcOH (229 ml,

4 mmol) was added, and stirring was continued for 2 h. The mixture was filtered through a pad of −Kieselgur×,

and the filtrate was washed with sat. aq. NaHCO₃soln. (50 ml) and H₂O ( 3Â 50 ml). The org. layer was dried

(MgSO₄) and evaporated. FC (^tBuOMe/pentane 1:19) furnished rac-33 (96 :4 diastereoisomer mixture; 122 mg,

80%) as a colorless liquid.

cis-Isomer: ¹H-NMR (200 MHz, CDCl₃): 0.80 (d, J 7.0, 3 H); 1.62 1.68 (m, 1 H); 1.79 1.91 (m, 3 H);

1.91 2.03 (m, 1 H); 2.21 2.36 (m, 3 H); 2.40 2.47 (m, 1 H); 2.48 2.56 (m, 1 H); 4.95 5.05 (m, 2 H); 5.64

5.80 (m, 1 H). ¹³C-NMR (75 MHz, CDCl₃): 14.0; 23.3; 30.7; 31.8; 35.5; 41.5; 54.6; 115.9; 136.4; 212.6. Anal. calc.

for C₁₀H₁₆O (152.2): C 78.89, H 10.59; found: C 78.67, H 10.80.

1

trans-Isomer: H-NMR (200 MHz, CDCl₃): 1.04 (d, J 6.1, 3 H).

20. (6RS,7RS)-6-Allyl-7-methyl-1,4-dioxaspiro[4.5]decane (34). At À788, 1,2-bis-[(trimethylsilyl)oxy]-

ethane (2.54 ml, 10 mmol) was added to a soln. of trimethylsilyl triflate (5 drops) in CH₂Cl₂(5 ml). Ketone rac-

33 (93 :7 diastereoisomer mixture; 761 mg, 5.0 mmol) was added dropwise within 10 min. The mixture was

allowed to reach r.t. over 12 h. Sat. aq. NaHCO₃soln. (15 ml) was added, the aq. phase extracted with ^tBuOMe

(3 Â 10 ml), the combined extract dried (MgSO₄) and evaporated, and the crude product submitted to FC

(^tBuOMe/pentane 1 :19): 34 (93 :7 diastereoisomer mixture (GC); 856 mg, 87%). Colorless liquid. ¹H-NMR

(200 MHz, CDCl₃): 0.90 (d, ³J 7.2, 3 H); 1.24 1.48 (m, 4 H); 1.59 1.73 (m, 4 H); 1.96 2.04 (m, 1 H); 2.13

2.24 (m, 1 H); 3.80 3.95 (m, 4 H); 4.90 (br. d, ³J 10.1, 1 H); 4.94 (br. d, ³J 17.1, 1 H); 5.73 5.93 (m, 1 H).

¹³C-NMR (75 MHz, CDCl₃): 16.6; 21.0; 29.7; 30.2; 31.9; 32.7; 47.3; 64.0; 64.6; 111.3; 114.3; 139.4. Anal. calc. for

C₁₂H₂₀O₂(196.3): C 73.43, H 10.27; found: C 73.50, H 10.31.

21. 2-{[(1RS,2SR,3SR)-2-Allyl-1,3-dimethylcyclohexyl]oxy}ethanol (35). At À788, 2m Me₃Al in hexane

(16 ml, 32 mmol) was added to a precooled soln. of 34 (93 :7 diastereoisomer mixture; 760 mg, 3.87 mmol) in

CH₂Cl₂(100 ml). After reaching 08 over 12 h, the mixture was hydrolyzed by careful addition of sat. aq. NH₄Cl

soln. (50 ml). The mixture was filtered and acidified to pH <1 with aq. HCl soln. The aq. layer was extracted

with ^tBuOMe (3 Â 40 ml) and the combined extract washed with brine (150 ml), dried (MgSO₄), and

evaporated: 35 (92 :8 diastereoisomer mixture (GC); 740 mg, 90%). Colorless oil. ¹H-NMR (300 MHz, CDCl₃):

0.94 (d, ³J 7.0, 3 H); 1.22 (s, 3 H); 1.24 1.42 (m, 3 H); 1.52 1.63 (m, 4 H and OH); 1.78 1.82 (m, 1 H); 2.02

2.17 (m, 2 H); 2.23 2.35 (m, 1 H); 3.41 (m, 2 H); 3.67 (m, 2 H); 4.90 4.97 (m, 2 H); 5.74 5.92 (m, 1 H).

