HELVETICA ACTA- Vol.

78 (1995)
CHIMICA 39 1

29. Total Synthesis of Crenulatan Diterpenes: Strategy and Stereocontrolled

Construction of a Bicyclic Keto-Lactone Building Block
by Wei He'), Emmanuel Pinard, and Leo A. Paquette*
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210, USA

(20.X.94)

The bicyclic keto lactone 26 was synthesized for the purpose of developing a viable route to marine diterpenes
of the crenulatan type. Following the efficient conversion of (S)-citronellol (5) to the allylated alcohol 9a (Scheme
2), the aJ -unsaturated lactone 12 was efficiently accessed in preparation for stereocontrolled conjugate addition.
The hydroxymethyl equivalent most suited to this task was (i-PrO)Me2SiCH2MgC1,which gave 13 predominantly
in the presence of CuI and Me,SiCl. Once the OH group was deprotected (+ 14), it proved an easy matter to
implement acid-catalyzed isomerization to lactone 15, oxidation of which gave the pivotal aldehyde 16. Condensa-
tion of 16 with PhSeCH,Li led via 21 to 22 (Scheme 3). Once the OH group was protected (+22b), it proved
possible to effect aldolization with crotonaldehyde (+ 23). Exposure of 23 to acid gave the sub-target compound
25. Its subsequent oxidation and thermal activation resulted in sequential selenoxide elimination with Claisen
rearrangement (+ 26). The structural features of 26 require that a chair-like transition state be adopted during the
(3.3]sigmatropicevent. With the clarification of these issues, a highly serviceable and more advanced assault on the
crenulatans should prove capable of being mounted.

Introduction. - Extensive study by several groups in Japan [l], the United States [2],
and Europe [3] has revealed brown algae of the genus Dictyota to be a particularly rich
source of xenicane [4] and crenulatan diterpenes. In recent work, Guella and Pietra have
shown that UV irradiation of (-)-4-hydroxydictyolactone (1) results in smooth photo-
isomerization to (+)-4-hydroxycrenulide (2) [S]. Consequently, as they concede, the
probability is high that this conversion actually occurs under the influence of tropical
sunlight acting on the seaweed at low tide.

The interesting structural and configurational characteristics of the crenulatans are

reflected in their central eight-membered ring [6], which features five stereogenic centers,
and to which cyclopropane and butenolide (or equivalent) rings are fused. Although
synthetic accomplishments in this area have been few [7], unique opportunities exist for

') Procter and Gamble Fellow, 1990-1991.

392 HELVETICA ACTA Vol. 78 (1995)
CHIMICA ~

the application of new and existing preparative methods. In the present paper, a general
synthetic strategy is described wherein the stereogenicity inherent in the 6-methylhept-5-
en-2-yl side chain is utilized as the point of reference for correlating the absolute configu-
ration at the other relevant chiral centers.
Results and Discussion. - The focus of this study was to determine if Claisen rear-
rangements such as that associated with the isomerization of 3 would prove serviceable in
providing the means for obtaining stereodefined cyclooct-4-enones (Scheme 1). At issue
was whether the ponderal effect of the C, side chain would prove to be a deterrent to
operation of the [3.3]-sigmatropic process via a requisite chair-like arrangement. This

Scheme I
I

3 4

facet of the problem is somewhat simplified in 3, since the C,H,, side chain is projected
equatorially during the electronic organization to give 4. 111 future work, the conse-
quences of orienting the R group axially (as ultimately required) are to be examined.
Failure of either system to rearrange precisely as indicated would, of course, result in
erosion of the capability to introduce a cis endocyclic double bond and provide an
M -oriented secondary Me group.
In the selection of an optically active starting material for the synthesis at hand, the
decision was made to take advantage of the existing chirality in (S)-citronellol (5). Since
oxidations of 5 in acidic media are known to produce cyclic compounds rather than
(S)-citronellic acid (6)as a consequence of the nearby presence of a highly reactive double
bond, milder conditions are required to produce 6 . Although recourse to pyridinium
dichromate (PDC) in D M F [8] works well on small scale, disadvantages arise during the
processing of large amounts chiefly because of difficulties in workup. Much superior is a
two-step sequence via (S)-citronella1 in which the aldehyde produced by reaction with
PDC in CH,Cl, is oxidized with fresh silver oxide [9] (Scheme 2).
Having secured large quantities of 6 , we soon recognized that alkylation of its methyl
ester with allyl bromide gave a 1 : 1 mixture of diastereoisomers. Consequently, the chiral
center at the p -position is not capable of exerting diastereocon trol. Recourse was there-
fore made to (4S)-4-isopropyloxazolidin-2-one because of its predictable consequences
on product configuration [lo]. Indeed, when the lithium enolate of 7 was treated with allyl
bromide at O", 8 was produced in isomerically pure condition (8296). The elevated
reaction temperature was necessary to allow alkylation to proceed at a reasonable rate.
Following removal of the chiral auxiliary by LiAH, reduction, acetate 9b was pre-
pared and subjected to regioselective hydroboration with the bulky 9-BBN (9-borabi-
cyclo[3.3.llnonane) reagent. Mild in situ oxidation with sodium perborate [l I ] delivered
hydroxy acetate 10 in 98 YOoverall yield. The availability of 10 allowed access to be gained
 HELVETICA
CHIMICA
ACTA- Vol. 78 (1995) 393

Scheme 2

1. (COC1)Z
2. BuLi

3. 9-BBN, THF;
NaB03-4 H20
6 7 R-H 9a R = CH,=CH, R' = H
R = CHO 3. LDA, 8 R = CH2=CHCH2 b R = CH,=CH, R' = H
A@%, 10 R = HOCH,CH,, R' = Ac
6 R - C O O H Z NaOH

1. C03, HzS04,
acetone 1. )-O-SiCH2MgCI
1
2. KOH,MF I
3. T s O H . C ~ H ~ Cul, Me3SiCI.THF
4. KN(SiMe3)2;-
-
2. KHF2, H202, DMF
NPSP, THF
5. H202, PY.
CHpClp 11 saturated 13 R=)-O-SiM* 15
12 unsaturated
14 R - H

to lactone 11 via a one-pot three-step procedure consisting of Jones oxidation, saponifica-

tion, and acid-catalyzed ring closure. Conversion of this intermediate to 12 was accom-
plished by means of organoselenium technology involving N-(phenylse1eno)phthalimide
(NPSP).
At this stage, the plan called for the introduction of a hydroxymethyl substituent
in conjugate fashion to 12 [12]. When the cuprates derived from 4-MeO-C6H,OCH,Li,
4-Me0-C,H,CH20CH,Li, and MeOCH,OCH,Li [ 131were observed to add to 12 only in
low yield, recourse was made alternatively to (i-PrO)Me,SiCH,MgCI and a catalytic
quantity of CuI in the presence of Me,SiCI [14]. Under the best conditions, which
involved slow addition of the Grignard reagent to 12 admixed with the co-reagents at Oo,
13 was obtained in 76 '?LOyield with the j3 -isomer assumed to predominate heavily. The
addition product proved to be very sensitive to acid, requiring that Et,N be introduced
prior to workup to absorb any HCI generated from hydrolysis of the remaining Me,SiCl.
Desilylation of 13 with KHF, and H,O, in DMF [15] permitted exploration of the
equilibration of 14 with 15. Upon heating 14 with catalytic amounts of toluene-4-sulfonic
acid in benzene, a mixture rich in 15 was produced, as expected on both thermodynamic
and kinetic grounds [12]. The individual structural isomers were readily separated by
chromatography on silica gel, at which point 14 was resubjected to the isomerization
conditions. To safeguard structural integrity, 15 was invariably oxidized to 16 as soon as
possible with PDC in the presence of powdered 3-b, molecular sieves.
The singular ease with which minor constituent 17 could be obtained (from 13, after
oxidation) free of its epimer prompted brief examination of the equilibration of aldehyde
16. When 16 was exposed to trace quantities of toluene-4-sulfonic acid in benzene at
room temperature, epimerization was not observed. Rather, an ene reaction took place
rapidly to deliver homoallylic alcohol 18 in quantitative yield. Although the use of
4-chloroaniline in the mixed solvent system i-PrOH/AcOH 7: 1 [16] provided an unknown
394 HELVETICA ACTA-Vol. 78 (1995)
CHIMICA

aroinatic compound, and (lithium diisopropylamide) LDA proved to be totally destruc-

tive of 16, mildly alkaline conditions such as K,CO, in MeOH led to formation of the
addition product 19. Ultimately, heating 16 with 3 equiv. of DBU (1,8-diazabicyclo-
[5.4.0]undec-7-ene) in benzene effected isomerization to 20. At equilibrium, the two
aldehydes 16 and 20 were present in a 1:1 ratio (Scheme 3). Unfortunately, unlike 16 and
17, 16 and 26 proved to be chromatographically inseparable on a wide range of ab-
sorbents. As a consequence, designed epimerization should not be entertained here in the
synthetic scheme, since the diastereoisomers exhibit inadequate physical differences to
allow their isolation in pure form.
While initial efforts to achieve chemoselective 1,2-additiori to the aldehyde C=O in 16
proved troublesome because of steric shielding, these difficulties could be circumvented
by introducing PhSeCH,Li [ 171 under high-dilution conditions. The transient generation

