Application of Enelike Reactions of Aldehydes with Vinyl Ethers: A Stereoconvergent Synthesis of (±)-Phyllanthocin

Article abstract of DOI:10.1021/jo971151w

(±)-Phyllanthocin has been synthesized through a key step involving the enelike reaction of an aldehyde with 2-methoxypropene recently developed in these laboratories. This work demonstrates that our chemistry is suitable for multistep synthetic applicati

Full text of DOI:10.1021/jo971151w

7806
J . Org. Chem. 1997, 62, 7806-7811
Ap p lica tion of En elik e Rea ction s of Ald eh yd es w ith Vin yl Eth er s:
A Ster eocon ver gen t Syn th esis of (()-P h ylla n th ocin
Marco A. Ciufolini,* Shuren Zhu, and Melissa V. Deaton
Department of Chemistry, MS 60, Rice University, 6100 Main Street, Houston, Texas 77251-1892
Received J une 24, 1997X
(()-Phyllanthocin has been synthesized through a key step involving the enelike reaction of an
aldehyde with 2-methoxypropene recently developed in these laboratories. This work demonstrates
that our chemistry is suitable for multistep synthetic applications, and it shows that stereocontrol
in the creation of the phyllanthocin structure may be achieved by thermodynamic equilibration of
both peripheral stereogenic carbons.
Sch em e 1
We have recently disclosed that the 1:1 complex of
Yb(fod)3 and acetic acid (0.5 mol % or less) promotes an
unusual enelike1 reaction of ordinary aldehydes with
those vinyl ethers that display the oxygen functionality
at the central carbon of an allylic system, e.g., 2-meth-
oxypropene (MP, Scheme 1).2 This efficient, economical
process occurs at room temperature, it requires no drastic
measures to exclude air or moisture, it affords end-
products in nearly quantitative yield and in high purity,
and it may be easily conducted even on substantial
scales.3
Sch em e 2
Much strategic and tactical opportunity arises as a
result of this transformation. However, the potential
that new methodology seems to hold a priori must be
demonstrated in the context of a sensible synthetic
exercise, because not all new preparative techniques may
be capable to sustain the total synthesis of a molecule of
at least medium complexity. This is especially true if
such new techniques were needed at an early stage of a
synthetic scheme, and indeed, new reactions are often
demonstrated at a late stage of a synthetic route. Here,
we describe a total synthesis of the racemate of the
sesquiterpene, phyllanthocin, (()-1, that utilizes this
reaction as a key early step, thereby supporting the
notion that the new chemistry is indeed suitable for
multistep synthetic efforts.
may fully appreciate the value of a technique capable of
delivering 1.
With these goals in mind, we identified an advanced
intermediate for 1 in the form of diketone 2 (Scheme 2),
which may be envisioned to arise from the ene adduct of
MP, 4, with aldehyde 3.6 The starred stereogenic carbon
in 2 is created through the ene process, and it is the sole
nonepimerizable center in the entire molecule. At the
same time, 2 displays the thermodynamic relative con-
figuration of all stereocenters. Therefore, it seemed likely
Phyllanthocin is the methyl ester of the aglycon of the
antitumor agent, phyllanthoside.4 Both substances have
elicited much attention in the synthetic arena.5
A
number of factors influenced our selection of 1 as a
synthetic target. Previous syntheses of phyllanthocin
had clearly revealed the difficulties associated with its
deceptively simple structure and had underscored the
requirement for rather sophisticated plans and tech-
niques to build its molecular framework. As a result, a
frank assessment of the power and potential of our
enelike reaction would be possible. Also, phyllanthocin
may surely be regarded as a molecule of medium com-
plexity, and indeed, several published approaches to its
framework have yet to be translated into a total synthe-
sis. It thus seemed likely that the synthetic community
(5) Previous syntheses: (a) McGuirk, P. R.; Collum, D. B. J . Am.
Chem. Soc. 1982, 104, 4496. (b) Williams, D. R.; Sit, S. Y. J . Am. Chem.
Soc. 1984, 106, 2949. (c) Burke, S. D.; Cobb, J . E. Tetrahedron Lett.
1986, 27, 4237. (d) Burke, S. D.; Cobb, J . E.; Takeuchi, K. J . Org.
Chem. 1985, 50, 3420. (e) Smith, A. B., III; Fukui, M. J . Am. Chem.
Soc. 1987, 109, 1269. (f) Smith, A. B., III; Fukui, M.; Vaccaro, H. A.;
Empfield, J . R. J . Am. Chem. Soc. 1991, 113, 2071. (g) Smith, A. B.,
III; Fukui, M. J . Am. Chem. Soc. 1987, 109, 1272. (h) Smith, A. B.,
III; Rivero, R. A.; Hale, K. J .; Vaccaro, H. A. J . Am. Chem. Soc. 1991,
113, 2092. (i) Martin, S. F.; Dappen, M. S.; Dupre, B.; Murphy, C. J .
J . Org. Chem. 1987, 52, 3706. (j) Martin, S. F.; Dappen, M. S.; Dupre,
B.; Murphy, C. J .; Colapret, J . A. J . Org. Chem. 1989, 54, 2209. (k)
Trost, B. M.; Edstrom, E. D. Angew. Chem., Int. Ed. Engl. 1990, 29,
520. (l) Trost, B. M.; Kondo, Y. Tetrahedron Lett. 1991, 32, 1613.
Synthetic Studies: (m) Linderman, R. J .; Viviani, F. G.; Kwochka, W.
R. Tetrahedron Lett. 1992, 33, 3571. (n) Tenaglia, A.; Kammerer, F.
Synlett 1996, 576.
X Abstract published in Advance ACS Abstracts, September 15, 1997.
(1) The term “ene reaction” is used herein solely to describe the
outcome of our transformation, which is more likely to be mechanisti-
cally related to Prins-type reactions. Nomechanistic implications exist
in such usage.
(2) Deaton, M. V.; Ciufolini, M. A. Tetrahedron Lett. 1993, 34, 2409.
(3) Cf. (a) Ciufolini, M. A. In Advances in Heterocyclic Natural
Products Synthesis; Pearson, W. H., Ed.; J AI Press: Greenwich, CT,
1996; vol. 3, p 1.
(6) Prepared in 59% overall yield by allylation of butyrolactone
(LDA, THF, -78 °C, allyl bromide, 87%) followed by ozonolysis (O3,
5:1 CH2Cl2/MeOH, -78 °C, then Me2S) and chromatography (80%
EtOAc/hexanes, 68%).
(4) Isolation: Kupchan, S. M.; LaVoie, E. J .; Branfman, A. R.; Fei,
B. Y.; Bright, W. M.; Bryan, R. F. J . Am. Chem. Soc. 1977, 99, 3199.
S0022-3263(97)01151-1 CCC: $14.00 © 1997 American Chemical Society

