A modular enantioselective approach to construction of the macrolactone core of polycavernoside A

Article abstract of DOI:10.1021/jo981083t

A program directed toward a total synthesis of polycavernoside A is described. The synthesis of five building blocks is detailed. The first of two electrophilic units, the lactone 3, was prepared in four steps from the known enantiomerically pure oxirane 15. Pyranyl aldehyde 5 was elaborated in turn from L-malic acid via 10. While the route to 30 involved 3 as a starting material, dithiane 2 was obtained in a straightforward manner from 10 as well. The merging of the chiral sectors could not be accomplished by way of the lithiated dithianyl anions, presumably as a consequence of their heightened basicity. The strategic incorporation of the trienyl sector was accomplished, although no attempt was made to control the diastereoselectivity of the process.

Full text of DOI:10.1021/jo981083t

J . Org. Chem. 1998, 63, 7389-7398
7389
A Mod u la r En a n tioselective Ap p r oa ch to Con str u ction of th e
Ma cr ola cton e Cor e of P olyca ver n osid e A
Leo A. Paquette,* Dmitri Pissarnitski, and Louis Barriault
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
Received J une 8, 1998
A program directed toward a total synthesis of polycavernoside A is described. The synthesis of
five building blocks is detailed. The first of two electrophilic units, the lactone 3, was prepared in
four steps from the known enantiomerically pure oxirane 15. Pyranyl aldehyde 5 was elaborated
in turn from L-malic acid via 10. While the route to 30 involved 3 as a starting material, dithiane
2 was obtained in a straightforward manner from 10 as well. The merging of the chiral sectors
could not be accomplished by way of the lithiated dithianyl anions, presumably as a consequence
of their heightened basicity. The strategic incorporation of the trienyl sector was accomplished,
although no attempt was made to control the diastereoselectivity of the process.
The red alga Polycavernosa tsudai is a delicacy widely
consumed in the Far East. When several Guam natives
died suddenly following its ingestion in April 1991,
immediate attempts were launched to identify the re-
sponsible toxin. Shortly thereafter, Yasumoto succeeded
in characterizing polycavernoside A (1) as one of the
principal risk factors.1 Other structurally related me-
tabolites originating from the same source were later
reported.2 Since the production of these toxins is sea-
sonal and they are expressed in vanishingly small
F igu r e 1.
quantities, only planar representations of these archi-
sidic linkages were selected on the basis of their regular
appearance in macrolide antibiotics.7
tecturally unusual macrolide disaccharides were initially
defined. Insufficient material was initially available with
which to elucidate absolute stereochemistry.
These conclusions have been reinforced by the work
of Murai, whose group has prepared several disaccha-
rides8 and concluded that this segment of 1 must be
defined by a combination of D-xylose and L-fucose or the
enantiomers thereof.9 Their efforts have also extended
to the tetrahydrofuran10 and tetrahydropyran compo-
nents11 of the polycavernoside structure.12
Although the carbon backbone of 1 deviates from that
resident in known macrocyclic lactones, some similarity
with the smaller trioxadodecane subunit of the aplysia-
toxins3 has been noted.1 J ohnston, while working in this
laboratory,4 has pointed out the considerable structural
homology between an “unraveled” view of polycaverno-
side A and the Celmer model of macrolide stereostruc-
ture5 (Figure 1). We arrived at a working model for the
absolute configuration of 1 (as shown) on this basis and
Resu lts a n d Discu ssion
As a continuation of our efforts directed toward the
development of methodology relevant to the total syn-
thesis of the polycavernoside toxins, we have addressed
two retrosynthetic pathways defined as A and B in
Scheme 1. The two routes share in common the expecta-
tions that the conjugated trienyl side chain will be
amenable to incorporation by 1,2-addition to a suitable
aldehyde precursor and that introduction of the disac-
(4) J ohnston, J . N. Ph.D. Dissertation, The Ohio State University,
1997.
(5) Celmer, W. D. Pure Appl. Chem. 1971, 28, 413.
(6) J ohnston, J . N.; Paquette, L. A. Tetrahedron Lett. 1995, 36, 4341.
The stereochemistry depicted for 1 in this paper was that tentatively
proposed by Yasumoto.1
(7) (a) Celmer, W. D. J . Am. Chem. Soc. 1965, 87, 1799. (b) Celmer,
W. D. J . Am. Chem. Soc. 1965, 87, 1801.
(8) Fujiwara, K.; Amano, S.; Murai, A. Chem. Lett. 1995, 191.
(9) Fujiwara, K.; Amano, S.; Murai, A. Chem. Lett. 1995, 855.
(10) Hayashi, N.; Mine, T.; Fujiwara, K.; Murai, A. Chem. Lett. 1994,
2143.
have previously described an enantioselective synthesis
of its disaccharide component.6 The R-L- and â-D-glyco-
(11) Fujiwara, K.; Amano, S.; Oka, T.; Murai, A. Chem. Lett. 1994,
2147.
(12) For additional synthetic work in this area, see: Robarge, L.
A.; Wardrop, D. J .; White, J . D. Abstracts of Papers, 213th National
Meeting of the American Chemical Society, San Francisco, CA;
American Chemical Society: Washington, DC, 1997; Abstract 557.
(1) Yotsu-Yamashita, M.; Haddock, R. L.; Yasumoto, T. J . Am.
Chem. Soc. 1993, 115, 1147.
(2) Yotsu-Yamashita, M.; Seki, T.; Paul, V. J .; Naoki, H.; Yasumoto,
T. Tetrahedron Lett. 1995, 36, 5563.
(3) Kato, Y.; Scheuer, P. J . J . Am. Chem. Soc. 1974, 96, 2245.
S0022-3263(98)01083-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/01/1998

7390 J . Org. Chem., Vol. 63, No. 21, 1998
Paquette et al.
Sch em e 1
charide unit via the preformed phenylthio derivative6 will
be serviceable. Beyond that, the building blocks 2 and 3
are distinguished from 5 and 6 in terms of their projected
use as electrophilic or nucleophilic reaction partners. The
anticipated successful conjoining of the major structural
segments within 1 by the coupling of lithiodithianes to a
carbonyl compound was founded on several literature
reports.13-15 The feasibility of directly producing R-keto
thioacetals such as 7 and 8 by condensation with esters
and lactones was of particular interest.
The general guidelines to be followed in plan A were
to implement the coupling of 2 to 3 in advance of the in-
troduction of an acetic acid moiety at the anomeric center
and ensuing macrolactonization. For plan B, consider-
ations based on functional group compatibility suggested
that 5 might be constituted of the full complement of
carbon atoms from the outset, although the opportunities
for â-oxido elimination would be enhanced accordingly.
attempts to transform 9 into the p-methoxybenzyl-
protected derivative 10 via base-promoted alkylation via
the chloride could not be successfully implemented,
recourse was made instead to use of the trichloroace-
timidate under mildly acidic conditions (Scheme 2).17
Arrival at 10 in this manner made possible chemoselec-
tive Dibal-H reduction to the lactol and protection as the
methyl acetal. When the latter transformation was
performed with silver(I) oxide and methyl iodide at the
reflux temperature,18 only the â-anomer 11 was iso-
lated.19 Since this stereoisomer does not conform to
expectations based on the anomeric effect, this quite
satisfactory route clearly operates under kinetic control.
Following desilylation to give 12, attempts were made
to implement the one-step conversion of this alcohol to
iodide 14 by employing the triphenylphosphine-iodine
reagent. However, this protocol was accompanied by
significant byproduct formation. For this reason, opti-
mum yields and improved selectivity were realized by the
two-step route involving SN2 displacement by iodide ion
on mesylate 13. The intermediacy of 14 was warranted
since its condensation with lithio 1,3-dithiane proceeded
satisfactorily when promoted by Schlosser’s base.20 Com-
parable studies on mesylate 13 were not productive.
Ar r iva l a t 3. Synthesis of the lactone subunit 3 was
initiated by structural modification of (R)-(-)-pantolac-
(13) Fujisawa, T.; Kojima, E.; Itoh, T.; Sato, T. Chem. Lett. 1985,
1751.
(14) Flores-Parra, A.; Khuong-Huu, F. Tetrahedron 1986, 42,
5925.
(15) Blarer, S. J . Tetrahedron Lett. 1985, 26, 4055.
(16) Fukui, M.; Okamoto, S.; Sano, T.; Nakata, T.; Oishi, T. Chem.
Pharm. Bull. J pn. 1990, 38, 2890. We thank Dr. Tadashi Nakata of
RIKEN for providing us with experimental details for this 10-step
procedure.
(17) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron
Lett. 1988, 29, 4139.
(18) Greene, A. E.; Le Drian, C.; Crabbe´, P. J . Am. Chem. Soc. 1980,
102, 7583.
(19) This lactol proved unreactive to acidic methanol at room
temperature. Warming of such solutions led to decomposition.
(20) J ones, A. B.; Villalobos, A.; Linde, R. G., II; Danishefsky, S. J .
J . Org. Chem. 1990, 55, 2786.
Syn th esis of 2. The targeted precursor to 2 was
lactone 9, previously prepared in enantioselective fashion
by Fukui and co-workers from L-malic acid.16 When

Macrolactone Core of Polycavernoside A
J . Org. Chem., Vol. 63, No. 21, 1998 7391
Sch em e 2a
that attempts to achieve the complete consumption of 17
resulted in unwanted R,R-dimethylation. The compro-
mise position was to allow monoalkylation to proceed to
approximately the 80% level and to recycle the uncon-
sumed 17. The methylation step reveals a high level of
stereocontrol in that only the â-isomer 18 is formed as a
consequence of the presence of a bulky side chain at C-5.
Advantage could be taken of this steric bias to orient the
methyl on the R surface as in 3. Formation of the lithium
enolate and ensuing protonation with ammonium chlo-
ride was equally stereoselective and gave rise exclusively
to 3.
P r ep a r a tion of 5. Following a series of preliminary
experiments, the method of choice for stereocontrolled
introduction of an acetic acid unit into 10 was considered
to be that devised by Kishi,23 despite accompanying loss
of the p-methoxybenzyl protecting group. Thus, treat-
ment of 10 with lithio ethyl acetate gave the aldol adduct
19 in 70% yield as a single major anomer (1H NMR
analysis) (Scheme 4). Reduction of 19 with triethylsilane
and titanium tetrachloride in CH2Cl2 cleanly furnished
20 as a consequence of exclusive hydride delivery to the
oxonium ion from the axial direction. No conditions were
found that arrested the concomitant unmasking of the
4-hydroxy substituent. In light of this development, it
proved somewhat more expeditious to advance to 20 via
the preliminary trimethylsilation of 9.