Schrme 3

16 21 22a R = H
b R = MeOC(Me),

LDA,
H,C;qH, THF
0

20

1. Na104, NaHC03
H20, MeOH
2. EtZNH,
mesitylene, A

ii
26

0 0 0

17 18 19
 HRLVETICA
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ACTA- Vol. 78 (1995) 395

of a reactive alkoxide ion in this fashion resulted in kinetically controlled intramolecular

attack at the lactone C=O to provide 21 as a single diastereoisomer in 90% yield. As a
consequence of the lesser strain energy in 22, efforts directed to the acid-catalyzed
isomerization of 21 to 22 proved to work well and to shift the equilibrium well back in the
direction of the five-ring lactone. Protection of the OH group in 22 permitted the direct
aldol condensation of 22 with crotonaldehyde. On the basis of our past experiences, it was
clear that the blocking group had to be introduced under acidic conditions to bypass
reconversion to 21. In addition, its ultimate removal under acidic conditions could also
prove highly desirable since this transformation could be performed in tandem with the
impending pyran-ring formation. For these reasons, 22 was treated with 2-
methoxypropene in the presence of a catalytic amount of POCI, [18]. LDA proved
adequately reactive as a promoter of the aldol process, this step delivering 23 as a 1:l
mixture of diastereoisomers in quantitative yield.
Upon heating 23 in benzene solution containing toluene-4-sulfonic acid, ring closure
occurred to afford the bicyclic phenylseleno-substituted lactones 24 and 25 in 34 and 37 %
yield, respectively, after chromatographic separation. The stereoselectivity of these cy-
clizations is in agreement with the kinetically controlled ionization of the allylic OH
group and with intramolecular capture of the cation on one of its two planar surfaces via
a six-membered transition state. The specific reaction course dictates whether the
propenyl substituent is projected axially as in 24 or equatorially as in 25. The near-equal
distribution of the two epimers suggested that ring closure occurred under kinetic control.
In actuality, the cyclization was stereospecific since the two separated epimers of 23
cyclized cleanly in turn to 24 or to 25. It would appear, therefore, that the surface from
which the OH departs is sufficiently cluttered to invite nucleophilic attack from the
backside direction. Lactones 24 and 25 could readily be distinguished on the basis of
'H,'H coupling constants exhibited by the protons residing on the tetrahydropyran ring
(see Exper. Part, J(3a,4) = 5 Hz for 24 and 9.5 Hz for 25). Also made evident by these
spectral data was the fact that the PhSeCH, unit resides in an equatorial disposition. This
finding formed the basis for the configurational assignment to this center in 21-25. A
further relevant point was the finding that 24 could indeed be converted into 25 upon
being heated in benzene containing toluene-4-sulfonic acid. However, this process was
very slow. After 1 week, only 50% of 24 had undergone isomerization. At longer reaction
times, significant decomposition was observed; higher boiling solvents, e.g., mesitylene,
or stronger acids, e.g., CF,SO,H, had the same effect only much more rapidly. No
reaction occurred in more polar solvents such as 1,Zdimethoxyethane or when other
possible catalysts, e.g., [Pd(PPh,),], were present. Treatment with DBU resulted in
epimerization at C(2).
Finally, 25 was oxidized to the selenoxide level with sodium periodate. Without
purification, this intermediate was heated in mesitylene to bring about both the 1,2-elimi-
nation and Claisen rearrangement. Since this two-step process is mediated by a reactive
vinyl ether, preservation of its integrity required that Et,NH be present to neutralize the
electrophilic PhSeOH liberated during its very formation. Under these conditions, 26 was
obtained in 80% Overdl1 yield. The configurational assignments to 26 are soundly based
on nuclear Overhauser experiments as indicated in the Exper. Part.
Consequently, the electronic reorganization association with this [3.3]-sigmatropic
process unquestionably proceeds via the chair arrangement depicted in 3. The transition-
396 CHIMICA ACTA- VOl. 78 (1995)
HELVETICA

state geometry guarantees the desired a-orientation of the ring Me group and the
cis-configuration of the cyclooctenone double bond. Furthermore, the rearrangement
occurs without adventitious epimerization at the two enolizable sites and without migra-
tion of the P,y -unsaturated double bond into conjugation wirh the lactone C=O group.
The present achievements provide considerable insight into the requirements neces-
sary for the actual adaptation of this scheme to the synthesis of crenulatan diterpenes of
marine origin. The recent discovery [S] that the xenicane and crenulatan frameworks
share in common a (R)-configurated stereocenter demands, of course, that (R)-citronel-
lo1 be utilized at the outset. Beyond that, it is not just a matter of producing the
(R,R)-isomer of 9a, for this course of action will ultimately provide only the enantiomer
of 26, since the remaining stereocenters are introduced under the full control of those
present in this alcohol. Consequently, a different stratagem is required to reach the
proper diastereoisomer of 21 and of 25. Once this essential rnatter is settled, there will
remain the need for operation of the normal chair-like kinetic bias of the Claisen
rearrangement as in 4 despite the axial orientation of the alkeniyl chain R. We hope to be
in a position to report on the outcome of these studies in due course.

We thank the National Institutes of Health (grant GM-30827) for financial support, Dirk Frredrich for NMR
measurements, and Kurt Loening for assistance with nomenclature.