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Helvetica Chimica Acta Vol. 86 (2003)

¹³C-NMR (75 MHz, CDCl₃): 17.9; 20.4; 23.2; 29.1; 30.6; 31.4; 33.3; 48.8; 61.2; 62.5; 77.1; 114.1; 140.6. Anal. calc.

for C₁₃H₂₄O₂(212.3): C 73.54, H 11.39; found: C 73.49, H 11.64.

22. (1RS,2SR,6RS)-2-(2-Hydroxyethoxy)-2,6-dimethylcyclohexaneacetic Acid (36). As described in

Exper. 3, with 35 (396 mg, 1.87 mmol): crude aldehyde (314 mg, 78%). ¹H-NMR (300 MHz, CDCl₃): 0.90

(d, ³J 6.9, 3 H); 0.94 1.08 (m, 1 H); 1.27 (s, 3 H); 1.33 1.47 (m, 3 H); 1.56 1.70 (m, 2 H); 1.80 1.95

(m, 1 H); 2.19 (dd, ³J 3.7, ²J 15.4, 1 H); 2.27 (br. dd, ³J 8.8, ³J 4.0, 2 H and OH); 2.48 (ddd, ³J 8.8, ³J

4.8, ²J 15.4, 1 H); 3.33 3.47 (m, 2 H); 3.53 3.60 (m, 2 H); 9.64 (d, ³J 4.7, 1 H). ¹³C-NMR (75 MHz, CDCl₃):

19.8; 21.9; 22.4; 28.7; 30.6; 31.5; 39.0; 45.4; 61.8; 62.1; 77.2; 204.0.

The aldehyde (29 mg, 135 mmol) was oxidized as described in Exper. 3: 36 (29 mg, 93%). Colorless solid.

M.p. 1328. ¹H-NMR (300 MHz, (D ₆)DMSO): 0.80 (d, ³J 6.9, 3 H); 0.97 1.07 (m, 1 H); 1.00 (s, 3 H); 1.27

1.41 (m, 3 H); 1.50 1.54 (m, 1 H); 1.71 1.78 (m, 1 H); 2.00 2.07 (m, 2 H); 2.14 2.18 (m, 1 H); 2.44 2.49

(m, 1 H); 3.22 3.33 (m, 2 H); 3.38 3.46 (m, 2 H). ¹³C-NMR (75 MHz, (D₆)DMSO): 18.9; 21.4; 22.1; 28.7; 29.1;

31.4; 32.7; 43.9; 61.3; 61.7; 75.8; 175.7. Anal. calc. for C₁₂H₂₂O₄(230.3): C 62.58, H 9.63; found: C 62.41, H 9.60.

23. (6aRS,7RS,10aSR)-2,3,6a,7,8,9,10,10a-Octahydro-7,10a-dimethyl-1,4-benzodioxocin-5(6H)-one (37). A

soln. of 36 (29 mg, 126 mmol) in pyridine (2 ml) was heated to 808. Ac₂O ( 18ml, 190 mmol) and 1,8-

diazabicyclo[5.4.0]undec-7-ene (DBU; 30 ml, 201 mmol) were added, and the mixture was stirred for 2 h at 808.