Following reintroduction of the PMB protecting group
and liberation of the primary carbinol as in 22, the stage
was set to carry out the proper homologation of this side
chain. Oxidation with the Dess-Martin periodinane24
provided 23 without any evidence of epimerization.
Equally uneventful was the subsequent Wittig olefination
with (methoxymethyl)triphenylphosphorane.25 Finally,
liberation of the acetaldehyde unit as in 5 by hydrolysis
with 1 M HCl in THF was accomplished in 45% overall
yield.
a
Key: (a) PMBOC(dNH)CCl3, (TfOH), ether; (b) (i-Bu)2AlH,
CH2Cl2, -78 °C; (c) Ag2O, CH3I, reflux; (d) (n-Bu)4N+ F-, THF;
(e) CH3SO2Cl, Et3N, CH2Cl2, -10 °C; (f) (n-Bu)4N+ I-, C6H6, reflux;
(g) 1,3-dithiane, 1:1 n-BuLi/KO-t-Bu, 2:1 THF/hexanes, -78 °C.
Sch em e 3a
Th e Rou te to 30. It was recognized that the config-
uration at C-3 in 3 and the relationship of this center to
that at C-5 mapped well with the requirements of the
two stereogenic centers in 30. Successful implementation
of a strategy that would lead from 3 to 30 would require
reductive cleavage of the lactone ring, permutation of the
terminal silyl ether to a vinyl group, and appropriate
protecting group modification.
A satisfying resolution of these requirements began by
Dibal-H reduction of 3 to γ-lactol 24 (Scheme 5). Ap-
plication of the TiCl4-mediated procedure for the dithio-
ketalization26 of this masked hydroxy aldehyde produced
25 efficiently (93%). Following chromatographic purifi-
cation, the interchange of hydroxyl protection groups was
achieved by conversion of 25 to diol 26, formation of
p-methoxybenzylidene acetal 27, and reduction with
Dibal-H.27 With generation of 28 as the very major
product, a primary hydroxyl group was made available
for oxidation to aldehyde 29 under Swern conditions.28
a
Key: (a) TBDPSCl, imid, CH2Cl2; (b) CH2dC(OLi)OLi (9
equiv), DME, reflux; H3O+; (c) LiHMDS, THF, -78 °C; CH3I; (d)
LDA, THF, -78 °C; NH4Cl.
tone to give 15 as earlier described by Lavalle´e et al.21
Silylation of this epoxy alcohol under conditions designed
to generate a reasonably robust Si-O bond afforded 16
(Scheme 3). The structural features of this intermediate
are particularly conducive to regiocontrolled nucleophilic
attack by dilithioacetate.22 This strongly basic reagent
is tolerant of the tert-butyldiphenylsiloxy group, but not
of the TBDMS equivalent. Beyond that, 1,2-dimethoxy-
ethane is the solvent of choice. When THF was utilized,
considerable decomposition was encountered and only
40% of 17 could be isolated.
(22) Creger, P. L. J . Org. Chem. 1972, 37, 1907.
(23) Lewis, M. D.; Cha, J . K.; Kishi, Y. J . Am. Chem. Soc. 1982,
104, 4976.
(24) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. (b)
Ireland, R. E.; Liu, L. B. J . Org. Chem. 1993, 58, 2899.
(25) (a) Wittig, G.; Schlosser, M. Chem. Ber. 1961, 94, 1373. (b)
Wittig, G.; Bo¨ll, W.; Kru¨ck, K.-H. Chem. Ber. 1962, 95, 2514.
(26) Bulman-Page, P. C.; Roberts, R. A.; Paquette, L. A. Tetrahedron
Lett. 1983, 24, 3555.
In initial methylation experiments designed to com-
plete the assembly of this building block, we recognized
(21) Lavalle´e, P.; Ruel, R.; Grenier, L.; Bissonnette, M. Tetrahedron
Lett. 1986, 27, 679.
(27) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett.
1983, 1593.

7392 J . Org. Chem., Vol. 63, No. 21, 1998
Paquette et al.
Sch em e 4a
Sch em e 5a
a
Key: (a) (i-Bu)2AlH, CH2Cl2, -78 °C; (b) HS(CH2)3SH, TiCl4,
C6H6; (c) (n-Bu)4N+ F-, THF; (d) p-CH3OC6H4CHO, (CSA), C6H6,
reflux, Dean-Stark trap; (e) (i-Bu)2AlH, CH2Cl2, 0 °C f rt; (f)
(COCl)2, DMSO, CH2Cl2; (C2H5)3N; (g) Ph3PdCH2, THF.
Sch em e 6a
a
Key: (a) CH2dC(OLi)OC2H5, THF, -78 °C; (b) (C2H5)3SiH,
TiCl4, CH2Cl2, -78 °C f rt; (c) (Me3Si)2NH, (Me3SiCl), reflux; (d)
(C2H5)3SiH,SnCl4,CH2Cl2,-78 °C f-20 °C;(e)PMBOC(dNH)CCl3,
(TfOH), ether; (n-Bu)4N+ F-, THF; (g) Dess-Martin periodinane,
CH2Cl2; (h) Ph3PdCHOCH3, THF, 0 °C; (i) 1 M HCl/THF (1:4).
a
Key: (a) LDA, (C2H5O)2P(O)CH2COOC2H5, THF, -40 °C; (b)
After this, it proved possible to generate 30 in high yield
by application of the Wittig olefination protocol.
(i-Bu)2AlH (excess), THF, -78 °C; (c) Ph3P, CBr4, CH3CN; (d)
NaP(O)(OCH3)2, THF; (e) n-BuLi, THF, -78 f -40 °C; i-PrCHO,
-78 °C.
Acqu isition of 34. The straightforward route devel-
oped for the purpose of obtaining the triene fragment 34
is outlined in Scheme 6. With the ready availability of
trans-3-(tributylstannyl)-2-propenal (31),29,30 its conver-
sion to dienyl ester 32 under Wadsworth-Emmons
conditions31 could quickly be established to proceed
satisfactorily under mild conditions. As has been estab-
lished by other workers in a closely related context,32
chemoselective reduction of the ester functionality and
transformation of the resulting allylic alcohol into the
rather sensitive bromide with carbon tetrabromide and
triphenylphosphine33 was immediately followed by a
Michaelis-Becker reaction.34 Formation of the halide
and its ensuing treatment with the sodium salt of
dimethyl phosphite in THF proceeded in 43% overall
yield. The ultimate elaboration of 34 was accomplished
by metalation of 33 with n-butyllithium and condensation
with isobutyraldehyde. The all-trans geometry was
assigned to 34 on the strength of extensive precedent.
Attem p ts to Ach ieve Su bu n it Assem bly. With 34
in hand, its practical coupling to aldehyde 29 was initially
scrutinized. Transmetalation of 34 with n-butyllithium
in THF at -78 to -40 °C proved to be uncomplicated.
When generation of the trienyllithium reagent in this
manner was followed by the introduction of 29, conver-
(28) Mancuso, A. J .; Brownfain, D. S.; Swern, D. J . Org. Chem. 1979,
44, 4148.
(29) J ohnson, C. R.; Kadow, J . F. J . Org. Chem. 1987, 52, 1493.
(30) J ung, M. E.; Light, L. A. Tetrahedron Lett. 1982, 23, 3851.
(31) Wadsworth, W. S., J r. Org. React. 1977, 25, 73.
(32) Evans, D. A.; Gage, J . R.; Leighton, J . L. J . Am. Chem. Soc.
1992, 114, 9434.
(33) (a) Axelrod, E. H.; Milne, G. M.; van Tamelen, E. E. J . Am.
Chem. Soc. 1970, 92, 2139. (b) Hayashi, H.; Nakanishi, K.; Brandon,
C.; Marmur, J . J . Am. Chem. Soc. 1973, 95, 8749. (c) Shue, Y.-K.;
Carrera, G. M., J r.; Nadzan, A. M. Tetrahedron Lett. 1987, 28,
3225.
(34) Michaelis, A.; Becker, T. Chem. Ber. 1897, 30, 1003.

Macrolactone Core of Polycavernoside A
J . Org. Chem., Vol. 63, No. 21, 1998 7393
grade and in most cases dried prior to use. The purity of all
compounds was shown to be >95% by TLC and high-field 1H
and 13C NMR. The high-resolution and fast-atom-bombard-
ment spectra were recorded at The Ohio State University
Campus Chemical Instrumentation Center. Elemental analy-
ses were performed at the Scandinavian Microanalytical
Laboratory, Herlev, Denmark, or at Atlantic Microlab, Inc.,
Norcross, GA.
sion to 35 was accomplished in 83% yield. Although the
efficiency of this C-C bond-forming step is considered
acceptable, the 2:1 diastereoselectivity is not. However,
further work on the stereocontrol of this reaction was not
pursued in light of the developments described below.
(3R,4S,6S)-6-[(ter t -Bu t yld ip h e n ylsiloxy)m e t h yl]t e t -
r a h yd r o-4-[(p -m et h oxyb en zyl)oxy]-3-m et h yl-2H -p yr a n -
2-on e (10). A solution of 916 (317 mg, 0.80 mmol) in ether (6
mL) and CH2Cl2 (1 mL) was treated sequentially with ethereal
triflic acid (0.023 mL of 0.1 M in ether, 0.3 mol %) and a
solution of p-methoxybenzyl trichloroacetamidate (337 mg,
0.80 mmol) in ether (1 mL) in dropwise fashion via syringe.
The reaction mixture was allowed to stir overnight, taken up
in ether (50 mL), washed in turn with 1 M NaOH solution, 1
M HCl, water, and brine, dried, and concentrated. Purification
of the residue by chromatography on silica gel (elution with
30% ether in hexanes) furnished 10 as a colorless oil (316 mg,
77%): IR (film, cm-1) 1732; 1H NMR (300 MHz, CDCl3) δ 7.67-
7.60 (m, 4 H), 7.46-7.32 (m, 6 H), 7.28-7.22 (m, 2 H), 6.91-
6.85 (m, 2 H), 4.61 (d, J ) 11.3 Hz, 1 H), 4.44 (d, J ) 11.3 Hz,
1 H), 4.22 (dq, J ) 11.4, 4.0 Hz, 1 H), 3.80-3.72 (m, 5 H), 3.46
(td, J ) 3.6, 10.1 Hz, 1 H), 2.49 (dq, J ) 9.7, 7.0 Hz, 1 H), 2.36
(dt, J ) 13.3, 3.6 Hz, 1 H), 1.79 (dt, J ) 13.2, 11.4 Hz, 1 H),
1.37 (d, J ) 7.0 Hz, 3 H), 1.06 (s, 9 H); 13C NMR (75 MHz,
CDCl3) δ 173.1, 159.4, 135.6 (2 C), 135.5 (2 C), 133.1 (2 C),
132.8, 129.8, 129.7, 129.3 (2 C), 127.8 (4 C), 113.9 (2 C), 76.4,
76.3, 70.8, 65.6, 55.3, 43.4, 31.0, 26.8 (3 C), 19.2, 13.9; MS m/z
(M+ - t-Bu) calcd 461.1787, obsd 461.1767; [R] -38.2 (c 0.39,
CHCl3).