Experimental Part
General. M.p.: uncorrected. Solvents: reagent grade and in most cases dried before use. Column Chromatog-
raphy (CC): Woelm silica gel (230400 mesh) or Merck Lobar columns (Lichroprep Si-60); FC = flash chromatog-
raphy. The purity of all compounds was shown to be 2 95 % by TLC and high-field 'H-NMR analyses. 'H-NMR
Spectra: at 300 MHz. ',C-NMR Spectra: at 75 MHz unless otherwise noted. HF:-MS: obtained at the Ohio State
University Campus Chemical Instrumentation Center. Elemental analyses were performed at the Scandinavian
Microanalytical Laboratory, Herlev, Denmark.
(S)-Citronellic Acid (= (S)-3,7-Dimethyloct-6-enoic Acid: 6). To a well stirred suspension of 5 (48.32 g,
0.320 mmol) and dried, powdered 3 A molecular sieves (150 g) in dry CH,C12 (500 ml) was added PDC (150 g,
0.399 mmol). The dark mixture was stirred at r.t. for 3 h before being diluted with Et 2 0 (1 I). The solid that was
separated by filtration was extracted with Et,O (2 x 250 ml), and the combined org. s o h . were evaporated to give
impure aldehyde.
A soln. of NaOH (51 g, 1.28 mol) in H 2 0(220 ml) was treated dropwise with an aq. soln. (220 ml) of AgNO,
(100 g, 0.588 mol). The brown silver oxide suspension was stirred vigorously for 30 min and the aldehyde was
introduced dropwise. After overnight agitation, the insoluble solid was separated and washed with hot H,O
(2 x 30 ml). The combined aq. soln. was acidified and extracted with Et 2 0 (2 x 500 ml) and the org. phase dried
and evaporated: 40.0 g (76%) of pure 6 [S].
(4S)-3-[ (3S)-3,7-Dimethyloct-6-enoyl~-4-isopropyloxazol~din-2-one (7). To a soln. of 6 (58.46g, 0.344 mol) in
280 ml of dry benzene and 1 10 ml of 2-methylbut-2-ene was added oxalyl chloride (33.74 ml, 0.380 mol). The light
yellow s oh. was stirred at r.t. for 2 h before being evaporated to give the crude acyl chloride as a yellow liquid. To
a cold (-78") soln. of (4S)-4-isopropyloxazolidin-2-one (48.5 g, 0.363 mol) in 2 1 of dry THF was added dropwise
1.5M BuLi in hexane (251.3 ml, 0.377 mol) during 0.5 h before the above acyl chloiide was introduced via cannula.
The mixture was stirred at -78' for 3 h before being quenched with sat. NH,C1 soln. (250 ml). The aq. so h . was
extracted with Et,O (2 x 250 mi), the combined org. phase dried and evaporated, and the yellow residue chro-
matographed (silica gel, 30% Et20/petroleumether): 93.33 g (97 %a) of7. Colorles:; liquid. [a12= +58.2 ( c = 0.95,
CHCI,). IR (neat): 1780, 1700, 1380, 1200. 'H-NMR (CDCI,): 5.10 (m. 1 H);4.44 I'm, 1 H); 4.22 (w, 2 H); 3.02 (dd,
~=15.9,5.5,1H);2.68(dd,J=15.9,8.2,1H);2.37(m,1H);2.03(m,3H);1.68(s,3H);1.60(s,3H);1.42(m,1
H); 1.27 (m, 1 H); 0.95 (d, J = 6.7, 3 H); 0.91 (d, J = 7.0, 3 H); 0.97 (d, J = 7.0, 3 H). I3C-NMR (CDCI,): 172.8,
154.0, 131.4, 124.4, 63.2, 58.4, 42.4, 36.9, 29.5, 28.4, 25.7, 25.4, 19.5, 18.0, 17.6, 14.6. MS: 281.1978 (M', calc.
281.1991). Anal. calc. for C,,H2,NO,: C 68.29, H 9.67; found: C 68.52, H 9.69.
 HELVETICA ACTA- Vol. 78 (1995)
CHIMICA 397

( 4 S)-3-[ (2S,3S)-2-AllyI-3,7-dimethyloct-6-enoyl]-4-isopropyloxazolidin-2-one (8). To a cold (-78") LDA

(lithium diisopropylamide) so h . prepared from i-Pr2NH (51.4 ml, 0.367 mol) and I S M BuLi in hexanes (230 ml,
0.345 mol) in 600 ml of dry THF was added dropwise within 1 h a soh. of 7 (93.33 g, 0.332 mol) in 200 ml of dry
THF. The light yellow-brown soln. was vigorously stirred at -78" for 3 hand warmed to 0" during 30 min at which
point ally1 bromide (86.2 ml, 0.996 mol) was added via syringe. The mixture was stirred at 0" overnight, cooled
to -78", and quenched with sat. NH4CI soln. (100 ml). The resulting orange soln. was poured into 400 ml of
ice-cold IN HCI and extracted with Et2 0(2 x 300 ml). The combined org. phase was dried and evaporated and the
residue purified by CC (silica gel, 20% Et20/petroleum ether): 76.95 g (72%) of 8 and 11.3 g (12%) of recovered 7.
Overall yield of 8 82%. Colorless liquid. [ a ] g = +66.6 (c = 0.65, CHCI,). IR (neat): 1770, 1690, 1380, 1200.
'H-NMR (200 MHz, CDCI,): 5.86-5.66 (series of m,1 H); 5.084.76 (series of m,3 H); 4.45 (m, 1 H); 4.18 (m, 2 H);
3.97(m, 1 H);2.51-2.25(seriesofm,3H);2.10-1.72(seriesofm,3H);1.66(s,3H); 1.58(s,3H); 1.48(m, 1 H); 1.16
(m,1 H); 0.93 (d, J = 6.8, 3 H); 0.88 (d, J = 7.1, 3 H); 0.83 (d,J = 6.9, 3 H). I3C-NMR (50 MHz, CDCI,): 175.6,
153.8, 135.6, 131.5, 124.2, 116.7, 62.8, 58.7, 47.0, 34.7, 33.9, 32.9, 28.2, 25.7, 25.2, 18.0, 17.6, 17.1, 14.5. MS:
321.2341 ( M + , calc. 321.2304). Anal. calc. for CI9H,,NO,: C 70.99, H 9.72; found: C 71.10, H 9.80.
(2S,3S)-2-ANyl-3,7-dimefhyloct-6-eno/ (9a). To 8 (8.03 g, 0.0250 mol) in 1.25 1 of dry Et20 at -7X0, LiAIH,
(2.85 g, 0.0750 mol) was added at once, and the gray suspension was stirred vigorously as the temp. was raised
from -78" to 20" within 2 hand at r.t. overnight. H 2 0(4 ml) was added at 0" to carefullydestroy the excess hydride,
followed by 2M NaOH (4 ml) and H 2 0(10 ml). After filtration of solid, the Et 2 0filtrate was washed with 2 M H2S04
(100 ml), dried, and evaporated and the residue chromatographed (silica gel, 30% Et20/petroleum ether): 3.68 g
(75 %) of9a. The acid aq. so h . was neutralized with 2N NaOH and extracted with Et20 (2 x 100 ml). Evaporation
of the dried E t20s oh . gave 2.0 g (25%) of (2S)-2-{N-[(2S,3S)-2-al1yl-3,7-dimethyloct-6-enyl]-N-methylamino}-
3-methyibutanol27.
9a: Colorless liquid. [ a ] E = -10.1 (c = 1.60, CHCI,). IR (neat): 3340, 1440, 1380, 1040, 910. 'H-NMR
(CDCI,):5.83(dddd,J=15.6,10.0,7.1,2.9,1H);5.134.98(seriesofm,3H);3.65(dd,J=10.8,5.1,1H);3.55
(dd, J = 10.8,6.5. 1 H); 2.13 (tt, J = 17.0, 1.3,2 H); 2.03 (m. 1 H); 1.93 (m. 1 H); 1.68 (d, J = 1.1,3 H); 1.60 (s, 3 H);
1.66-1.50(seriesofm,2H); 1.43 (m, 1H); 1.33 (br.s, 1 H); 1.19(m, 1 H);0.88(d,J = 6.8,3H). '3C-NMR(CDC13):
138.2, 131.4, 126.7, 115.8, 63.6, 45.3, 34.1, 33.8, 33.0, 26.0, 25.7, 17.7, 16.1. MS: 196.1807 ( M + , calc. 196.1827).
Anal. calc. for CI3H,O: C 79.53, H 12.32; found: C 79.12, H 12.40.
27: Colorless liquid. [a12 = -0.45 (c = 1.32, CHCI,). IR (neat): 3450, 1440, 1370, 1070, 1050,910. 'H-NMR
(200MHz,CDCI3):5.74(dddd,J=14.0,10.1,7.0,3.0, lH);5.134.94(seriesofm,3H);3.53(dd,J=10.3,5.0,
2H); 3.19(t,J = 10,4, 1 H); 2.55(dd,J = 13.0, 5.9, 1 H); 2.42(dd,J = 13.0,7.5, 1 H);2.38-2.21 (seriesofm, 1 H);
2.29(s, 3 H ) ; 2.02(t,J=6.9,2 H); 1.96-1.74(seriesofm, 3 H); 1.67(s, 3 H ) ; 1.63-1.51 (seriesofm,2H); 1.59(s,
3 H); 1.40-1.23 (series of m,1 H); 1.21-1.04 (series of m, 1 H); 0.99 (d, J = 6.7,3 H); 0.83 (d, J = 6.8, 3 H); 0.81 (d,
J = 6.7, 3 H). ',C-NMR (50 MHz, CDCI,): 138.1, 131.3, 124.7, 115.5, 70.6, 59.5, 55.7, 44.3, 36.9, 34.1, 33.4, 32.6,
27.5, 26.2, 25.7, 22.6, 19.9, 17.6, 15.8. MS: 295.2877 (M', calc. 295.2875). Anal. calc. for C&H,,NO: C 77.23, H
12.62; found: C 77.27, H 12.68.