Toluene (2 ml) was added and the mixture evaporated, a process that was repeated (3Â). The residue was

adsorbed on silica gel followed by FC (^tBuOMe/pentane 3 :7): 37 (19 mg, 71%). Colorless oil. ¹H-NMR

(500 MHz, CDCl₃): 0.93 (d, ³J 6.8, MeÀC(7)); 1.04 1.15 (m, 1 HÀC(8)); 1.30 (s, MeÀC(10a)); 1.36 1.47

(m, 2 HÀC(9), 1 HÀC(10)); 1.56 1.64 (m, 1 HÀC(10)); 1.65 1.71 (m, 1 HÀC(8)); 1.72 1.80 (m, HÀC(7));

2.25 2.29 (m, HÀC(6a)); 2.33 (dd, ²J 14.0, ³J 4.9, 1 HÀC(6)); 2.48 (dd, ²J 14.0, ³J 10.2, 1 HÀC(6)); 3.63

(−dt×, ²J 12.0, ³J 2.4, 1 HÀC(2)); 3.79 (ddd, ³J 10.2, ³J 3.1, ²J 12.6, 1 HÀC(2)); 4.09 (ddd, ²J 12.0, ³J

3.1, ³J 2.2, 1 HÀC(3)); 4.61 (ddd, ³J 10.2, ³J 2.6, ²J 12.0, 1 HÀC(3)). ¹³C-NMR (100 MHz, CDCl₃): 20.0

(MeÀC(10a)); 21.9 (MeÀC(7)); 22.7 (C(9)); 27.8 (C(6)); 30.6 (C(8)); 31.7 (C(7)); 32.3 (C(10)); 47.3 (C(6a));

62.2 (C(3)); 70.2 (C(2)); 78.4 (C(10a)); 177.4 (C(5)). HR-MS (EI): 212.1417 (C₁₂H₂₀O₃; calc. 212.1413),

12

213.1444 (¹³C₁C₁₁H₂₀O₃; calc.: 213.1446).

24. 2-{[(1RS,2SR,3SR)-2-Allyl-1,3-dimethylcyclohexyl]oxy}ethyl (3R,4R)-4-(Benzyloxy)-3-{[(tert-butyl)-

dimethylsilyl]oxy}pentanoate (38). As described in Exper. 5, with 35 (122 mg, 575 mmol) and 15 (194 mg,

575 mmol); 38 (243 mg, 79%). Colorless liquid. ¹H-NMR (200 MHz, CDCl₃): 0.01 (s, 3 H); 0.02 (s, 3 H); 0.84

(s, 9 H); 0.95 (d, J 7.0, 3 H); 1.14 (d, J 6.5, 3 H); 1.20 (s, 3 H); 1.23 1.44 (m, 4 H); 1.46 1.70 (m, 3 H); 1.72

1.89 (m, 1 H); 1.97 2.17 (m, 1 H); 2.27 2.44 (m, 1 H); 2.40 (dd, J 15.1, 8.8, 1 H); 2.67 (dd, J 15.1, 3.6, 1 H);

3.39 3.64 (m, 3 H); 4.08 4.20 (m, 2 H); 4.29 4.41 (m, 1 H); 4.52 (d, J 12.0, 1 H); 4.59 (d, J 12.0, 1 H); 4.91

(br. d, J 10.0, 1 H); 5.00 (br. d, J 17.0, 1 H); 5.81 (dddd, J 17.0, 10.0, 7.2, 6.8, 1 H); 7.27 7.38 (m, 5 H).

¹³C-NMR (50 MHz, CDCl₃): À5.0; À4.8; 13.4; 17.9 (2 C); 20.1; 23.0; 25.7 (3 C); 28.3 (spurious); 29.0; 30.8; 31.4;

33.5; 36.9; 48.4; 58.5; 64.2; 70.1; 70.9; 77.2 (2 C); 114.3; 127.46; 127.51 (2 C); 128.3 (2 C); 138.6; 140.4; 172.3.

Anal. calc. for C₃₁H₅₂O₅Si (532.8): C 69.88, H 9.84; found: C 69.63, H 9.72.