At this juncture, the focus of our attention turned to
proper identification of a method for conjoining 2 with 3
or, alternatively, 30 with 5. Williams and Sit have
demonstrated that 2-substituted 1,3-dithianes readily
attack epoxides once they are lithiated.35 However,
deprotonation of 30 under their conditions (t-BuLi, THF-
HMPA (9:1), -78 °C, 5 min) followed by the introduction
of 5 resulted predominantly in recovery of unreacted
dithiane. At somewhat warmer temperatures (-60 °C
f -50 °C f -65 °C), total degradation of the aldehyde
was observed. The response of this reactant combination
to various alternative base-solvent combinations36-38
and a wide variety of time and temperature regimens was
equally capricious.39,40 Since there are many instances
in the literature of dithianes that could not be deproto-
nated under standard or more elaborate conditions, and
30 could be plagued by competitive deprotonation at the
benzylic position, deuteration studies were undertaken.
Under the first set of conditions specified above, followed
by quenching with D2O after 5 and 15 min, 41% and 92%
d1 incorporation, respectively, was observed (1H NMR
analysis) exclusively at the dithiane site (doublet at δ
4.10). Some modest onset of degradation was noted at
the longer reaction time.
Our second specific objective of bringing about the
union of 2 and 3 proved likewise to be unrewarding. The
highly oxygenated nature of 2-Li+ could be responsible
for an increase in kinetic basicity.41,42 The partial epi-
merization of 3 witnessed on a number of occasions can
be rationalized in these terms. Whatever the cause un-
derlying the unwillingness of 2 to exhibit a capacity for
favorable 1,2-addition to 3, it has become clear that new
protocols need to be uncovered to make operative the de-
sired merging of these chiral segments. We hope to re-
port on a workable solution to this assembly problem as
well as a completed synthesis of polycavernoside A soon.
Anal. Calcd for C31H38O5Si: C, 71.78; H, 7.39. Found: C,
71.86; H, 7.45.
ter t-Bu tyld ip h en yl[[(2S,4S,5R,6R)-tetr a h yd r o-6-m eth -
oxy-4-[(p-m eth oxyben zyl)oxy]-5-m eth yl-2H-p yr a n -2-yl]-
m eth oxy]sila n e (11). To a solution of 10 (570 mg, 1.10 mmol)
in CH2Cl2 (20 mL) at -78 °C was added diisobutylaluminum
hydride in hexanes (1.2 mL of 1 M, 1.2 mmol). The reaction
mixture was stirred for 5 min, quenched with saturated
sodium potassium tartrate solution (15 mL), and extracted
with ether (3 × 5 mL). After drying and evaporation of the
organic phase, the residue was eluted through a column of
silica gel with 40% ether in hexanes, concentrated, dissolved
in methyl iodide (10 mL), treated with silver oxide (509 mg,
2.20 mmol), and refluxed for 6 h. After dilution with ether
(20 mL), the insoluble solids were separated by filtration, and
the filtrate was evaporated. Purification of the product by
chromatography (silica gel, elution with 15% ether in hexanes)
provided 365 mg (62%) of 11 as a colorless oil: IR (film, cm-1
)
1
1613; H NMR (300 MHz, C6D6) δ 7.86-7.82 (m, 4 H), 7.26-
7.21 (m, 8 H), 6.83-6.80 (m, 2 H), 4.46 (d, J ) 11.6 Hz, 1 H),
4.21 (d, J ) 11.6 Hz, 1 H), 3.87 (dd, J ) 5.9, 10.5 Hz, 1 H),
3.80 (d, J ) 8.5 Hz, 1 H), 3.70 (dd, J ) 4.5, 10.5 Hz, 1 H), 3.39
(s, 3 H), 3.39-3.31 (m, 1 H), 3.31 (s, 3 H), 2.95 (td, J ) 11.6,
5.1 Hz, 1 H), 1.82-1.75 (m, 2 H), 1.27 (q, J ) 11.6 Hz, 1 H),
1.21 (d, J ) 7.0 Hz, 3 H), 1.20 (s, 9 H); 13C NMR (75 MHz,
CDCl3) δ 159.7, 136.09 (2 C), 136.06 (2 C), 134.11, 134.06,
131.4, 130.0 (2 C), 129.3 (2 C) 128.1 (4 C), 114.0 (2 C), 106.3,
79.0, 72.8, 70.1, 67.4, 56.1, 54.8, 43.2, 33.4, 27.1 (3 C), 19.5,
12.9; MS m/z (M+) calcd 534.2801, obsd 534.2751; [R] +13.0 (c
0.95, CHCl3).
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. The
column chromatographic separations were performed with
Woelm silica gel (230-400 mesh). Solvents were reagent
(35) Williams, D. R.; Sit, S.-Y. J . Am. Chem. Soc. 1984, 106,
2949.
(36) Lipshutz, B. H.; Garcia, E. Tetrahedron Lett. 1990, 31,
7261.
Anal. Calcd for C32H42O5Si: C, 71.87; H, 7.92. Found: C,
71.83; H, 7.95.
(37) Smith, A. B., III; Condon, S. M.; McCauley, J . A.; Leazer, J . L.,
J r.; Leahy, J . W.; Maleczka, R. E., J r. J . Am. Chem. Soc. 1997, 119,
947.
(38) Cere`, V.; De Angelis, S.; Pollicino, S.; Ricci, A.; Kishan Reddy,
C.; Knochel, P.; Cahiez, G. Synthesis 1997, 1174.
(39) Oppong, I.; Pauls, H. W.; Liang, D.; Fraser-Reid, B. J . Chem.
Soc., Chem. Commun. 1986, 1241.
(40) Kinoshita, M.; Taniguchi, M.; Morioka, M.; Takami, H.; Mi-
zusawa, Y. Bull. Chem. Soc. J pn. 1988, 61, 2147.
(41) Hanessian, S.; Pougny, J .-R.; Boessenkool, I. K. Tetrahedron
1984, 40, 1289.
(2S,4S,5R,6R)-Tet r a h yd r o-6-m et h oxy-4-[(p -m et h oxy-
ben zyl)oxy]-5-m eth yl-2H-p yr a n -2-m eth a n ol (12). A solu-
tion of 11 (309 mg, 0.58 mmol) in THF (20 mL) was treated
with a 1.0 M solution of tetra-n-butylammonium fluoride in
THF (0.75 mL, 0.75 mmol) and stirred for 8 h. Following
solvent evaporation, the product was purified by chromatog-
raphy on silica gel (elution with 75% ether in hexanes) to
provide 166 mg (97%) of 10 as a colorless oil: IR (film, cm-1
)
1
3460 (br), 1613; H NMR (300 MHz, C6D6) δ 7.24-7.20 (m, 2
(42) De Brabander, J .; Vandewalle, M. Synthesis 1994, 855.
H), 6.84-6.80 (m, 2 H), 4.43 (d, J ) 11.5 Hz, 1 H), 4.15 (d, J

7394 J . Org. Chem., Vol. 63, No. 21, 1998
Paquette et al.
) 11.5 Hz, 1 H), 3.73 (d, J ) 8.5 Hz, 1 H), 3.50 (m, 2 H), 3.32
(s, 3 H), 3.30 (s, 3 H), 3.16-3.08 (m, 1 H), 2.91 (dt, J ) 4.7,
10.5 Hz, 1 H), 2.03 (br s, 1 H), 1.83-1.75 (m, 1 H), 1.59 (ddd,
J ) 1.8, 4.6, 12.4 Hz, 1 H), 1.28 (q, J ) 11.6 Hz, 1 H), 1.17 (d,
J ) 6.5 Hz, 3 H); 13C NMR (75 MHz, C6D6) δ 159.7, 131.3,
129.3 (2 C), 114.1 (2 C), 106.3, 78.8, 72.6, 70.1, 65.7, 56.2, 54.8,
43.1, 32.8, 12.8; MS m/z (M+) calcd 296.1623, obsd 296.1617;
[R] +31.1 (c 0.84, CH2Cl2).
C), 106.2, 79.1, 70.2, 67.8, 56.0, 54.8, 44.3, 43.0, 41.9, 37.0,
30.3, 30.0, 26.2, 12.8; MS m/z (M+) calcd 398.1585, obsd
398.1617; [R] +19.5 (c 1.93, CH2Cl2).
Anal. Calcd for C20H30O4S2: C, 60.27; H, 7.59. Found: C,
60.06; H, 7.64.
ter t-Bu tyl[(S)-3,4-ep oxy-2,2-d im eth ylbu toxy]d ip h en yl-
sila n e (16). A solution of 1521 (229 mg, 1.92 mmol) and
imidazole (262 mg, 3.84 mmol) in CH2Cl2 (10 mL) was admixed
with a solution of tert-butyldiphenylsilyl chloride (581 mg, 2.11
mmol) in CH2Cl2 (3 mL). After 2.5 h of stirring, the reaction
mixture was diluted with ether (50 mL), washed with water
(10 mL) and brine (10 mL), dried, and concentrated. Purifica-
tion of the residue by chromatography on silica gel (elution
with 3% ether in hexanes) gave 16 as a colorless oil (647 mg,
95%): IR (film, cm-1) 1361, 1111; 1H NMR (300 MHz, CDCl3)
δ 7.71-7.67 (m, 4 H), 7.48-7.37 (m, 6 H), 3.54 (d, J ) 9.7 Hz,
1 H), 3.44 (d, J ) 9.7 Hz, 1 H), 2.99 (t, J ) 3.5 Hz, 1 H), 2.68
(d, J ) 3.5 Hz, 2 H), 1.09 (s, 9 H), 0.92 (s, 3 H), 0.89 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 135.6 (4 C), 133.6, 133.5, 129.6
(2 C), 127.6 (4 C), 70.6, 57.2, 44.0, 36.1, 26.8 (3 C), 20.2, 19.8,
19.4; MS m/z (M+) calcd 354.2015, obsd 354.2030; [R] +9.0 (c
1.30, CHCl3).
Anal. Calcd for C16H24O5: C, 64.84; H, 8.16. Found: C,
64.62; H, 8.64.