A
(2S,3S)-2-Allyl-3,7-dimethyloct-6-en-I-yl Acetuze (9b). Four lots of 13.12 g (40.9 mmol) of 8 were reduced
with LiA1H4(4.66 g, 0.123 mol) in the predescribed manner, and the reaction mixtures were combined for workup.
The crude alcohol so produced, 4-(dimethy1amino)pyridine (0.3 g), and pyridine (66.3 ml, 0.820 mol) in 400 ml of
CH2C12were cooled to -20" and treated with acetyl chloride (35 ml, 0.49 mol) over 10 min. The white suspension
was stirred while being allowed to warm to r.t. during 1 h, and at r.t. for 4 h. After being cooled to Oo, the brown
suspension was washed with 10% HCI (100 ml) and sat. NaHCO, so h . (100 ml), dried, and evaporated. The
residue was purified by CC (silica gel, 5 YOEt20/petroleumether): 27.7 g (71 %) of9b. Colorless liquid. [ct]g= +4.3
(c = 0.44, CHCI,). IR (neat): 1720, 1230. 'H-NMR (250 MHz, CDCI,): 5.73 (m. 1 H); 5.1 14.98 (series of m, 3 H);
4.06(dd,J = 11.1, 5.8, 1 H); 3.95(dd,J = 11.2,6.6, 1 H);2.09(t,J = 7.0,2H);2.03 (s,3H); 1.97(m, 3H); 1.74(m,
lH);1.68(s,3H);I.60(~,3H);1.39(m,lH);1.19(m, 1H);0.86(d,J=6.8,3H).'3C-NMR(62.5MHz,CDCI,):
398 HELVETICA ACTA- Val. 78 (1995)
CHIMICA