25. 2-{[(1RS,2SR,3SR)-2-Allyl-1,3-dimethylcyclohexyl]oxy}ethyl (3R,4R)-4-(Benzyloxy)-3-hydroxypenta-

noate. As described in Exper. 6, with 38 (218 mg, 409 mmol). FC (^tBuOMe/pentane 3 :7) furnished the product

1

(113 mg, 66%). Colorless liquid. H-NMR (200 MHz, CDCl₃): 0.93 (d, J 7.0, 3 H); 1.20 (s, 3 H); 1.25 (d, J

6.3, 3 H); 1.27 1.43 (m, 4 H); 1.46 1.68 (m, 3 H); 1.70 1.89 (m, 1 H); 1.96 2.17 (m, 1 H); 2.25 2.43

(m, 1 H); 2.55 (br. d, J 6.5, 2 H); 2.91 (br. d, J 4.8, 1 H); 3.40 3.60 (m, 3 H); 4.01 (ddd, J 11.2, 6.3, 4.8,

1 H); 4.20 (br. t, J 5.0, 2 H); 4.46 (d, J 11.6, 1 H); 4.66 (d, J 11.6, 1 H); 4.91 (br. d, J 10.1, 1 H); 5.00

(br. d, J 17.2, 1 H); 5.81 (dddd, J 17.2, 10.1, 7.0, 6.9, 1 H); 7.22 7.43 (m, 5 H). ¹³C-NMR (50 MHz, CDCl₃):

15.1; 17.9; 20.3; 23.0; 28.9; 30.6; 31.4; 33.4; 37.8; 48.3; 58.3; 64.5; 71.0 (2 C); 76.5; 77.2; 114.3; 127.65; 127.71 (2 C);

128.4 (2 C); 138.2; 140.4; 172.3. HR-MS (ESI): 441.2600 ([C₂₅H₃₈O₅ Na] ; calc. 441.2617).

26. 2-{[(1RS,2SR,3SR)-2-Allyl-1,3-dimethylcyclohexyl]oxy}ethyl (3R,4R)-4-(Benzyloxy)-3-(but-2-eno-

yloxy)pentanoate. The alcohol obtained in Exper. 25 (67 mg, 0.16 mmol) was esterified with (2E)-but-2-enoyl

chloride and isomerized as described in Exper. 7. FC (^tBuOMe/pentane 1:9) furnished the (2Z)- (21 mg, 28%)

and (2E)-but-2-enoyl derivatives (50 mg, 68%) as colorless oils.

Data of (2E)-But-2-enoyl Derivative: ¹H-NMR (200 MHz, CDCl₃): 0.87 (d, J 7.0, 3 H); 1.10 (d, J 6.4,

3 H); 1.12 (s, 3 H); 1.14 1.35 (m, 4 H); 1.39 1.63 (m, 3 H); 1.64 1.78 (m, 1 H); 1.80 (dd, J 6.9, 1.7, 3 H);

1.91 2.12 (m, 1 H); 2.21 2.34 (m, 1 H); 2.60 (dd, J 16.0, 8.2, 1 H); 2.71 (dd, J 16.0, 5.0, 1 H); 3.32 3.48

(m, 2 H); 3.72 (qd, J 6.4, 3.9, 1 H); 4.04 4.11 (m, 2 H); 4.46 (d, J 11.8, 1 H); 4.56 (d, J 11.8, 1 H); 4.84

(br. d, J 10.0, 1 H); 4.93 (br. d, J 16.9, 1 H); 5.35 5.43 (m, 1 H); 5.66 5.79 (m, 1 H); 5.79 (br. d, J 15.2,

1 H); 6.93 (dq, J 15.2, 6.9, 1 H); 7.17 7.29 (m, 5 H). ¹³C-NMR (50 MHz, CDCl₃): 14.8; 17.7; 17.9; 20.1; 22.9;

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28.9; 30.7; 31.3; 33.4; 34.5; 48.3; 58.3; 64.4; 71.05; 71.09; 73.6; 77.0; 114.2; 122.4; 127.5; 127.7 (2 C); 128.3 (2 C);

138.2; 140.4; 145.2; 165.5; 170.7. HR-MS (ESI): 509.2909 ([C ₂₉H₄₂O₆ Na] ; calc. 509.2879).