(2S,4S,5R,6R)-Tet r a h yd r o-6-m et h oxy-4-[(p -m et h oxy-
b en zyl)oxy]-5-m et h yl-2H -p yr a n -2-m et h a n ol Met h a n e-
su lfon a te (13). A cold (-10 °C) solution of 12 (22 mg, 0.073
mmol) and triethylamine (0.20 mL) in CH2Cl2 (2.5 mL) was
treated with methanesulfonyl chloride (8.5 µL, 0.11 mmol). The
reaction mixture was allowed to warm to room temperature,
stirred for 1 h, and concentrated under reduced pressure. The
product, purified by chromatography on silica gel (elution with
60% ether in hexanes), was a white solid: mp 98-99 °C (27
mg, 95%): IR (film, cm-1) 1512, 1367, 1339; 1H NMR (300
MHz, C6D6) δ 7.31-7.24 (m, 2 H), 6.94-6.85 (m, 2 H), 4.46 (d,
J ) 11.4 Hz, 1 H), 4.19 (d, J ) 6.4 Hz, 1 H), 4.02-3.94 (m, 2
H), 3.67 (d, J ) 8.6 Hz, 1 H), 3.38 (s, 3 H), 3.31 (s, 3 H), 3.26-
3.12 (m, 1 H), 2.87 (dt, J ) 4.6, 10.6 Hz, 1 H), 2.38 (s, 3 H),
1.82-1.68 (m, 2 H), 1.18 (d, J ) 6.5 Hz, 3 H), 1.15 (q, J ) 11.9
Hz, 1 H); 13C NMR (75 MHz, C6D6) δ 159.8, 131.1, 129.3 (2 C),
114.1 (2 C), 106.1, 78.2, 71.6, 70.3, 69.7, 56.3, 54.8, 42.9, 37.0,
32.5, 12.6; MS m/z (M+) calcd 374.1399, obsd 374.1387; [R]
+24.8 (c 0.93, CH2Cl2).
Anal. Calcd for C22H30O2Si: C, 74.53; H, 8.53. Found: C,
74.27; H, 8.53.
(R)-5-[2-(ter t-Bu tyld ip h en ylsiloxy)-1,1-d im eth yleth yl]-
d ih yd r o-2(3H)-fu r a n on e (17). To a solution of LDA, pre-
pared by the addition of n-butyllithium (81.2 mL of 1.6 M in
hexanes, 130 mmol) to diisopropylamine (14.6 g, 144 mmol)
in DME (120 mL) cooled to -20 °C with a subsequent warming
to 0 °C, was added acetic acid (3.89 g, 64.9 mmol). The reaction
mixture was stirred at room temperature for 40 min and at
+40 °C for 20 min to complete the metalation. This white
suspension was treated with 16 (2.60 g, 7.22 mmol) in a small
amount of DME, heated to reflux overnight, cooled, and diluted
with water. The separated aqueous phase was acidified to pH
3 and extracted with ether, and the combined organic solutions
were washed with 1 M HCl until the washes were acidic. The
organic phase was refluxed for 4 h in order to complete the
lactonization process and then evaporated. The product was
chromatographed on silica gel (elution with 20% ether in
petroleum ether) and obtained as a colorless oil (2.05 g, 72%):
IR (film, cm-1) 1778; 1H NMR (300 MHz, CDCl3) δ 7.70-7.63
(m, 4 H), 7.47-7.37 (m, 6 H), 4.61 (dd, J ) 7.1, 8.9 Hz, 1 H),
3.57 (d, J ) 9.9 Hz, 1 H), 3.41 (d, J ) 9.9 Hz, 1 H), 2.59-2.49
(m, 2 H), 2.15-2.00 (m, 2 H), 1.08 (s, 9 H), 0.95 (s, 3 H), 0.91
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 177.2, 135.6 (4 C), 133.3,
133.2, 129.7 (2 C), 127.6 (4 C), 84.1, 69.6, 38.9, 29.3, 26.9 (3
C), 22.7, 19.6, 19.3, 19.2; MS m/z (M+ - t-Bu) calcd 339.1416,
obsd 339.1427; [R] -17.8 (c 2.35, CHCl3).
(3S,5R)-5-[2-(ter t-Bu t yld ip h en ylsiloxy)-1,1-d im et h yl-
eth yl]d ih yd r o-3-m eth yl-2(3H)-fu r a n on e (18). A solution
of 17 (1.05 g, 2.65 mmol) in cold (-78 °C) THF (10 mL) was
treated with lithium hexamethyldisilazide (3.17 mL of 1.0 M
in THF, 3.17 mmol), stirred for 1 h at this temperature,
quenched with methyl iodide (0.3 mL), and diluted with ether
prior to washing with saturated NH4Cl solution and brine,
drying, and concentration. Chromatographic purification of
the residue on silica gel (elution with 15% ether in petroleum
ether) afforded 18 as a colorless oil (2.15 g, 81%): IR (film,
cm-1) 1777; 1H NMR (300 MHz, CDCl3) δ 7.68-7.60 (m, 4 H),
7.47-7.34 (m, 6 H), 4.61 (t, J ) 7.4 Hz, 1 H), 3.53 (d, J ) 9.9
Hz, 1 H), 3.39 (d, J ) 9.9 Hz, 1 H), 2.65 (ddq, J ) 9.5, 7.4, 5.4
Hz, 1 H), 2.28 (ddd, J ) 13.1, 7.0, 9.5 Hz, 1 H), 1.79 (ddd, J )
13.1, 7.7, 5.4 Hz, 1 H), 1.29 (d, J ) 7.4 Hz, 3 H), 1.07 (s, 9 H),
0.93 (s, 3 H), 0.88 (s, 3 H); 13C NMR (75 MHz, C6D6) δ 178.6,
136.02 (2 C), 135.99 (2 C), 133.8, 133.6, 130.13, 130.10, 128.14
(2 C), 128.11 (2 C), 80.6, 69.9, 39.3, 34.7, 30.1, 27.1 (3 C), 19.8,
19.6, 19.0, 16.5; MS m/z (M+ - CH3) calcd 395.2042, obsd
395.2038; [R] -25.7 (c 3.39, CHCl3).
Anal. Calcd for C17H26O7S: C, 54.53; H, 7.00. Found: C,
54.37; H, 7.04.
(2R,3R,4S,6S)-Tetr a h yd r o-6-(iod om eth yl)-2-m eth oxy-
4-[(p-m eth oxyben zyl)oxy]-3-m eth yl-2H-pyr an (14). A mix-
ture of 13 (90 mg, 0.24 mmol) and tetra-n-butylammonium
iodide (622 mg, 1.68 mmol) in benzene (10 mL) was refluxed
for 40 h, cooled, diluted with ether (20 mL), washed with water
and brine, and then dried. After solvent evaporation, the
residue was purified by chromatography on silica gel (elution
with 30% ether in hexanes) to provide 93 mg (95%) of 14 as a
white solid: mp 58 °C; IR (film, cm-1) 1614; 1H NMR (300
MHz, C6D6) δ 7.22-7.17 (m, 2 H), 6.84-6.78 (m, 2 H), 4.40 (d,
J ) 11.5 Hz, 1 H), 4.13 (d, J ) 11.5 Hz, 1 H), 3.63 (d, J ) 8.5
Hz, 1 H), 3.38 (s, 3 H), 3.33 (s, 3 H), 2.97-2.86 (m, 2 H), 2.86-
2.73 (m, 2 H), 1.83-1.75 (m, 1 H), 1.75-1.66 (m, 1 H), 1.13 (d,
J ) 6.5 Hz, 3 H), 1.04-0.93 (m, 1 H); 13C NMR (75 MHz, C6D6)
δ 159.7, 131.2, 129.3 (2 C), 114.1 (2 C), 106.0, 78.5, 71.5, 70.3,
56.3, 54.8, 42.7, 36.5, 12.6, 8.5; MS m/z (M+) calcd 406.0641,
obsd 406.0657; [R] +37.8 (c 2.52, CH2Cl2).
Anal. Calcd for C16H23IO4: C, 47.30; H, 5.71. Found: C,
47.17; H, 5.67.
(2R,3R,4S,6S)-6-(m -Dit h ia n -2-ylm et h yl)t et r a h yd r o-2-
m eth oxy-4-[(p-m eth oxyben zyl)oxy]-3-m eth yl-2H-pyr an (2).
To a slurry of potassium tert-butoxide (38 mg, 0.34 mmol) in
hexanes (0.5 mL) cooled to 0 °C was added n-butyllithium in
hexanes (0.19 mL of 1.6 M, 0.31 mmol). The mixture was
stirred at room temperature for 1 h, cooled to -78 °C, and
treated with a solution of 1,3-dithiane (37 mg, 0.31 mmol) in
THF (0.5 mL). After 20 min of stirring at this temperature, a
THF solution (0.5 mL) of 14 (25 mg, 0.06 mmol) was intro-
duced, and the reaction was allowed to proceed for 10 min prior
to an aqueous quench (1 mL) and extraction with ether (2 ×
3 mL). The organic layers were washed with brine, dried, and
evaporated. Chromatography of the residue (silica gel, elution
with 30% ether in hexanes) furnished 2 as a colorless oil (18
1
mg, 72%): IR (film, cm-1) 1614; H NMR (300 MHz, C6D6) δ
7.22 (d of m, J ) 8.7 Hz, 2 H), 6.82 (dm, J ) 8.7 Hz, 2 H), 4.41
(d, J ) 11.4 Hz, 1 H), 4.41-4.36 (m, 1 H), 4.13 (d, J ) 11.4
Hz, 1 H), 3.80 (d, J ) 8.6 Hz, 1 H), 3.62 (tm, J ) 8.5 Hz, 1 H),
3.40 (s, 3 H), 3.31 (s, 3 H), 2.89 (dt, J ) 4.7, 10.5 Hz, 1 H),
2.48-2.30 (m, 4 H), 2.17 (ddd, J ) 4.6, 11.8, 14.1 Hz, 1 H),
1.90 (ddd, J ) 3.4, 10.1, 14.1 Hz, 1 H), 1.84-1.80 (m, 1 H),
1.73 (ddd, J ) 2.0, 4.7, 12.3 Hz, 1 H), 1.65-1.57 (m, 1 H), 1.50-
1.42 (m, 1 H), 1.18 (d, J ) 6.5 Hz, 3 H), 1.22-1.09 (m, 1 H);
13C NMR (75 MHz, C6D6) δ 159.7, 131.5, 129.4 (2 C), 114.0 (2
Anal. Calcd for C25H34O3Si: C, 73.13; H, 8.35. Found: C,
73.13; H, 8.43.