171.1, 137.1, 131.4, 124.5, 116.1, 64.9,41.5,34.2, 33.7, 32.9, 25.9.25.6.21.0, 17.6, 15.6. MS: 178.1698(Mi,calc.
178.1721). Anal. calc. for C15H2603: C 75.58, H 10.99; found: C 75.28, H 10.87.
(2S.3S)-2-(3-Hydroxyprop.vl)-3,7-dimethyloct-6-enyl Acetate (10). To a well-stirred soln. of Yb (27.7 g,
0.1 17 mol) in 220 ml of dry T H F was added a soln. O f 0.5M 9-BBN in T H F (280 ml, 0.140 mol) via syringe over 10
min. The mixture was vigorously stirred for 7 h, then quenched with 150 ml cf H 2 0 . Sodium perborate hydrate
(66.5 g, 0.433 mol) was added to the cloudy s o h , and the suspension was vigorously stirred overnight. The aq. s o h .
was extracted with E t 2 0 (2 x 300 ml), the combined org. phase dried and evaporated, and the residue chromato-
graphed (silica gel, 5% MeOH/CH2C12):29.32 g (98%) of 10. Colorless oil. "x]g= -1.4 (c = 1.55, CHCI,). IR
(neat): 3400, 1730, 1230. 'H-NMR (250 MHz, CDC1,): 5.04 (m, 1 H); 4.02 (td, J = 11.1, 5.4, 1 H); 3.92 (dd,
J = 11.1, 6.3, 1 H); 3.58 ( t , J = 6.5, 2 H); 2.00 (s, 3 H); 1.95 (m, 2 H); 1.64 (s, 3 H); 1.56 (s, 3 H); 1.60-1.42 (series
ofm, 5 H); 1.35 (m, 3 H); 1.18 (m?1 H); 0.83 (d, J = 6.8, 3 H). I3C-NMR (62.5 IMHz, CDCI,): 171.2, 131.3, 124.5,
65.3,62.8,41.5,34.1,33.3,30.7,25.9,25.6,25.3,20.9,17.5, 15.6.MS:241.1823(M+,calc.241.1804).
(5 S)-S-[( I S ) - I,S-Dimethylhex-4-enyl]tetrahydro-2H-pyran-2-one (11). T D a brown soln. of CrO, (39.6 g,
0.396 mol) and 1 S M H2S0, (620 ml, 0.931 mol) in 100 ml of acetone was added within 40 min a soln. of 10 (26.8 g,
0.105 mol) in 1 1 of acetone at 0". The resulting black mixture was stirred vigorously for 3 h. quenched with i-PrOH
(40 ml), and filtered through a pad of Celite. The Celite was washed with acetone (2 x 500 ml). The filtrate was
concentrated under vacuum to remove volatile compounds and treated with a soln. of KOH (56 g, I .O mol) in 100
ml of H 2 0 at 0'. This mixture was vigorously stirred overnight. After acidificaton at 0" with conc. HCI soln., the
s o h . was extracted with Et,O (3 x 500 ml). The combined Et20 phase was dried and evaporated and the residue
dissolved in 1.5 I of benzene, treated with TsOH.H,O (0.2 g), and refluxed for 4 h under a Dean-Stark trap. The
brown s o h . was washed with sat. NaHCO, soln. (100 ml), dried, and evaporated. The yellow residue was purified
by CC (silica gel, 15% Et20/petroleurn ether): 10.22 g (4%) of 11. Colorless liquid. [x]g= -16.2 (c =0.60,
CHCI,). IR (neat): 1745. 'H-NMR (250 MHz, CDCI,): 5.06 (dd, J = 7.0, 5.7, 1 H); 4.33 (ddd,J = 11.0, 4.5, 1.6, 1
H); 4.07 (dd, J = 10.7, 10.3, 1 H); 2.67-2.40 (series of m, 2 H); 2.07-1.88 (series of m,3 H): 1.85-1.56 (series of m,
2 H); 1.68 (s, 3 H); 1.60 (s, 3 H); 1.52-1.33 (series of m,2 H); 1.25-1.10 (series of m, 1 H); 0.92 (d,J = 6.7, 3 H).
"C-NMR (20 MHz, CDCI,): 171.8, 131.9, 124.0, 71.5, 37.8, 34.0, 33.9, 29.4, 25.6, 25.4, 23.1, 17.7, 16.2. MS:
210.1629 (M', calc. 210.1620). Anal. calc. for C13H2202:C 74.24, H 10.54; found: C 74.09, H 10.52.
(3R,5 S/- and ( 3 S,5S j-5-1( I S)-l,5-Dimethylhex-4-enyl]tetruhydro-3-(pitenylseleno)-2H-pyran-2-one(28
and 29, resp.). To 0 . 5 potassium
~ hexamethyldisilazide in toluene (62.9 ml, 0.031 5 mol) dissolved in 100 ml o f T H F
at -78" was added dropwise within 10 min a soln. of 11 (3.00 g, 0.0143 mol) in 25 ml of THF. The mixture was
stirred at -78" for 1.5 h before solid N-(phenylse1eno)phthalimide (NPSP; 4.97 g, 0.0164 mol) was added in one
portion. The white suspension was stirred at -78" for I h before being warmed tc~20"during 2 h, maintained at r.t.
for 1 h, and poured into a mixture of 100 ml of Et20 and 100 ml of H20. The all. phase was extracted with Et,O
(100 ml), the combined org. phase dried and evaporated, and the residue chromatographed (silica gel, 10%
Et,O/petroleum ether): 4.22 g (81%) of 28 and 29 as well as 0.24 g (8%) of recovered 11. Yield 88% based
on unconsumed 11. When I equiv. of base was used, ( S S j - 5 - [ ( 1 S)-l.5-tlimet~iyfhex-4-e~~yl]-tetrahydro-3.3-bis-
(phenylscleno)-2H-pyran-2-one (30) was also isolated in small amounts.
28: Yellow oil. [m]g= -49.1 (c = 1.00, CHCI,). IR (neat): 1730, 1475, 1190. 'H-NMR (250 MHz, CDCI,):
7.63 (m,2 H); 7.29 (m, 3 H); 5.01 (m, 1 H); 4.26 (dd, J = 11.0, 4.4, 1 H); 4.09 (dd, J = 11.0, 10.3, 1 H); 3.95 (dd,
J = 9.0,8.1, 1 H);2.33 (m, 1 H);2.01-1.70(seriesof,n,4H); 1.65 (s,3 H); 1.56(s, 3 H); 1.46-1.21 (seriesofm, 2H);
1.20-1.05 (series of m, 1 H); 0.84 (a', J = 6.8 Hz, 3 H). ',C-NMR (20 MHz, CDCl,): 170.6, 135.2. 131.9, 129.2,
128.8, 127.8, 123.8, 70.8, 38.6, 37.8, 34.2, 33.8, 31.6, 25.6, 25.3, 17.6, 16.0. MS: 366.1158 (M+,calc. 366.1097).
29: Yellow oil. [a]b= -3.2 (c = 0.74, CHCI,). IR (neat): 1740, 1385, 1440, 1230, 1190, 1090. IH-NMR
(CDCI,): 7.68-7.65 (m, 2 H); 7.35-7.28 (m, 3 H); 5.04 (m, 1 H); 4.44 (ddd,J = 11.4. 5.0, 1.7, I H); 4.1 1 (d, J = 11.2,
1 H); 4.04 (dd, J = 4.0, 5.4, 1 H); 2.19-1.97 (series of m, 4 H); 1.90 (m, 1 H); 1.69 (d, J = 1.0, 3 H); 1.60 (s, 3 H);
1.46-1.32 (series of m, 2 H); 1.20 (m, I H); 0.89 (d, J = 6.8, 3 H). I3C-NMR (CDCI,): 170.6, 135.4, 132.0, 129.3,
128.7, 128.3, 123.9, 71.9, 39.4, 35.3, 33.8, 33.7, 31.2, 25.7, 25.2, 17.7, 16.1. MS: 366.1079 (M+,calc. 366.1097).
30: Yellow oil. [ a ] g = -127.1 (c = 0.70, CHC1,). IR (neat): 1720, 1175, 1125. 'H-NMR (250 MHz, CDCI,):
7.77-7.67 (series of m,4 H); 7.49-7.30 (series of m, 6 H); 4.95 (m, 1 H); 4.29 (m, I H); 3.78 (m, 1 H); 2.14-1.77 (series
of rn, 4 H); 1.68 (d, J = 0.9, 3 H); 1.56 (s, 3 H); 1.26, 1.01 (series of m, 2 H); 0.95"l.85 (series of m, 2 H); 0.69 (d,
J = 6.8, 3 H). ',C-NMR (62.5 MHz, CDCI,): 169.6, 137.7, 137.0, 131.9, 130.0, 129.6, 129.09, 129.05, 127.9, 123.8,
72.4.49.0, 38.7, 36.3, 33.7, 33.5,25.6, 25.2, 17.6, 15.9. MS: 522.0570 (M', calc. 522.0576).
( 5 sj - 5 - [ ( 1 S)-l.5-Dimethylhex-4-eny1]-5,6-dihydro-2H-pyrun-2-one (12). To a well stirred s o h . of 29 and 30