Data of (2Z)-But-2-enoyl Derivative: ¹H-NMR (200 MHz, CDCl₃): 0.86 (d, J 7.1, 3 H); 1.11 (d, J 6.4,

3 H); 1.12 (s, 3 H); 1.15 1.36 (m, 4 H); 1.40 1.60 (m, 3 H); 1.66 1.78 (m, 1 H); 1.92 2.05 (m, 1 H); 2.08

(dd, J 7.3, 1.7, 3 H); 2.21 2.33 (m, 1 H); 2.59 (dd, J 15.8, 8.7, 1 H); 2.74 (dd, J 15.8, 4.2, 1 H); 3.32 3.48

(m, 2 H); 3.73 (dq, J 3.9, 6.3, 1 H); 4.08 (br. t, J 5.3, 2 H); 4.47 (d, J 12.0, 1 H); 4.56 (d, J 12.0, 1 H); 4.84

(br. d, J 10.0, 1 H); 4.94 (br. d, J 17.1, 1 H); 5.37 5.43 (m, 1 H); 5.67 5.79 (m, 1 H); 5.74 (dq, J 11.5, 1.5,

1 H); 6.23 (dq, J 11.5, 7.3, 1 H); 7.17 7.30 (m, 5 H). ¹³C-NMR (50 MHz, CDCl₃): 14.9; 15.4; 17.8; 20.2; 23.0;

29.0; 30.7; 31.4; 33.4; 34.6; 48.4; 58.3; 64.5; 70.7; 71.2; 73.7; 77.0; 114.2; 120.3; 127.6; 127.7 (2 C); 128.3 (2 C);

138.2; 140.4; 145.9; 165.4; 170.7. HR-MS (ESI): 509.2870 ([C ₂₉H₄₂O₆ Na] ; calc. 509.2879).

27. (7R,10E,12aS,13S,16aR)-7-[(1R)-1-(Benzyloxy)ethyl]-2,3,6,7,12a,13,14,15,16,16a-decahydro-13,16a-di-

methyl-5H-1,4,8-benzotrioxacyclotetradecine-5,9(12H)-dione (39) and (7R,10E,12aR,13R,16aS)-7-[(1R)-1-

(Benzyloxy)ethyl]-2,3,6,7,12a,13,14,15,16,16a-decahydro-13,16a-dimethyl-5H-1,4,8-benzotrioxacyclotetradecine-

5,9(12H)-dione (40). A mixture of the (2Z)- (16 mg, 32 mmol) and (2E)-but-2-enoyl derivative (38 mg, 78 mmol)

obtained in Exper. 26 was cyclized as described in Exper. 8 in the presence of 6.4 mol-% of the catalyst. FC

(^tBuOMe/pentane 1 :3) furnished 39 (or 40?; 20 mg, 41%) and 40 (or 39?; 14 mg, 28%) as colorless oils.

Data of 39: [a]²_D⁰ 16.5 (c 2.01, CHCl₃). ¹H-NMR (300 MHz, CDCl₃): 1.00 (d, J 6.8, 3 H); 1.20 (d, J

6.6, 3 H); 1.22 (s, 3 H); 1.28 1.50 (m, 4 H); 1.61 1.76 (m, 3 H); 1.78 1.90 (m, 1 H); 2.17 2.31 (m, 2 H); 2.55

(dd, J 13.4, 2.7, 1 H); 2.77 (dd, J 13.4, 10.3, 1 H); 3.46 (ddd, J 10.6, 6.9, 1.2, 1 H); 3.53 (ddd, J 11.0, 5.0, 1.5,