(3R,5R)-5-[2-(ter t-Bu t yld ip h en ylsiloxy)-1,1-d im et h yl-
eth yl]d ih yd r o-3-m eth yl-2(3H)-fu r a n on e (3). A solution of
LDA (9.39 mmol) in THF (10 mL), prepared in the predescribed

Macrolactone Core of Polycavernoside A
J . Org. Chem., Vol. 63, No. 21, 1998 7395
manner, was cooled to -78 °C, treated with a solution of 18
(772 mg, 1.88 mmol) in THF (1 mL), stirred for 2 h at -78 °C,
and quenched with saturated NH4Cl solution. The product
was extracted into ether, washed with brine, dried, evaporated,
and purified chromatographically (silica gel, elution with 35%
ether in hexanes). There was obtained 741 mg (96%) of 3 as
a colorless oil: IR (film, cm-1) 1770; 1H NMR (300 MHz, CDCl3)
δ 7.66-7.60 (m, 4 H), 7.46-7.35 (m, 6 H), 4.45 (dd, J ) 5.6,
11.1 Hz, 1 H), 3.55 (d, J ) 9.9 Hz, 1 H), 3.40 (d, J ) 9.9 Hz, 1
H), 2.67 (ddq, J ) 7.0, 8.6, 12.5 Hz, 1 H), 2.23 (ddd, J ) 5.6,
8.6, 12.5 Hz, 1 H), 1.68 (q, J ) 12.2 Hz, 1 H), 1.26 (d, J ) 7.0
Hz, 3 H), 1.07 (s, 9 H), 0.93 (s, 3 H), 0.89 (s, 3 H); 13C NMR
(75 MHz, CDCl3) δ 179.5, 135.6 (4 C), 133.4, 133.3, 129.7 (2
C), 127.7 (4 C), 81.6, 69.7, 38.5, 36.0, 31.9, 26.9 (3 C), 19.6,
19.4, 19.2, 14.9; MS m/z (M+) calcd 410.2277, obsd 410.2316;
[R] -8.3 (c 3.95, CHCl3).
reaction mixture was stirred for 5 min, quenched with
saturated NH4Cl solution (1 mL), diluted with ether (50 mL),
washed with 1 M HCl, dried, and concentrated. The resulting
material was dissolved in CH2Cl2 (2 mL), cooled to -78 °C,
treated with triethylsilane (292 mg, 2.51 mmol) and then tin
tetrachloride (0.25 mL of 1 M in CH2Cl2, 0.25 mmol), allowed
to warm during 1 h to -20 °C, and stirred at this temperature
for an additional 30 min before being quenched with water (2
mL). The product was extracted into ether and purified in
the predescribed manner to deliver 69 mg (59% for 3 steps) of
20.
Eth yl (2S,3R,4S,6S)-6-[(ter t-Bu tyld ip h en ylsiloxy)m eth -
yl]tetr a h yd r o-4-[(p-m eth oxyben zyl)oxy]-3-m eth yl-2H-p y-
r a n -2-a ceta te (21). A solution of 20 (594 mg, 1.26 mmol) in
dry ether (20 mL) was treated with triflic acid (0.037 mL of
0.1 M in ether, 0.3 mol %) followed immediately by p-
methoxybenzyl trichloroacetimidate (535 mg, 1.89 mmol)
dissolved in ether (1 mL). The reaction mixture was stirred
for 20 min, washed with water and saturated NaHCO3
solution, dried, and concentrated. Chromatography of the
residue on silica gel (elution with 15% ether in petroleum
ether) gave 437 mg (59%) of 21 as a colorless oil: IR (film,
cm-1) 1738; 1H NMR (300 MHz, CDCl3) δ 7.71-7.68 (m, 4 H),
7.46-7.36 (m, 6 H), 7.28 (dm, J ) 8.6 Hz, 2 H), 6.90 (dm, J )
8.6 Hz, 2 H), 4.60 (d, J ) 11.2 Hz, 1 H), 4.39 (d, J ) 11.2 Hz,
1 H), 4.17-4.06 (m, 2 H), 3.81 (s, 3 H), 3.74 (dd, J ) 5.2, 10.0
Hz, 1 H), 3.62-3.50 (series of m, 3 H), 3.18 (td, J ) 4.5, 10.6
Hz, 1 H), 2.63 (dd, J ) 3.2, 15.1 Hz, 1 H), 2.42 (dd, J ) 9.1,
15.1 Hz, 1 H), 2.23-2.18 (m, 1 H), 1.50-1.41 (m, 1 H), 1.35-
1.25 (m, 1 H), 1.21 (t, J ) 7.1 Hz, 3 H), 1.07 (s, 9 H), 0.98 (d,
J ) 6.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 171.6, 159.2,
135.68 (2 C), 135.65 (2 C), 133.7 (2 C), 130.7, 129.6 (2 C), 129.4
(2 C), 127.6 (4 C), 113.8 (2 C), 80.0, 78.2, 76.1, 70.2, 66.9, 60.4,
55.3, 41.9, 39.4, 33.6, 26.8 (3 C), 19.3, 14.2, 13.1; FAB MS m/z
(M+ + H) calcd 591.31, obsd 591.42; [R] +23.3 (c 1.22, CHCl3).
Anal. Calcd for C35H46O6Si: C, 71.15; H, 7.85. Found: C,
71.04; H, 7.82.
Anal. Calcd for C25H34O3Si: C, 73.13; H, 8.35. Found: C,
72.72; H, 8.44.
Eth yl (3R,4S,6S)-6-[(ter t-Bu tyld ip h en ylsiloxy)m eth yl]-
tetr a h yd r o-2-h yd r oxy-4-[(p-m eth oxyben zyl)oxy]-3-m eth -
yl-2H-p yr a n -2-a ceta te (19). A solution containing 0.77 mmol
of LDA in THF (2 mL) was cooled to -78 °C, treated during
10 min with dry ethyl acetate (0.073 mL, 0.75 mmol), and
stirred for 10 min prior to the introduction of 10 (100 mg, 0.19
mmol) dissolved in THF (1 mL). The reaction mixture was
agitated for an additional 10 min, quenched with saturated
NH4Cl solution (1 mL), and extracted with ether. The
combined organic layers were dried and concentrated to leave
a residue that was purified chromatographically (silica gel,
elution with 10% ether in petroleum ether). There was
isolated 82 mg (70%) of 19 as a colorless oil: IR (film, cm-1
)
1
3443, 1713; H NMR (300 MHz, C6D6) δ 7.82-7.76 (m, 4 H),
7.29-7.19 (m, 8 H), 6.81 (dm, J ) 8.7 Hz, 2 H), 5.56 (d, J )
1.8 Hz, 1 H), 4.44 (d, J ) 11.3 Hz, 1 H), 4.40-4.18 (m, 1 H),
4.21 (d, J ) 11.3 Hz, 1 H), 3.97-3.82 (m, 2 H), 3.78 (dd, J )
5.7, 10.5 Hz, 1 H), 3.72-3.63 (m, 2 H), 3.30 (s, 3 H), 2.51 (d, J
) 15.3 Hz, 1 H), 2.37 (d, J ) 15.3 Hz, 1 H), 2.02 (ddd, J ) 2.3,
4.5, 12.2 Hz, 1 H), 1.58-1.40 (m, 1 H), 1.38-1.27 (m, 1 H),
1.21 (d, J ) 6.5 Hz, 3 H), 1.19 (s, 9 H), 0.87 (t, J ) 7.1 Hz, 3
H); 13C NMR (75 MHz, CDCl3) δ 172.8, 159.2, 135.7 (2 C), 135.6
(2 C), 133.8 (2 C), 130.9, 129.58, 129.56, 129.3 (2 C), 127.6 (4
C), 113.8 (2 C), 98.8, 76.2, 70.7, 69.1, 66.9, 60.9, 55.3, 45.2,
Eth yl (2S,3R,4S,6S)-Tetr a h yd r o-6-(h yd r oxym eth yl)-4-
[(p-m eth oxyben zyl)oxy]-3-m eth yl-2H-pyr an -2-acetate (22).
To a solution of 21 (486 mg, 0.82 mmol) in THF (5 mL) was
added tetra-n-butylammonium fluoride (1.07 mL of 1 M in
THF, 1.07 mmol). The reaction mixture was stirred for 1.5 h,
diluted with ether (50 mL), washed with water and brine,
dried, and concentrated. Purification of the residue by chro-
matography (silica gel, gradient elution with 30-70% ethyl
acetate in petroleum ether) provided 275 mg (95%) of 22 as a
42.3, 33.8, 26.8 (3 C), 19.3, 14.1, 12.4; MS m/z (M+ - C4H9
-
H2O) calcd 531.2203, obsd 531.2216; [R] +36.3 (c 1.84, CHCl3).
Anal. Calcd for C35H46O7Si: C, 69.28; H, 7.64. Found: C,
69.28; H, 7.66.
1
Eth yl (2S,3R,4S,6S)-6-[(ter t-Bu tyld ip h en ylsiloxy)m eth -
yl]t et r a h yd r o-4-h yd r oxy-3-m et h yl-2H -p yr a n -2-a cet a t e
(20). A. By Ion ic Red u ction of 19. A solution of 19 (15
mg, 0.025 mmol) in CH2Cl2 (1 mL) at 0 °C was treated
sequentially with titanium tetrachloride (0.025 mL of 1 M in
CH2Cl2, 0.025 mmol) and triethylsilane (6 mg, 0.050 mmol),
allowed to warm to room temperature, washed with water and
brine, dried, and evaporated. Purification of the residue by
chromatography on silica gel (elution with 30% ether in
petroleum ether) furnished 9 mg (74%) of 20 as a colorless oil:
IR (film, cm-1) 3471, 1738; 1H NMR (300 MHz, CDCl3) δ 7.67-
7.65 (m, 4 H), 7.44-7.27 (m, 6 H), 4.15-4.05 (m, 2 H), 3.71-
3.60 (m, 1 H), 3.57-3.41 (m, 4 H), 2.62 (dd, J ) 3.3, 15.1 Hz,
1 H), 2.41 (dd, J ) 8.9, 15.1 Hz, 1 H), 2.07 (dd, J ) 4.3, 11.6
Hz, 1 H), 1.57 (br s, 1 H), 1.39-1.23 (m, 2 H), 1.20 (t, J ) 7.1
Hz, 3 H), 1.04 (s, 9 H), 1.00 (d, J ) 6.5 Hz, 3 H); 13C NMR (75
MHz, CDCl3) δ 171.6, 135.63 (2 C), 135.60 (2 C), 133.6 (2 C),
129.6 (4 C), 127.6 (2 C), 77.8, 76.0, 73.3, 66.6, 60.4, 43.8, 39.2,
37.6, 26.8 (3 C), 19.2, 14.2, 12.8; FAB MS m/z (M+ + H) calcd
471.26, obsd 471.32; [R] -17.8 (c 0.54, CHCl3).
colorless oil: IR (film, cm-1) 3454, 1732; H NMR (300 MHz,
CDCl3) δ 7.25 (dm, J ) 8.5 Hz, 2 H), 6.87 (dm, J ) 8.5 Hz, 2
H), 4.58 (d, J ) 11.1 Hz, 1 H), 4.36 (d, J ) 11.1 Hz, 1 H), 4.41
(q, J ) 7.1 Hz, 2 H), 3.80 (s, 3 H), 3.61-3.42 (m, 4 H), 3.17
(td, J ) 4.6, 10.6 Hz, 1 H), 2.64 (dd, J ) 3.4, 15.1 Hz, 1 H),
2.40 (dd, J ) 9.1, 15.1 Hz, 1 H), 2.11-1.46 (m, 2 H), 1.51-
1.44 (m, 1 H), 1.43-1.29 (m, 1 H), 1.25 (t, J ) 7.1 Hz, 3 H),
0.96 (d, J ) 6.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 171.4,
159.1, 130.4, 129.2 (2 C), 113.7 (2 C), 79.2, 78.0, 75.8, 70.1,
65.7, 60.4, 55.2, 41.8, 39.2, 32.7, 14.1, 12.9; FAB MS m/z (M+
+ H) calcd 353.20, obsd 353.21; [R] +48.9 (c 2.22, CHCl3).