(4.53 g, 0.0124 mmol) in 150 rnl CH,CI2 and 3.0 ml(O.0372 mmol) of pyridine was added dropwise a soln. of 30%
H202(2.97 ml, 0.0262 mmol) in 3 ml of H 2 0 at 0". The mixture was stirred at 0" for 30 rnin before being quenched
with 7 %O NaHCO, soh. (100 ml) and extracted with CH2C12(2 x 100 ml). The combined org. phase was dried and
 CHIMICA
HELVETICA ACTA- Vol. 78 (1995) 399
evaporated and the residue chromatographed (silica gel, 50 % Et20/petroleumether): 2.15 g (83%) of 12. Colorless
liquid. [ a ] $ = -1 16.6 (c = 0.79,CHCI,). IR (neat): 1740,1240,1080,830.'H-NMR (CDCI,): 6.84 (dd,J = 9.9,
3.9,1H);6.00(dd,J=9.9,2.0,1H);5.04(m,1H);4.38(ddd,J=11.3,5.3,0.8,1H);4.27(dd,J=11.2,7.2,1H);
2.41 (m. 1 H); 2.06-1.90 (series of m, 2 H); 1.76-1.68 (series of m, 1 H); 1.66 (d,J = 1.0, 3 H); 1.58 (s, 3 H);
1.50-1.39 (series of m, 1 H); 1.30-1.18(series ofm, 1 H); 0.95 (d,J = 6.9,3 H). "C-NMR (CDCI,): 163.8,149.6,
132.1, 123.6,120.9,68.5,38.6,33.9,33.80,25.6,25.4, 17.6,16.3.MS: 208.1476(M+,calc. 208.1464).Anal. calc. for
C,,H,oO,: C 74.96,H 9.68;found: C 75.04,H 9.80.
(4S,5R) -5-[(1 S)-l,5-Dimethylhex-4-enyI]tetrahydro-4- {((isopropoxy)dimethylsilyloxy]methyl)-2H-pyran-
bone (13). To a refluxing suspension of Mg turnings (2.43g, 0.10mol) in 100 ml of THF was added CH,Br, (10
drops) and (chloromethyl)dimethyl(isopropoxy)silane (10 ml, 0.10 mol) over 10 min. The suspension was refluxed
for 1.5 h to form a black-green soh. which was cannulated into a 100-ml flask to remove small particles of Mg
turnings and stored under N,. A soh. of 12 (1.13 g, 0.00543 mol) in 100 ml of dry THF was treated with CuI
(103mg, 0.541 mmol) and MejSiCI (2.0ml, 0.0159 mmol) at 0". To the suspension at 0" was added dropwise within
30 min a 1 . 0 ~soh. of the Grignard reagent (6.7ml, 0.0067 mol). The light yellow soh. was stirred at O0 for 1 h
before 5 ml of Et,N were introduced, followed by H 2 0(50ml). The aq. soh. was extracted with Et,O (3 x 100 ml),
the combined org. extract dried and evaporated, and the residue subjected to MPLC (30% Et20/petroleum ether):
1.4 g(76%) of 13. Colorless liquid. [a]$ = +10.8 ( c = 0.66,CHCI,). IR (neat): 1750,1030,880. 'H-NMR(CDC1,):
5.07 (m, 1 H); 4.24(dd,J = 11.5, 5.0, 1 H); 4.09(dd,J = 11.5, 8.2,1 H); 3.99(sept.,J = 6.1Hz, 1 H); 2.73 (dd,
J = 16.2,6.4,1 H); 2.28 (dd,J = 16.2,8.0,1 H); 2.25-1.71(series ofm, 3 H); 1.68 (s, 3 H); 1.60(s, 3 H); 1.56(m,
lH);1.42-1.22(seriesofm,3H);1.14(d,J=6.1,6H);0.86(d,J=6.9,3H);0.61(m, 1H);0.14(s,6H);O.lO(m,
1 H). I3C-NMR (62.5MHz, CDCI,): 172.7,131.9,124.0,68.1, 65.2,45.9,37.3,35.1, 30.3,25.9,25.8(2C ) , 25.7,
24.4,17.7,14.8,-0.4,-0.6.MS: 340.2462 (M+,calc. 340.2434).
(4S S R)-5- / ( I S)-l,5-Dirnethylhex-l-enyl/~etrahydro-4-
(hydroxymethyl)-2 H-pyran-2-one (14) and (4s) -4.5-
Dihydro-4-/( I R,2S)-I-(hydroxymethyl)-2,6-dimethylhept-5-enyl]furan-2(3H)-one(15). To a soh. of 13 (1 .O g,
2.9 mmol) in DMF (50 ml) was added successively KHF2 (460mg, 5.9 mmol) and 30% H20, s o h (4ml, 35 mmol).
The resulting mixture was heated to 60" with vigorous stirring for 4 h to generate a colorless soln. which was cooled
to 20°, diluted with EtzO (200ml), and washed with sat. NH4C1soh. (100 ml). The aq. phase was acidified with HCI
to pH 1 and extracted with Et,O ( 5 x 100 ml). The combined org. layer was washed in turn with 10% NaHSOj
soln. (200 ml) and H,O (200mi), dried, and evaporated: 730 mg of yellow oil. This material was divided into two
365-mg batches, each of which was diluted with benzene (150 ml) and refluxed under N, in the presence of
toluene-4-sulfonic acid (1 1 mg, 4 mol- %) for 1 h. The cooled mixture was treated with four drops of pyridine,
evaporated, and subjected to MPLC (silica gel, Et,O) to provide 14 (1 10 mg) and 15 (95 mg).
Lactone 15 was immediately taken up in dry CH,CI, (60ml), stirred vigorously with 4-Amolecular sieves
(210mg) and PDC (210mg, 0.56 mmol) for 1.5 h, and diluted with Et,O (200ml). This s o h was filtered through a
thick pad of 4-Asieves and evaporated: 86 mg of pure ( x R,3S)-a-[( I S)-1,5-dimethylhex-4-eny[l-tetrahydro-5-
oxofuran-3-acetaldehyde(16).
Lactone 14 was resubjected to the original isomerization conditions. In this way, 1 g of 13 provided 250 mg
(36% overall) of 16.
Depending on the purity of 13, small quantities of the epimeric (c( R,3R)-x-[(IS)-l,5-dimethylhex-4-enyl]-
tetrahydro-5-oxofuran-3-acetaldehyde(17) were obtained.
14: Colorless oil. IR (neat): 3400,1740.'H-NMR (CDCI,): 5.07 (m, 1 H); 4.23 (dd,J = 11.5,5.0, 1 H); 4.12
(dd,J= 11.5,8.3, 1 H); 3.66(dd,J= 10.6,4.4, 1 H);3.53(dd,J= 10.6,6.6, 1 H);2.57(d,J=6.6,2H); 2.11-1.95
(series of m, 3 H); 1.69 (s,3 H); 1.61(s, 3 H); 1.43(m, 2 H); 1.34-1.21(series of m, 2 H); 1.23 (br. s, 1 H); 0.93(d,
J = 6.8,3 H). ' k - N M R (CDCI,): 173.3,132.1, 123.9,67.9, 65.5,39.2,36.5,34.7,33.9,31.8,25.8,17.7,15.6.MS:
222.1632 ( [ M - HzO]+,calc. 222.1619).
15: Colorless oil. IR (neat): 1780. 'H-NMR (CDCI,): 5.07(m, 1 H); 4.43 (m, 1 H); 3.97 (m, 1 H); 3.76 (dd,
J=10.7,4.6,1H);3.67(m,1H);2.76-2.56(seriesofm,2H);2.46(m,1H);2.01(m,2H);1.70(d,J=4.5,3H);
1.62(d,J = 4.5, 3 H); 1.52-1.34(series of m, 4 H); 1.27 (br. s, 1 H); 0.90 (d,J = 6.5, 3 H). "C-NMR (CDCI,):
177.5,132.0,124.0,72.6,61.9,47.5, 37.1,35.3,33.7,32.7,26.0,25.7,17.7,15.6.MS: 222.1613([M-H,O]+,calc.
222.1619).
16: Colorless oil. [ a ] E = -32.7 (c = 1.8, CHCI,). IR(CHC1,): 1740,1730.'H-NMR (CDCI,): 9.78(d,J = 1.8,
1 H); 5.08 (m. I H); 4.42(dd,J = 7.8,9.0,1 H); 3.94 (t,J = 9.0,1 H); 2.95 (m, 1 H); 2.78 (dd,J = 8.3,17.1,1 H);
2.48 (ddd,J= 1.8, 3.8,10.0, 1 H);2.14(dd,J=9.9,17.5,1 H); 2.15-1.95 (m,2H); 1.70(d.J= 1.0,3 H); 1.62(s,
3H);1.52-1.35(seriesofm,3H);0.97(d,J=7.0,3H).'3C-NMR(CDCI3):202.8, 176.3,132.6,123.1,70.9,58.8,
15.8.MS:238.1568(Mi,calc.238.1568).
35.2,33.4,33.1,32.5,25.7,25.6,17.7,
400 HELVETICA ACTA Vol. 78 (1 995)
CHIMICA -