1 H); 3.82 (qd, J 6.2, 4.8, 1 H); 3.99 (ddd, J 12.0, 6.7, 1.5, 1 H); 4.31 (ddd, J 12.0, 5.6, 1.5, 1 H); 4.55 (d, J

11.8, 1 H); 4.64 (d, J 11.8, 1 H); 5.28 (ddd, J 10.3, 4.4, 2.9, 1 H); 5.64 (d, J 15.6, 1 H); 7.27 7.35 (m, 5 H);

7.47 (ddd, J 15.6, 7.9, 7.9, 1 H). ¹³C-NMR (50 MHz, CDCl₃): 14.9; 19.8; 21.8; 22.3; 28.4; 29.1; 31.1; 33.1; 35.6;

51.4; 58.5; 65.9; 71.2; 71.9; 74.2; 78.7; 119.0; 127.6; 127.7 (2 C); 128.3 (2 C); 138.2; 154.4; 166.4; 171.8. HR-MS

(EI): 444.2537 (C₂₆H₃₆O₆; calc. 444.2512).

Data of 40: [a]²_D⁰ À6.02 (c 0.83, CHCl₃). ¹H-NMR (500 MHz, CDCl₃): 0.93 (d, J 6.7, 3 H); 1.22 (d, J

6.4, 3 H); 1.27 (s, 3 H); 1.26 1.32 (m, 2 H); 1.34 1.40 (m, 2 H); 1.42 1.49 (m, 1 H); 1.53 1.58 (m, 1 H); 1.63

1.69 (m, 1 H); 1.82 1.93 (m, 1 H); 2.28 (ddd, J 16.4, 9.9, 9.7, 1 H); 2.36 (br. d, J 16.3, 1 H); 2.55 (dd, J 13.5,

3.0, 1 H); 2.80 (dd, J 13.4, 10.5, 1 H); 3.43 (ddd, J 10.8, 5.5, 2.0, 1 H); 3.54 (ddd, J 10.7, 7.6, 2.0, 1 H); 3.79

(qd, J 6.2, 4.6, 1 H); 4.03 (ddd, J 11.6, 5.4, 1.9, 1 H); 4.10 (ddd, J 11.6, 7.5, 1.8, 1 H); 4.56 (d, J 11.9, 1 H);

4.65 (d, J 11.9, 1 H); 5.33 (ddd, J 10.5, 4.3, 3.1, 1 H); 5.56 (d, J 15.7, 1 H); 7.26 7.30 (m, 1 H); 7.31 7.35

(m, 5 H). ¹³C-NMR (50 MHz, CDCl₃): 15.0; 19.8; 22.3; 25.6; 28.3; 28.9; 29.5; 32.6; 35.5; 49.7; 57.8; 65.6; 71.2;

72.1; 74.4; 78.5; 116.4; 127.6; 127.7 (2 C); 128.3 (2 C); 138.3; 155.4; 166.3; 171.9. HR-MS (ESI): 467.2440

([C₂₆H₃₆O₆ Na] ; calc. 467.2410).

28. (7R,12aS,13S,16aR)-7-[(1R)-1-Hydroxyethyl]-2,3,6,7,11,12,12a,13,14,15,16,16a-dodecahydro-13,16a-di-

methyl-5H-1,4,8-benzotrioxacyclotetradecine-5,9(10H)-dione (11). As described in Exper. 9, with 39 (22 mg,

50 mmol). FC (^tBuOMe) furnished 11 (or epi-11?; 160 mg, 91%). Colorless oil. [a]_D²⁰ À16.7 (c 1.28, CHCl₃).