Anal. Calcd for C19H28O6: C, 64.75; H, 8.01. Found: C,
64.47; H, 8.08.
E t h yl (2S,3R,4S,6S)-6-F or m ylt et r a h yd r o-4-[(p -m et h -
oxyben zyl)oxy]-3-m eth yl-2H-p yr a n -2-a ceta te (23). A so-
lution of 22 (264 mg, 0.75 mmol) in CH2Cl2 (10 mL) was treated
with the Dess-Martin periodinane (508 mg, 1.20 mmol),
stirred for 1 h, and subjected directly to chromatography on
silica gel. Elution with 50% ether in petroleum ether provided
187 mg (71%) of 23 as a colorless oil: IR (film, cm-1) 1732; 1H
NMR (300 MHz, CDCl3) δ 9.61 (s, 1 H), 7.24 (dm, J ) 8.5 Hz,
2 H), 6.87 (dm, J ) 8.5 Hz, 2 H), 4.61 (d, J ) 11.1 Hz, 1 H),
4.36 (d, J ) 11.1 Hz, 1 H), 4.16 (q, J ) 7.1 Hz, 2 H), 3.84-3.79
(m, 1 H), 3.80 (s, 3 H), 3.61 (td, J ) 3.3, 9.7 Hz, 1 H), 3.18 (td,
J ) 4.4, 10.3 Hz, 1 H), 2.67 (dd, J ) 3.3, 15.3 Hz, 1 H), 2.49
(dd, J ) 9.0, 15.3 Hz, 1 H), 2.36 (ddd, J ) 2.5, 4.4, 12.6 Hz, 1
H), 1.54-1.49 (m, 1 H), 1.47-1.32 (m, 1 H), 1.26 (t, J ) 7.1
Hz, 3 H), 0.97 (d, J ) 6.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3)
δ 201.2, 171.3, 159.3, 130.1, 129.4 (2 C), 113.9 (2 C), 79.6, 78.7,
Anal. Calcd for C27H38O5Si: C, 68.90; H, 8.14. Found: C,
68.78; H, 8.22.
B. Alter n a te Rou te fr om 9. A solution of 9 (100 mg, 0.25
mmol), hexamethyldisilazane (2 mL), and chlorotrimethylsi-
lane (1 drop) was refluxed for 2 h, cooled, and freed of solvent
under reduced pressure. In a separate flask, a THF solution
containing 1.76 mmol of LDA was cooled to -78 °C, treated
with ethyl acetate (155 mg, 1.76 mmol), and stirred for 1 h at
-78 °C prior to introduction of the silylated lactone. The

7396 J . Org. Chem., Vol. 63, No. 21, 1998
Paquette et al.
78.4, 70.3, 60.6, 55.3, 41.6, 39.1, 31.6, 14.2, 12.9; FAB MS m/z
(M+ + H) calcd 351.18, obsd 351.17; [R] +17.5 (c 1.50, CHCl3).
Eth yl (2S,3R,4S,6S)-6-(F or m ylm eth yl)tetr a h yd r o-4-[(p-
m eth oxyben zyl)oxy]-3-m eth yl-2H-p yr a n -2-a ceta te (5). A
magnetically stirred suspension of (methoxymethyl)triph-
enylphosphonium chloride (94 mg, 0.37 mmol) in THF (2 mL)
was cooled to 0 °C, treated with potassium hexamethyldisi-
lazide (0.55 mL of 0.5 M in toluene, 0.27 mmol), and stirred
for 15 min in advance of the addition of 23 (32 mg, 0.091 mmol)
dissolved in THF (0.5 mL). The reaction mixture was stirred
at 0 °C for 30 min, quenched with saturated NH4Cl solution,
and extracted with ether. The combined organic phases were
dried, concentrated, and passed through a pad of silica gel
(elution with 30% ether in petroleum ether). The resulting
enol ether was dissolved in THF (1 mL), treated with 1 M HCl
(0.25 mL), stirred for 5 h, diluted with ether, and washed with
water and saturated NaHCO3 solution prior to drying, con-
centration, and chromatography on silica gel (elution with 50-
60% ether in petroleum ether) to furnish 15 mg (45%) of 5 as
a colorless oil: IR (film, cm-1) 1731; 1H NMR (300 MHz, CDCl3)
δ 9.70 (m, 1 H), 7.24 (dm, J ) 8.6 Hz, 2 H), 6.87 (dm, J ) 8.6
Hz, 2 H), 4.57 (d, J ) 11.1 Hz, 1 H), 4.36 (d, J ) 11.1 Hz, 1 H),
4.11 (q, J ) 7.1 Hz, 2 H), 3.92-3.83 (m, 1 H), 3.79 (s, 3 H),
3.52 (td, J ) 3.2, 9.7 Hz, 1 H), 3.17 (td, J ) 4.5, 10.3 Hz, 1 H),
2.65-2.57 (m, 2 H), 2.45 (ddd, J ) 1.7, 4.7, 16.4 Hz, 1 H), 2.35
(dd, J ) 9.5, 14.9 Hz, 1 H), 2.15 (ddd, J ) 1.8, 4.5, 12.4 Hz, 1
H), 1.48-1.39 (m, 1 H), 1.36-1.24 (m, 1 H), 1.23 (t, J ) 7.1
Hz, 3 H), 0.95 (d, J ) 6.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3)
δ 200.8, 171.4, 159.2, 133.8 (2 C), 130.3, 129.3 (2 C), 79.1, 78.3,
70.7, 70.3, 60.5, 55.2, 49.2, 41.5, 39.2, 36.8, 14.1, 12.9; FAB
MS m/z (M+ + H) calcd 365.20, obsd 365.27; [R] +41.3 (c 1.21,
CHCl3).
(3R,5R)-5-[2-(ter t-Bu t yld ip h en ylsiloxy)-1,1-d im et h yl-
eth yl)-tetr a h yd r o-3-m eth yl-2-fu r a n ol (24). Lactone 3 (247
mg, 0.60 mmol) was dissolved in CH2Cl2 (5 mL), cooled to -78
°C, treated with diisobutylaluminum hydride (0.72 mL of 1 M
in CH2Cl2, 0.72 mmol), stirred for 10 min, quenched with
saturated sodium potassium tartrate solution (2 mL), and
partitioned between ether (10 mL) and water (10 mL). The
aqueous phase was extracted with ether (3 × 10 mL), and the
combined organic solutions were processed as described earlier.
Passage through a short silica gel column (elution with 30%
ether in hexanes) afforded 245 mg (99%) of 24 as a colorless
oil: IR (film, cm-1) 3409; 1H NMR (300 MHz, C6D6) (major
anomer) δ 7.88-7.79 (m, 4 H), 7.30-7.25 (m, 6 H), 4.93 (m, 1
H), 4.26 (dd, J ) 5.9, 10.3 Hz, 1 H), 3.69 (d, J ) 9.5 Hz, 1 H),
3.61 (d, J ) 9.5 Hz, 1 H), 3.11 (br s, 1 H), 1.78-1.52 (m, 1 H),
1.28 (m, 1 H), 1.23 (s, 9 H), 1.15-1.00 (m, 1 H), 1.00-0.87 (2
singlets (3H each) and a doublet (3H)soverlapping with minor
anomer); 13C NMR (75 MHz, C6D6) δ (136.2, 136.1, 4 C),
(134.23, 134.10, 134.17, 2 C), 129.9 (4 C), 128.2 (2 C), (104.9,
98.8), (84.3, 82.2), (71.0, 70.9), (41.4, 39.5), (38.73, 38.66), (34.2,
31.8), 27.2 (3 C), 19.7, (21.3, 20.9), (19.9, 19.8), (17.5, 12.9);
MS m/z (M+ - OH) calcd 395.2406, obsd 395.2438; [R] +1.3 (c
1.38, CHCl3).
75.9, 73.0, 56.8, 38.9, 36.3, 35.0, 31.0, 30.8, 26.9 (3 C), 26.4,
22.4, 19.5, 19.1, 16.3; MS m/z (M+) calcd 502.2395, obsd
502.2391; [R] +29.5 (c 1.47, CHCl3).
Anal. Calcd for C28H42O2S2Si: C, 66.88; H, 8.42. Found:
C, 66.79; H, 8.44.
(3R,5R)-5-m -Dith ia n -2-yl-2,2-d im eth yl-1,3-h exa n ed iol
(26). A solution of 25 (188 mg, 0.37 mmol) in THF (5 mL)
was reacted with tetra-n-butylammonium fluoride (0.45 mL
of 1.0 M in THF, 0.45 mmol) as described previously to give
after chromatography (silica gel, gradient elution with 50 f
80% ether in petroleum ether) 93 mg (94%) of 26 as a colorless
1
oil: IR (film, cm-1) 3408; H NMR (300 MHz, CDCl3) δ 4.19
(d, J ) 3.9 Hz, 1 H), 3.58-3.42 (series of m, 3 H), 2.95-2.77
(series of m, 6 H), 2.23-2.05 (m, 2 H), 1.90-1.75 (m, 1 H),
1.65 (ddd, J ) 3.8, 10.5, 14.0 Hz, 1 H), 1.49 (ddd, J ) 1.8, 9.8,
14.0 Hz, 1 H), 1.09 (d, J ) 6.8 Hz, 3 H), 0.87 (s, 3 H), 0.86 (s,
3 H); 13C NMR (75 MHz, CDCl3) δ 76.5, 71.8, 56.3, 38.2, 36.3,
35.1, 30.9, 30.6, 26.1, 22.4, 18.7, 16.3; FAB MS m/z (M+ + H)
calcd 265.13, obsd 265.11; [R] +27.8 (c 1.44, CHCl3).