17: Colorless liquid. [ a ] g = -17.5 (c = 1.5, CHCI,). IR (CHCI,): 1750, 1730. 'H-NMR (CDCI,): 9.75 (d,
J = 1.7, 1 H); 5.04 (m, 1 H); 2.41 (ddd, J = 1.7,3.7, 10.1, I H ) ;2.18 (dd, J = 10.4, 17.3, 1 H); 2.15-1.87 (series ofm,
2 H); 1.69 (s, 3 H); 1.60 (s, 3 H); 1.55-1.32 (series of m, 3 H); 1.11 (d, J = 7.0, 3 H). I3C-NMR (CDCI,): 202.4,
176.2, 132.8, 123.1, 71.1, 60.0, 33.3, 33.2, 33.0, 31.9, 25.72, 25.68, 17.8, 17.1. MS: 239.1638 ( [ M + H ] + ,calc.
239.1647).
Conversion of16 to 18-20. A soh. of 16 (5.8 mg, 0.024 mmol) in dry benzene (3 ml) was treated with a crystal
of toluene-4-sulfonic acid, stirred at r.t. for 3 h, washed with H20, dried, and evaporated: 5.7 mg (98%) of
(4 S)-4,5-dihydro-4-[ ( I R.6S)-2-hydroxy-3-isopropenyl-~-methylcyclohex.~l]fuian-2(3H)-one (18). Colorless oil.
IR(CHC13):2900, 1780. 'H-NMR(CDC1,): 5.01 (s, 1 H);4.84(s, 1 H);4.48(t,.I = 8.1, 1 I1);3.94(t.J = 8.1, 1 H);
3.75(s, 1 H); 3.14-3.04(m, 1 H);2.70(dd,J = 8.1, 17.0, 1 H);2.26(dd.J = 11.0, 17.0, 1 H);2.00(d.J= 12.4,l H);
1.92-1.70(m, 1H); 1.79(s,3H); 1.62-1.48(m,4H); 1.47-1.30(m,2H); l.10(d,J=7.3,3H).MS:238.1549(Mf,
calc. 238.1569).
A soln. of 16 (10.7 mg, 0.045 mmol) in MeOH (2 rnl) was treated with K,CO, (6 mg, 0.045 mmol), stirred at r.t.
for 40 min, diluted with CH2CI,, washed with sat. NH4CI soln. (3 x 10 ml), dried, and evaporated: 10.3 mg (85%)
of (ci R,3S)-ci-[ ( I S)-I,5-dimethylhex-4-enyl]tetrahydro-5-oxafuran-3-acetaldehyde 3-(methyl herniacetal) (19).
Colorless oil. IR (CHCI,): 1760. IH-NMR (CDCI,): 5.24 (br. m, 1 H); 5.10 (b.r. t, J = 7.1, 1 H); 4.16 (I, J = 8.4,
1 H);3.75(t,J = 8.4, 1 H); 3.68(s, 3 H);2.64(dd, J = 4.7, 16, 1 H); 2.50(dd,J ==9.1,1.6, 1 H ) ; 2.15-1.85(m, 3H);
1.85-1.73(m,1H);1.68(s,3H);1.60(s,3H);1.50-1.30(m,1H);1.25-1.10(m,1H);1.25-1.10(rtl,3H);0.93(d,
J=6.7,3H).MS:270.1833(M+,calc.270.1831).
A soln. of 16 (1 1.5 mg, 0.048 mmol) in dry benzene (1 ml) was treated with DBU (22 pl, 0.15 mmol), refluxed
for 48 h, cooled to 20°, diluted with CH2C1,, washed with NH&I soh., dried, and evaporated: 10 mg (87%) of
16/20 1: I . Although these epimers could not be chromatographically separated, they were easily distinguished
by 'H-NMR. ( a S.3S)-a-[ (I S)-1,5-Dimethylhex-4-enyl]tatrahydro-5-oxafura1i-3-aldehyde (20): 'H-NMR (300
MHz, CDCI,): characteristic peaks at 9.80 (d, J = 1.7, 1 H); 1.16 (d, J = 7.1, 3 IH) (16: 9.78 (d, J = 1.8, 1 H); 0.97
(d,J = 7.0, 3 H)).
(4 S.5 R.6 R) -5 -[(I S)- 15-Dimethylhex - 4- enyl] tetrahydro- 4- (hydroxymethyl) -6-[(phenylseleno)methyl]-
2H-pyran-2-one(21). A 0.05~ soh. ofPhSeCH,Li in THF was prepared by adding 1 . 6 ~ BuLi in cyclohexane (0.83
ml, 1.37 mniol) to a soln. of bis(phenylse1eno)methane (447 mg, 1.37 mmol) in dry THF (26 ml) at -78O under N,
and stirring at this temp. for 45 min. A 9.8 ml(0.49 mmol) aliquot of this soln. was slowly introduced via syringe
during 2.5 h to a s o h . of 16 (100 mg, 0.42 mmol) in THF (100 ml) at -7P. The mixture was vigorously stirred at
-78O for 1 h. Sat. NH4CI soln. was introduced and the org. phase washed with brine, dried, and evaporated. FC
(silica gel, Et20/petroleumether 4:6) of the residue provided 21 (85 mg) as a colorless oil and 45 mg of unreacted 16.
Yield of 21 based on recovered 16,90%. IR (neat): 3480, 1750, 1075. 'H-NMR i:CDCI,): 7.54 (m, 2 H); 7.26 (m, 3
H);4.98(m, IH);4.38(m, 1H);3.55(m,1H);3.40(m,1H);3.24(m,1H);3.1~!(dd,J=6.7,13.1,1H);2.65(m,
2 H); 2.42 (m, 1 H); 2.12 (m, 1 H); 2.02 (m, 1 H); 1.76 (m, 1 H); 1.67 (s, 3 H); 1.57(s, 3 H); 1.64-1.46 (series of m, 1
H); 1.26(m,2H); 1.13(m, lH);0.88(d,J=6.8,3H). I3C-NMR(CDC1,): 173.0, 133.3, 132.1, 129.9, 129.2, 127.4,
123.8, 78.5, 65.9,43.7, 34.6, 33.5, 31.9,31.8, 31.4,25.7, 17.7, 17.0. MS:410.1399(M+,calc. 410.1360).
(4s) -4,5-Dihydr0-4-[(1 R,2S) - I-( (I R) -I-hydroxy-2- (phenylseleno)ethyi]-2,6-dim~thylhept-S-enyl]furan-
2(3H)-one (22). A soh. of 21 (434 mg, 1.1 mmol) in benzene (434 ml) containing toluene-4-sulfonic acid (8 mg,
4 mol-%) was refluxed for 1 h, cooled to r.t., treated with 4 drops of pyridine, ansi evaporated. FC (silica gel, 10%
petroleum ether/Et,O) of the residue provided 245 mg of 22a and 147 mg of unreacted 21. 22a: IR (neat): 3500,
1780. 'H-NMR (CDCI,): 7.51 (m, 2 H); 7.29 (m, 3 H); 4.97 (m, 1 H); 4.36 (I, J = 8.2, 1 H); 4.00 (dd, J = 8.6, 10.1,
1H);3.68(m, 1 H);3.12(dd,J=3.3, 12.7, 1H);2.99-2.70(m,2H);2.67-2.50(m,2H);2.34(dd,J=11.4, 17.0,
I H); 1.90 (m, 2 H); 1.68 (d, J = 0.9, 3 H); 1.57 (m, 3 H); 1.50-1.30 (m. 1 H); 1 32-1.23 (m, 1 H); 1.08 (m, 1 H);
0.96-0.93 (m, 1 H); 0.89 (d, J = 6.9,3 H). I3C-NMR (CDCI,): 177.4, 133.3, 132.0, 129.4, 128.9, 127.7, 123.8,73.1,
67.9,49.7, 37.8, 34.4, 34.0, 33.0,25.9,25.7, 16.2. MS:410.1399(M+,calc.410.1360).
(4S)-4,5-Dihydro-4-[ (1 R,2S)-I-f (I R/-l-(I-methoxy-I-methylethoxy)-2-(~~henylseleno)ethyl]-2,6-dimethyl-
hept-5-enyl]furan-2(3H)-one (22b). The sample of 22a produced above was immediately taken up in 2-
methoxypropene (5 ml) and stirred at 20" for 6 h in the presence of 1 drop of POC1,. At this point, Et,N (4 drops)
was introduced and the mixture evaporated. FC (silica gel, petroleum ether/Et20 7:3 containing 5 % of Et,N) of the
residue gave 22b (250 mg, 74% overall). Colorless oil. [a]? = -53.2 ( c = 1.2, CHCI,). IR (CHCI,): 1780.
'H-NMR (CDCI,): 7.54-7.49 (m, 2 H); 7.30-7.23 (m, 3 H); 5.05 (m, 1 H); 4.39 (I J = 8.3, 1 H); 3.94 (dd, J = 8.8,
10.4, 1 H); 3.51 (dd, J = 3.6, 12.6, 1 H); 3.23 (3, 3 H); 2.99-2.85 (m, 2 H); 2.58 (dd, J = 8.0, 17.0, 1 H); 2.32 (dd,
J = 12.0, 17.0, 1 H); 2.07-1.90 (series ofm, 4 H); 1.70 (d, J = 1.0, 3 H); 1.61 (s, 3 H); 1.52-1.35 (series ofm, 3 H);
l.29(s,3H);1.27(.~,3H);0.85(d,J=6.9,3H).'3C-NMR(CDCI,): 177.4,133.1,131.9,129.7,129.2,127.3,124.1,
 HELVETICA
CHIMICA
ACTA- Val. 78 (1995) 40 1