¹H-NMR (500 MHz, CDCl₃): 0.91 (d, J 6.9, 3 H); 1.21 (d, J 6.4, 3 H); 1.09 1.19 (m, 2 H); 1.23 (s, 3 H); 1.30-

1.37 (m, 2 H); 1.38 1.42 (m, 1 H); 1.45 1.49 (m, 1 H); 1.56 1.62 (m, 2 H); 1.66 1.79 (m, 4 H); 2.12 (br. d, J

6.6, 1 H); 2.20 2.26 (m, 1 H); 2.47 (ddd, J 14.4, 6.5, 3.4, 1 H); 2.63 (dd, J 15.2, 2.4, 1 H); 2.76 (dd, J 15.2,

9.2, 1 H); 3.49 (ddd, J 10.2, 7.3, 2.2, 1 H); 3.56 (ddd, J 10.5, 5.8, 2.1, 1 H); 3.85 3.94 (m, 1 H); 4.11 (ddd, J

11.7, 7.2, 2.3, 1 H); 4.37 (ddd, J 11.7, 5.8, 2.1, 1 H); 5.10 (ddd, J 9.2, 4.5, 2.3, 1 H). ¹³C-NMR (50 MHz, CDCl₃):

19.4; 20.2; 22.1; 22.6; 23.5; 27.5; 28.9; 32.0; 32.5; 35.0; 37.1; 49.3; 58.0; 64.7; 69.2; 74.6; 77.6; 171.1, 173.9. HR-MS

(EI): 356.2220 (C₁₉H₃₂O₆; calc. 356.2199).

29. (7R,10E,12aS,13S,16aR)-7-[(1R)-1-Hydroxyethyl]-2,3,6,7,12a,13,14,15,16,16a-decahydro-13,16a-di-

methyl-5H-1,4,8-benzotrioxacyclotetradecine-5,9(12H)-dione (2,3-didehydro-11¹)). As described in Exper. 10,

with 39 (22 mg, 50 mmol): 2,3-didehydro-11¹) (or 2,3-didehydro-epi-11?; 13 mg, 74%). Colorless oil. [a]²_D⁰

60.8 (c 0.51, CHCl₃). ¹H-NMR (500 MHz, CDCl₃): 0.99 (d, J 6.9, 3 H); 1.23 (s, 3 H); 1.24 (d, J 6.4, 3 H);

1.29 1.43 (m, 2 H); 1.45 1.54 (m, 1 H); 1.59 1.71 (m, 3 H); 1.73 (br. dt, J 9.0, 4.2, 1 H); 1.81 1.89 (m, 1 H);

2.20 2.31 (m, 2 H); 2.39 (br. s, 1 H); 2.62 (dd, J 13.4, 3.7, 1 H); 2.73 (dd, J 13.4, 8.9, 1 H); 3.49 (ddd, J 11.1,

6.9, 1.9, 1 H); 3.53 (ddd, J 11.1, 5.4, 1.9, 1 H); 3.96 (br. dq, J 5.8, 5.9, 1 H); 4.04 (ddd, J 12.0, 7.0, 1.9, 1 H);

4.28 (ddd, J 11.9, 5.4, 1.8, 1 H); 5.04 (ddd, J 8.8, 5.2, 3.6, 1 H); 5.65 (dt, J 15.7, 1.0, 1 H); 7.46 (ddd, J 15.7,

7.8, 7.8, 1 H). ¹³C-NMR (50 MHz, CDCl₃): 14.2; 19.3; 19.8; 22.3; 27.0; 30.9; 33.1; 36.7; 51.6; 58.4; 66.1; 69.0; 74.6;

77.2; 78.7; 118.5; 155.2; 166.9; 171.5. HR-MS (ESI): 355.2107 ([C₁₉H₃₀O₆ H] ; calc. 355.2121).