Anal. Calcd for C12H24O2S2: C, 54.50; H, 9.15. Found: C,
54.23; H, 9.14.
(4R )-4-[(2R )-2-m -Dit h ia n -2-ylp r op yl]-2-(p -m e t h oxy-
p h en yl)-5,5-d im eth yl-m -d ioxa n e (27). A mixture of 26 (773
mg, 2.92 mmol), p-methoxybenzaldehyde (418 mg, 3.07 mmol),
and camphorsulfonic acid (10 mg) was refluxed under a
modified Dean-Stark trap filled with 4 Å molecular sieves for
6 h. The cooled reaction mixture was concentrated and the
residue was purified by chromatography on silica gel (elution
with 15% ether in petroleum ether) to furnish 993 mg (89%)
of 27 as a white solid: mp 144-145 °C (from ether-hexanes):
IR (CHCl3, cm-1) 1615, 1249, 1106; 1H NMR (300 MHz, CDCl3)
δ 7.42 (dm, J ) 8.7 Hz, 2 H), 6.88 (dm, J ) 8.7 Hz, 2 H), 5.41
(s, 1 H), 4.17 (d, J ) 3.8 Hz, 1 H), 3.80 (s, 3 H), 3.71 (d, J )
11.0 Hz, 1 H), 3.58 (d, J ) 11.5 Hz, 1 H), 3.51 (dd, J ) 1.6,
10.7 Hz, 1 H), 2.94-2.80 (m, 4 H), 2.26-2.20 (m, 1 H), 2.08
(dm, J ) 13.6 Hz, 1 H), 1.87-1.73 (m, 2 H) 1.48 (ddd, J ) 1.7,
10.2, 13.9 Hz, 1 H), 1.13 (s, 3 H), 1.11 (d, J ) 6.9 Hz, 3 H),
0.76 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 159.7, 131.3, 127.2
(2 C), 113.4 (2 C), 101.5, 82.5, 78.9, 56.4, 55.2, 34.5, 33.8, 32.6,
31.1, 30.7, 26.2, 21.3, 18.6, 16.1; MS m/z (M+) calcd 382.1636,
obsd 382.1647; [R] +29.6 (c 1.08, CHCl3).
Anal. Calcd for C20H30O3S2: C, 62.79; H, 7.90. Found: C,
62.89; H, 7.92.
(γR,ER)-γ-[(p -Met h oxyb en zyl)oxy]-â,â,E-t r im et h yl-m -
d ith ia n e-2-p en ta n ol (28). A cold (0 °C), magnetically stirred
solution of 27 (106 mg, 0.277 mmol) in CH2Cl2 (2 mL) was
treated with Dibal-H (0.42 mL of 1.0 M in hexanes, 0.42 mmol),
stirred for 1 h at 0 °C and 30 min at room temperature,
quenched with saturated sodium potassium tartrate solution
(5 mL), and extracted with ether (3 × 20 mL). The combined
organic layers were dried and concentrated, and the residue
was purified chromatographically (silica gel, elution with 30%
ether in petroleum ether) to give 28 (79 mg, 73%) as a white
solid: mp 46 °C; IR (film, cm-1) 3477, 1613; 1H NMR (300 MHz,
CDCl3) δ 7.27 (dm, J ) 8.5 Hz, 2 H), 6.86 (dm, J ) 8.5 Hz, 2
H), 4.56 (s, 2 H), 4.14 (d, J ) 3.8 Hz, 1 H), 3.78 (s, 3 H), 3.62
(d, J ) 10.8 Hz, 1 H), 3.37 (dd, J ) 1.8, 9.5 Hz, 1 H), 3.31 (d,
J ) 10.8 Hz, 1 H), 2.93-2.78 (m, 4 H), 2.70 (br s, 1 H), 2.17-
2.04 (m, 2 H), 1.92-1.75 (m, 2 H), 1.52 (dd, J ) 2.0, 10.5 Hz,
Anal. Calcd for C25H36O3Si: C, 72.77; H, 8.79. Found: C,
72.84; H, 8.83.
(rR,γR)-r-[2-(ter t-Bu t yld ip h en ylsiloxy)-1,1-d im et h yl-
eth yl]-γ-m eth yl-m -d ith ia n e-2-p r op a n ol (25). A solution of
24 (78 mg, 0.19 mmol) and 1,3-propanedithiol (41 mg, 0.38
mmol) in benzene (2 mL) was treated with titanium tetra-
chloride (0.19 mL of 1.0 M in CH2Cl2, 0.19 mmol), stirred for
30 min, and diluted with ether (7 mL) and water (5 mL). The
organic phase was washed with brine, dried, and evaporated
to leave a residue that was purified by chromatography on
silica gel (elution with 15% ether in petroleum ether) to give
1 H), 1.11 (d, J ) 6.8 Hz, 3 H), 1.02 (s, 3 H), 0.85 (s, 3 H); 13
C
NMR (75 MHz, CDCl3) δ 159.2, 130.4, 129.3 (2 C), 113.8 (2
C), 84.5, 74.6, 70.4, 56.5, 55.2, 39.8, 36.3, 35.8, 31.0, 30.7, 26.2,
23.2, 20.8, 16.7; MS m/z (M+) calcd 384.1793, obsd 384.1762;
[R] +7.0 (c 1.51, CHCl3).
Anal. Calcd for C20H32O3S2: C, 62.46; H, 8.39. Found: C,
62.46; H, 8.43.
1
89 mg (93%) of 25 as a colorless oil: IR (film, cm-1) 3500; H
(âR,δR)-â-[(p -Met h oxyb en zyl)oxy]-r,r,δ-t r im et h yl-m -
d ith ia n e-2-va ler a ld eh yd e (29). A solution of oxalyl chloride
(0.136 mL, 1.56 mmol) in CH2Cl2 (3 mL) was cooled to -78
°C, treated dropwise with a solution of DMSO (244 mg, 3.12
mmol) in CH2Cl2 (1 mL), and stirred for 15 min in the cold
prior to the dropwise addition of 28 (500 mg, 1.30 mmol)
dissolved in CH2Cl2 (1 mL). After 15 min at this temperature,
triethylamine (1.08 mL, 7.8 mmol) was introduced followed
by warming to -40 °C during 40 min. The reaction mixture
NMR (300 MHz, CDCl3) δ 7.71-7.63 (m, 4 H), 7.48-7.40 (m,
6 H), 4.20 (d, J ) 3.9 Hz, 1 H), 3.59-3.49 (m, 1 H), 3.56 (d, J
) 9.9 Hz, 1 H), 3.44 (d, J ) 9.9 Hz, 1 H), 3.17 (br s, 1 H),
2.97-2.81 (m, 4 H), 2.37-2.28 (m, 1 H), 2.16-2.06 (m, 1 H),
1.93-1.78 (m, 1 H), 1.70 (ddd, J ) 3.2, 11.1, 13.9 Hz, 1 H),
1.50-1.42 (m, 1 H), 1.13 (d, J ) 6.8 Hz, 3 H), 1.07 (s, 9 H),
0.88 (s, 3 H), 0.86 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 135.7
(2 C), 135.6 (2 C), 132.7, 132.6, 129.84, 129.80, 127.8 (4 C),

Macrolactone Core of Polycavernoside A
J . Org. Chem., Vol. 63, No. 21, 1998 7397
was poured into water, extracted with CH2Cl2, washed with
brine, dried, and concentrated. The residue was chromato-
graphed on silica gel (elution with 25% ether in petroleum
ether) to furnish 29 (428 mg, 86%) as a white solid: mp 63
A solution of the above alcohol (911 mg, 2.44 mmol) and
carbon tetrabromide (1.62 g, 4.88 mmol) in acetonitrile (10 mL)
was treated with triphenylphosphine (1.28 g, 4.88 mmol) in
portions during 30 min. The reaction mixture was poured
into saturated NaHCO3 solution (50 mL), extracted with a
1:10 mixture of ether and petroleum ether (2 × 50 mL),
dried, and concentrated. The solid was rinsed with petroleum
ether, and the filtrate was concentrated prior to rapid elution
through silica gel with 5% ether in petroleum ether. After
solvent evaporation, there remained 957 mg (91%) of the
bromide.
1
°C; IR (film, cm-1) 1724, 1612; H NMR (300 MHz, CDCl3) δ
9.62 (s, 1 H), 7.23 (dm, J ) 8.7 Hz, 2 H), 6.86 (dm, J ) 8.7 Hz,
2 H), 4.49 (s 2 H), 4.11 (d, J ) 3.9 Hz, 1 H), 3.79 (s, 3 H), 3.61
(dd, J ) 2.1, 9.7 Hz, 1 H), 2.92-2.87 (m, 4 H), 2.17-2.04 (m,
2 H), 1.91-1.77 (m, 2 H), 1.61-1.39 (m, 1 H), 1.13 (s, 3 H),
1.11 (d, J ) 6.8 Hz, 3 H), 1.05 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 206.0, 159.2, 130.3, 129.2 (2 C), 113.8 (2 C), 80.8,
74.1, 56.2, 55.2, 51.2, 36.2, 35.5, 31.0, 30.7, 26.2, 19.4, 17.6,
16.6; FAB MS m/z (M+ + H) calcd 383.17, obsd 383.25; [R] -1.5
(c 0.88, CHCl3).