101.3, 72.9, 70.8, 48.9, 47.1, 35.7, 35.1, 34.7, 32.8, 32.2, 26.1, 25.9, 25.7, 24.5, 17.7, 16.2. MS: 449.1607
( [ M - MeOHJ+, calc. 449.1595).
(3S,4R)-4,S-Dihydro-3-[(l'Sand l'R,2E)-l'-hydroxybut-2'-eny1]-4- { ( I R.2S)-I-[(IR)-I-(I-methoxy-I-
methylethoxy)-b (phenylseleno)ethyl]-2,6-dimethylhept-S-enyltfuran-2(3H)-one (23). A cold (OO), magnetically
stirred soln. of (i-Pr),NH (0.28 ml, 2 mmol) in THF (85 ml) was treated slowly with 1 . 6 ~ BuLi in cyclohexane
(1.23 ml, 2 mmol), stirred for 45 min, and cooled to -78". A soln. of 22b (730 mg, 1.5 mmol) in dry TH F was added
dropwise and the mixture stirred for 2 h before crotonaldehyde (2.27 ml, 9 mmol) as a 4~ s o h in TH F (dried over
sieves) was introduced. After quenching with sat. NH,CI soln., the phases were separated. The aq. layer was twice
extracted with Et20 and the combined org. so h . washed with sat. NH,CI soln., dried, and evaporated: 570 mg of
yellow oil. This material was customarily subjected directly to acid-catalyzed cyclization. MPLC purification (silica
gel, petroleum ether/Et206:4) gave the two pure epimers of 23.
(I'S.2'Ej-23: 'H-NMR (CDCI,): 7.57-7.51 (m, 2 H); 7.30-7.23 (m, 3 H); 5.87-5.76 (m, 1 H); 5.69 (dd,
J = 16.4,7.0, I H); 5.09(m, 1 H);4.63 (t, J = 9.4, I H);4.25 (m, 1 H);4.21 ( t , J = 9.3, 1 H); 3.93 (dd,J = 2.7, 11.3,
1H);3.59(dd,J=2.9,9.7,1H);3.21(s,3H);2.92-2.75(m,2H);2.57(dd,J=5.9,10.2,1H);2.07(m,4H);1.77
(d, J = 6.3,3H); 1.71 (s, 3H); 1.63(s, 3H); 1.52-1.35(seriesofm, 3 H); 1.26(s,3 H); 1.24(s, 3H);0.86(d,J = 6.9,
3 H). ',C-NMR (CDCl,): 178.2, 133.4, 132.2, 130.3, 130.2, 129.9, 129.2, 127.4, 123.9, 101.3, 73.0, 72.3, 70.3, 48.6,
48.4,43.9, 37.12, 37.09, 30.8, 30.0, 29.7,25.9, 25.72, 25.65,24.2, 18.0, 17.9. MS: 552.2365 (M+,calc. 552.2354).
(l'R,2'E)-23: 'H-NMR (CDCI,): 7.69-7.51 (m, 2 H); 7.31-7.24 (m, 3 H); 5.85-5.73 (m, 1 H); 5.52 (dd,
J = 7.4, 15.2, 1 H); 5 . 0 8 ( ~ 11, H);4.42(t.J ~ 9 . 11, H);4.20(t,J =9.3, 1 H);3.93(dd,J = 2.7, 11.2, 1 H);3.61 (dd,
J = 2.9, 12.5, 1 H); 3.21 (s, 3 H); 3.00-2.75 (m, 3 H); 2.70 (dd, J = 3.8, 10.7, 1 H); 2.10-1.95 (m. 3 H); 1.74 (dd,
J = 0.9,6.3,3 H); 1.71 (s, 3 H); 1.64(s, 3 H); 1.52-1.35 (series ofm, 4H); 1.26(s, 3 H); 1.24 (s, 3 H); 0.89 (d,J = 6.7,
3 H). ',C-NMR (CDCI,): 178.5, 133.3, 132.2, 130.0, 129.9, 129.2, 129.1, 127.4, 123.8, 101.3, 72.0,71.6,70.6,48.6,
48.5,43.5, 37.1, 36.0, 30.8, 29.69, 29.65,25.9, 25.6, 24.1, 17.9. MS: 552.2346(Mf,calc. 552.2354).
Acid-Catalyzed Cyclization of 23. The 570-mg sample of 23 produced above was dissolved in benzene (500 ml),
treated with 30 mg (10 mol-%) of toluene-4-sulfonic acid, refluxed for 2 days, and cooled to r.t. A few drops of
pyridine were added, and the solvent was evaporated. The residue was purified by MPLC (silica gel, petroleum
ether/Et204:l): 240 mg (34%) of 24 and 260 mg (37%) of 25.
When the (l'R,Z'E)- and (l'S,2'E)-23 were individually treated in analogous fashion, stereospecific conver-
sion to 24 and 25, respectively, occurred.
(3a S,4 S.6SS7S,7aS)-7-[(I S) -I.S-Dimethylhex-4-enyl]- I .3~,4.6,7,7a-lzexuhydro-4-(prop-2-enyl)-6- (phenyl-
thio)-3H-furo[3,4-c]pyran-3-one(24): Colorless oil. [a]? = -70.7 (c = 3.1, CHC1,). IR (CHCI,): 1740. 'H-NMR
(CDCI,): 7.54-7.50 (m, 2 H); 7.36-7.32 (m, 3 H); 5.98-5.88 (m, 1 H); 5.50-5.43 (m. 1 H); 4.99 (m, 1 H); 4.84 (m.
1H);4.46(dd,J=6.5,8.4,1H);3.94(dd,J=8.4,10.5,1H);3.86(ddd,J=3.0,9.0,1H);3.24(dd,J=3.0,9.0,
1H);3.07(dd,J=7.5,9.0,1H);2.60(dd,J=5.0,13.5,1H);2.43(dddd,~=l3.5,11.5,6.5,10.5, 1H);2.16-1.92
(m, 1 H); 1.90-1.77(m, 1 H); 1.74(dt.J = 6.6, 1.6, 3 H); 1.69-1.60(seriesofm, 2H); 1.65 ( d , J =0.8,3 H); 1.58 (s,
3 H); 1.33 (m, 1 H); 1.10(m, 1 H);0.85(d.J = 7.0, 3H). J(3a,4) = 5, J(3a,7a) = 13.5,J(6,7)= 9.5,J(7,7a) = 11.5.
',C-NMR (CDCI,): 173.6, 132.9, 132.4, 131.5, 130.8, 129.0, 126.9, 124.2, 123.6, 71.8, 71.5, 70.8, 51.7, 47.1, 36.9,
32.3,32.1,31.7,25.8,25.8,25.6,19.2,18.1, 17.7.MS:462.1674(M+,calc.462.1673).
(3uS,4 R,6 S,7S,7a S)-7-[ (1 S)-l,S-Dimethylhex-4-enyl]-1.3a,4,6.7,7a-hexahydro-4-(prop-2-enyl)-6-(phenyl-
thio)-3H-furo[3,4-c]pyran-3-one(25): Colorless oil. [a12 = -13.9 (c = 2.0, CHCI,). IR (CHCI,): 1780. 'H-NMR
(CDCI,): 7.57-7.50 (m, 2 H); 7.28-7.21 (m,2 H); 5.85-5.71 (m, 2 H); 4.99 (m, 1 H); 4.45 (dd,J = 8.4,6.1, 1 H); 3.94
(m. 2 H); 3.63 (ddd. J = 3.0, 7.0, 9.5, 1 H); 3.28 (dd, J = 3.0, 9.5, 1 H);3.14 (dd, J = 7.0, 9.5, 1 H); 2.29 (dddd,
J = 6.5, 10.5,11.5,13.0,1 H); 2.08 (dd,J = 9.5,13.0, 1 H); 2.08-1.98 (m. 1 H); 1.96-1.78 (m, 1 H); 1.74 (dd,J = 1.0,
5.9, 3 H); 1.73-1.60 (series of m, 2 H); 1.64 (d, J = 0.5, 3 H); 1.57 (s, 3 H); 1.35 (m, I H); 1.10 (m, 1 H); 0.87 (d,
J = 7.1, 3 H). J(3a,4) =9.5, J(3a,7a) = 13, J(6,7) = 9.5, J(7,7a) = 11.5. 13C-NMR (CDCI,): 173.2, 133.0, 132.5,
131.0, 129.0, 128.6, 127.2, 126.9, 123.6,78.2,77.4, 70.9, 50.5,48.4,43.0,32.1, 31.7, 31.6,25.8,25.6, 19.1, 17.9, 17.7.
MS: 462.1674 ( M + ,calc. 462.1673).
(3a R. 4 R. 7R, 9aR) -4- [ ( I S ) - Dimethylhex-4- enyl]-3a,6,7,9a- tetrahydro - 7-methylcycloocta[c]furan- 1.5-
(3H.IH)dione (26). To a soln. of 25 (40 mg, 0.50 mmol) in MeOH (1 5 ml) and H 2 0(2 ml) was added sequentially
Na2C03(47 mg, 0.56 mmol) and NaIO, (140 mg, 0.67 mmol). The heterogeneous mixture was stirred for 30 min,
diluted with H20, and extracted with CH2CI,. The separated org. phase was dried and evaporated. The residual
selenoxide was dissolved in dry mesitylene (48 ml), treated with Et2NH (0.21 ml, 2 mmol), and refluxed in an open
vessel for 20 min. The cooled mixture was directly chromatographed (silica gel, petroleum ether (removal of
mesitylene), then petroleum ether/Et,O 7:3): 26 (120 mg, 80% overall). Colorless solid. M.p. 170° (from petroleum
ether). [tl]d= +71.3 (c = 0.83, CHCI,). IR (CHCl,): 1780, 1710. 'H-NMR (CDCI,): 5.71-5.57 (m, 2 H); 5.04 (m,
1 H);4.42(dd,J = 7.0, 9.0, 1 H); 3.90(dd.J =8.9, 11.2, 1 H); 3.24(dd.J = 5.9, 12.7, 1 H); 3.08-3.00(seriesofm,
402 HELVETICA
CHIMICA
ACTA- Val. 78 ( 1 995)

2 H ) ; 2 . 7 8 ( d d , J = 5 . 2 , 12.1, lH);2.45-2.33(m,l H);2.21 (t,J=12.6,1H);2.07-1.94(seriesofm,3H);1.69(d,

J = 1.0, 3 H ) ; 1.61 (s, 3 H ) ; 1.35-1.20 (series o f m , 2 H ) ; 1.17 (d,J = 6.5, 3 H); 1.07 (d, J = 6.9, 3 H ) . NOE: irrad.
at Hp-C(3) + 3 % at H-C(9a); irrad. at H-C(9a) + 8% at Hl-C(4), 8 % at H,$-C(7). "C-NMR (CDCI,): 210.7,
176.4, 139.9, 132.2, 123.8, 123.5, 69.8, 58.0, 54.9, 45.5, 42.8, 35.1, 34.4, 29.5, 25.9, 25.7, 20.6, 17.7, 14.6. MS:
304.2035 ( M + ,calc. 304.2038). Anal. calc. for C19H2803: C 74.96, H 9.27; found: C 74.70. H 9.35.

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