30. (7R,12aR,13R,16aS)-7-[(1R)-1-Hydroxyethyl]-2,3,6,7,11,12,12a,13,14,15,16,16a-dodecahydro-13,16a-

dimethyl-5H-1,4,8-benzotrioxacyclotetradecine-5,9(10H)-dione (epi-11). As described in Exper. 9, with 40

(13 mg, 29 mmol). FC (^tBuOMe) furnished epi-11 (or 11?; 9.0 mg, 97%). Colorless oil. [a]²_D⁰ À10.7 (c 1.03,

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CHCl₃). ¹H-NMR (500 MHz, CDCl₃): 0.89 (d, J 6.9, 3 H); 1.10 1.16 (m, 2 H); 1.19 (d, J 6.6, 3 H); 1.21

(s, 3 H); 1.26 1.34 (m, 3 H); 1.35 1.42 (m, 1 H); 1.43 1.48 (m, 1 H); 1.55 1.69 (m, 4 H); 1.72 1.80 (m, 1 H);

2.15 2.22 (m, 1 H); 2.26 (d, J 5.3, 1 H); 2.55 2.60 (m, 1 H); 2.67 (dd, J 15.6, 8.1, 1 H); 2.82 (dd, J 15.4,

3.4, 1 H); 3.51 3.59 (m, 2 H); 4.00 (qdd, J 6.2, 5.5, 5.1, 1 H); 4.13 4.19 (m, 1 H); 4.25 (ddd, J 11.6, 5.0, 1.9,

1 H); 5.06 (ddd, J 8.0, 5.0, 3.3, 1 H). ¹³C-NMR (50 MHz, CDCl₃): 18.9; 19.4; 22.0; 22.4 (2 C); 26.9; 28.9; 31.2;

32.6; 34.5; 35.9; 49.4; 58.3; 65.5; 68.5; 73.7; 77.6; 170.9; 173.4. HR-MS (EI): 356.2196 (C₁₉H₃₂O₆; calc. 356.2199).

31. (7R,10E,12aR,13R,16aS)-7-[(1R)-1-Hydroxyethyl]-2,3,6,7,12a,13,14,15,16,16a-decahydro-13,16a-di-

methyl-5H-1,4,8-trioxabenzocyclotetradecine-5,9(12H)-dione (2,3-didehydro-epi-11¹)). As described in Ex-

per. 10 with 40 (22 mg, 50 mmol): 2,3-didehydro-epi-11¹) (or epi-11?; 12 mg, 68%). Colorless oil. [a]_D²⁰ 12.3

(c 1.38, CHCl₃). ¹H-NMR (500 MHz, CDCl₃): 0.93 (d, J 6.9, 3 H); 1.10 1.18 (m, 1 H); 1.25 (d, J 6.6, 3 H);

1.27 (s, 3 H); 1.29 1.33 (m, 2 H); 1.34 1.41 (m, 1 H); 1.42 1.48 (m, 1 H); 1.56 (br. s, 1 H); 1.63 1.69 (m, 1 H);

1.81 1.93 (m, 1 H); 2.25 2.32 (m, 2 H); 2.33 2.39 (m, 1 H); 2.62 (dd, J 13.3, 3.5, 1 H); 2.77 (dd, J 13.3, 9.3,

1 H); 3.46 (ddd, J 10.8, 3.9, 3.9, 1 H); 3.56 (ddd, J 10.8, 4.6, 4.6, 1 H); 3.93 (br. q, J 6.0, 1 H); 4.09 (br. t, J

3.9, 2 H); 5.07 (ddd, J 9.2, 5.3, 3.8, 1 H); 5.59 (br. d, J 15.7, 1 H); 7.35 (ddd, J 15.6, 9.0, 4.5, 1 H). ¹³C-NMR

(50 MHz, CDCl₃): 19.2; 19.7; 22.2; 26.8; 28.0; 28.6; 29.3; 32.4; 36.5; 49.6; 57.7; 65.6; 68.8; 74.7; 78.4; 116.1; 155.8;

166.5; 171.1. HR-MS (EI): 354.2042 (C₁₉H₃₀O₆; calc. 354.2048).

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Received November 7, 2002

Article Doi

Synthesis and conformational analysis of macrocyclic dilactones mimicking the pharmacophore of aplysiatoxin

DOI: 10.1002/hlca.200390151

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Article abstract of DOI:10.1002/hlca.200390151

Full text of DOI:10.1002/hlca.200390151

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