A solution of sodium dimethyl phosphite was prepared by
the addition of dimethyl phosphite (660 mg, 6.00 mmol) to a
suspension of sodium hydride (144 mg, 6.00 mmol) in dry THF
(22 mL), and the mixture was warmed with a heat gun until
Anal. Calcd for C20H30O3S2: C, 62.79; H, 7.90. Found: C,
62.64; H, 7.89.
a
clear solution was obtained. The above bromide was
2-[(1R,3R)-3-[(p-Meth oxyben zyl)oxy]-1,4,4-tr im eth yl-5-
h exen yl]-m -d ith ia n e (30). A suspension of methyltriphen-
ylphosphonium iodide (110 mg, 0.271 mmol) in dry THF (1
mL) was treated with potassium hexamethyldisilazide (542 µL
of 0.5 M in toluene, 0.271 mmol) at 0 °C and stirred for 0.5 h
prior to the addition of 29 (35 mg, 0.090 mmol) dissolved in
THF (2 mL) via cannula. After 20 min, the reaction mixture
was quenched with saturated NH4Cl solution (10 mL) and
extracted several times with ether. The combined organic
phases were dried, filtered, and concentrated to leave a
residue, chromatography of which on silica gel (elution with
20% ethyl acetate in hexanes) provided 30 (33 mg, 94%) as a
colorless oil: IR (film, cm-1) 1534; 1H NMR (300 MHz, CDCl3)
δ 7.28 (d, J ) 8.9 Hz, 2 H), 6.96 (d, J ) 8.9 Hz, 2 H), 5.86 (dd,
J ) 17.8, 10.5 Hz, 1 H), 5.00 (m, 2 H), 4.58 (d, J ) 10.6 Hz, 1
H), 4.51 (d, J ) 10.6 Hz, 1 H), 4.10 (d, J ) 3.8 Hz, 1 H), 3.79
(s, 3 H), 3.13 (dd, J ) 10.0, 2.0 Hz, 1 H), 2.87-2.80 (m, 4 H),
2.15-1.40 (m, 5 H), 1.06 (d, J ) 6.5 Hz, 3 H), 1.06 (s, 3 H),
1.04 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 146.0 (2 C), 131.2,
129.1 (2 C), 113.7, 111.9, 99.9, 84.6, 74.8, 56.6, 55.3, 42.4, 36.7,
35.5, 31.1, 30.7, 26.3, 24.0, 22.9, 16.5; MS m/z (M+) calcd
308.1844, obsd 308.1847; [R] +13.1 (c 0.99, CHCl3).
dissolved in THF (5 mL), added to the anion solution, and
stirred for 2 h during which time sodium bromide precipitated.
The mixture was diluted with ether and water, and the organic
phase was dried, concentrated, and chromatographed on silica
gel (elution with ether) to provide 491 mg (43% for two steps)
of 33 as a colorless oil: IR (film, cm-1) 1032; 1H NMR (300
MHz, CDCl3) δ 6.49 (dd, J ) 9.8, 18.9 Hz, 1 H), 6.22-6.10 (m,
2 H), 5.64-5.51 (m, 1 H), 3.75 (d, J ) 10.8 Hz, 6 H), 2.64 (ddd,
J ) 1.1, 7.6, 22.4 Hz, 2 H), 1.52-1.40 (m, 6 H), 1.36-1.20 (m,
6 H), 1.00-0.15 (series of m, 15 H); 13C NMR (75 MHz, CDCl3)
δ 145.8 (d, J ) 4.3 Hz), 138.5 (d, J ) 14.6 Hz), 134.4 (d, J )
3.9 Hz), 120.4 (d, J ) 12.3 Hz), 52.7 (d, J ) 7.1 Hz, 2 C), 29.6
(d, J ) 139.4 Hz), 29.1 (3 C), 27.3 (3 C), 13.7 (3 C), 9.5 (3 C);
MS m/z (M+ - C4H9) calcd 409.0954, obsd 409.0989.
Anal. Calcd for C19H39O3PSn: C, 49.06; H, 8.45. Found:
C, 48.56; H, 8.36.
Tr ibu tyl [(1E,3E,5E)-7-Meth yl-1,3,5-octa tr ien yl]sta n -
n a n e (34). A cold (-78 °C) solution of 33 (152 mg, 326 mmol)
in dry THF (1 mL) was treated with n-butyllithium (0.24 mL
of 1.5 M in hexanes, 0.36 mmol), stirred for 5 min, and treated
with isobutyraldehyde (24 mg, 0.33 mmol). After 10 min at
-78 °C, the reaction mixture was placed in an ice bath for 30
min, diluted with ether, washed with water and brine, dried,
and concentrated. The residue was chromatographed on silica
gel (elution with petroleum ether) to provide 34 (83 mg, 62%)
as a colorless oil: 1H NMR (300 MHz, C6D6) δ 6.81 (ddd, J )
1.9, 7.2, 18.7 Hz, 1 H), 6.30-6.20 (m, 2 H), 6.05 (ddd, J ) 1.0,
9.3, 15.3 Hz, 1 H), 5.61 (d, J ) 6.9 Hz, 1 H), 5.59 (dd, J ) 6.9,
15.0 Hz 1 H), 2.24-2.17 (m, 1 H), 1.63-1.51 (m, 6H), 1.50-
1.27 (m, 6 H), 1.08-0.87 (series of m, 21 H); 13C NMR (75 MHz,
CDCl3) δ 147.0, 142.9, 133.7, 133.4, 132.2, 127.4, 31.3, 29.1 (3
E t h yl (2E,4E)-5-(Tr ib u t ylst a n n yl)-2,4-p en t a d ien oa t e
(32). A solution of LDA in THF (1.74 mmol) was cooled to
-60 °C, treated with triethyl phosphonoacetate (338 mg, 1.51
mmol), and allowed to warm to -40 °C, at which point 3129
(400 mg, 1.16 mmol) dissolved in THF (3 mL) was introduced.
The reaction mixture was brought to room temperature during
2 h, diluted with an equal volume of ether, washed with water
and brine, dried, and concentrated. Chromatographic purifi-
cation of the residue on silica gel (elution with 1% ether in
petroleum ether) furnished 340 mg (71%) of 32 as a colorless
C), 27.3 (3 C), 22.3 (2 C), 13.7 (3 C), 9.6 (3 C); MS m/z (M+
C4H9) calcd 355.1448, obsd 355.1422.
-
1
oil: IR (film, cm-1) 1716, 1626; H NMR (300 MHz, CDCl3) δ
7.18 (dd, J ) 10.0, 15.4 Hz, 1 H), 6.81 (d, J ) 18.7 Hz, 1 H),
6.64 (dd, J ) 10.0, 18.7 Hz, 1 H), 5.79 (d, J ) 15.4 Hz, 1 H),
4.20 (q, J ) 7.1 Hz, 2 H), 1.55-1.41 (m, 6 H), 1.36-1.24 (series
of m, 9 H), 1.03-0.85 (series of m, 15 H); 13C NMR (75 MHz,
CDCl3) δ 167.4, 147.2, 146.3, 144.2, 119.9, 60.2, 29.0 (3 C), 27.2
(3 C), 14.3, 13.6 (3 C), 9.6 (3 C); MS m/z (M+) calcd 416.1737,
obsd 416.1693.
Cou p lin g of 34 to 29. A solution of 34 (90 mg, 0.219 mmol)
in dry THF (0.7 mL) was cooled to -78 °C, treated dropwise
with n-butyllithium in hexanes (0.160 mL of 1.5 M, 0.241
mmol), allowed to warm to -40 °C during 70 min, and cooled
back to -78 °C. A solution of 29 (59 mg, 0.15 mmol) in THF
(0.5 mL) was introduced via cannula, and the reaction mixture
was allowed to warm to 0 °C, diluted with ether, washed with
water and brine, dried, and concentrated. The residue was
passed down a column of silica gel (elution with 30% ether in
petroleum ether) to furnish 64 mg (83%) of a 2:1 diastereomeric
mixture of 35. Partial separation could be achieved by MPLC
(silica gel, elution with 10:1:14 dichloromethane-acetone-
hexanes). For the major alcohol: 1H NMR (300 MHz, CDCl3)
δ 7.26 (dm, J ) 8.6 Hz, 2 H), 6.86 (dm, J ) 8.6 Hz, 2 H), 6.26-
6.18 (m, 1 H), 6.17-6.15 (m, 2 H), 6.13-6.01 (m, 1 H), 5.98-
5.62 (m, 2 H), 4.57 (s, 2 H), 4.19-4.16 (m, 1 H), 4.13 (d, J )
3.9 Hz, 1 H), 3.79 (s, 3 H), 3.64 (br s, 1 H), 3.39 (dd, J ) 1.6,
9.5 Hz, 1 H), 2.88-2.80 (m, 4 H), 2.47-2.30 (m, 1 H), 2.15-
1.75 (series of m, 4 H), 1.68-1.55 (m, 1 H), 1.10 (d, J ) 6.8
Hz, 3 H), 1.00 (s, 3 H), 0.99 (d, J ) 6.7 Hz, 6 H), 0.81 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 159.3, 142.4, 133.0, 132.2, 131.9,
130.5, 130.2, 129.3 (2 C), 127.3, 113.9 (2 C), 86.0, 78.7, 74.9,
56.5, 55.3, 42.2, 36.2, 35.9, 31.2, 31.1, 30.7, 26.3, 22.3 (2 C),
20.5, 17.1, 16.7; FAB MS m/z (M+ + H) calcd 505.2810, obsd
505.2825.
Dim eth yl [(2E,4E)-5-(Tr ibu tylstan n yl)-2,4-pen tadien yl]-
p h osp h on a te (33). A solution of 32 (301 mg, 725 mmol) in
THF (5 mL) was cooled to -78 °C and treated dropwise with
Dibal-H (2.17 mL of 1 M in hexanes, 2.17 mmol). After 20
min, saturated sodium potassium tartrate solution was intro-
duced, vigorous stirring was maintained for 2, and the
separated aqueous layer was extracted with ether. The
combined organic layers were dried and concentrated to leave
a residue that was purified chromatographically (silica gel,
elution with 25% ether in petroleum ether) to furnish 247 mg
(91%) of the primary alcohol as a colorless oil: IR (film, cm-1
)
3330; 1H NMR (300 MHz, CDCl3) δ 6.54 (dd, J ) 9.8, 18.7 Hz,
1 H), 6.28-6.19 (m, 2 H), 5.79 (dt, J ) 5.8, 15.4 Hz, 1 H), 4.19
(dt, J ) 0.9, 5.7 Hz, 2 H), 1.59-1.24 (series of m, 13 H), 0.98-
0.77 (series of m, 15 H); 13C NMR (75 MHz, CDCl3) δ 145.9,
135.0, 134.6, 130.7, 63.3, 29.1 (3 C), 27.2 (3 C), 13.7 (3 C), 9.5
(3 C); MS m/z (M+ - C4H9) calcd 317.0927, obsd 317.0896.
Anal. Calcd for C17H34OSn: C, 54.72; H, 9.18. Found: C,
54.85; H, 9.25.

7398 J . Org. Chem., Vol. 63, No. 21, 1998
Paquette et al.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of 30
(3 pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
Ack n ow led gm en t. This research was supported by
the National Institutes of Health. A postdoctoral fel-
lowship to L.B. from the Ministe`re de l’Enseignement
Supe´rieur et de la Science (FCAR, Que´bec, Canada)
is gratefully acknowledged. The authors are indebted
to Dr. Kurt Loening for his assistance with nomen-
clature.
J O981083T