Enelike Reactions of Aldehydes with Vinyl Ethers
J . Org. Chem., Vol. 62, No. 22, 1997 7807
Sch em e 3a
Sch em e 4a
a
(a) CH2Cl2, SiO2, rt, 100%; (b) THF, -78 °C, 75%; (c)
Ph3PdCH2, THF, rt, 79%; (d) TBS-Cl, imidazole, DMF, 0 °C, 96%;
(e) 1.5 equiv; CH2Cl2, MeOH, K2CO3, 0 °C, 73%; (f) cat. TPAP,
NMO, 4 Å mol sieves, CH2Cl2, rt, 100%. Overall 41% from 3 to 9
over six steps.
that the configuration of the starred carbon may be
relayed through epimerization to the rest of the mol-
ecule,7 in particular, to the methyl- and carbomethoxy-
bearing stereocenters, thereby alleviating some of the
issues presented by the stereocontrolled creation of 2.
This is in fact the case. A stereoconvergent synthesis of
2/1 was thus realized as follows.
a
(a) -78 °C, 30 min; (b) cat. TPAP, NMO, 4 Å mol sieves,
Compound 5 (MIP ) 2-methoxyisopropyl) emerged in
99% yield as a 1.5:1 mixture of unassigned diastereomers
upon stirring a mixture of 3 and 4 in CH2Cl2 at room
temperature in the presence of 0.2 mol % of catalyst.
Notice that the presence of a lactone in 3 would probably
disallow more traditional carbonyl-ene reactions.8 For
reasons that will be apparent shortly, adduct 5 was
advanced to 6 through DIBAL reduction and Wittig
methylenation. Silylation and treatment of the inter-
mediate 7 with MCPBA in CH2Cl2/MeOH produced
alcohol 8 (73%), which was oxidized to aldehyde 9 (N-
methylmorpholine N-oxide [“NMO”]/cat. tetrapropylam-
monium perruthenate [“TPAP”], Scheme 3). The Li
acetylide prepared from 10 added readily to 9 (Scheme
4), and the emerging carbinol 11 was oxidized (TPAP,
89% overall) to ynone 12. Exposure to Triton B resulted
in conjugate addition of MeOH to give a mixture of
compounds 13a and 13b, which, without further purifi-
cation, were subjected to acid-catalyzed spirocyclization
to 15.9 It became clear later that compound 15 had
arisen as a mixture of diastereomers that were epimeric
at the level of the methyl and the vinyl groups, but that
displayed substantially only the thermodynamic config-
uration of the spirocenter. This relative configuration
is probably controlled by the preference of the tetrahy-
drofuran for the cis 2,5-dialkyl arrangement and by an
CH2Cl2, rt, 89% a-b; (c) i. Triton B, MeOH, rt, 2 h, then ii. TFA,
H2O, THF, rt, 1 h, 62%; (d) CSA, CH2Cl2, rt, 10 h, 71%; (e) MsCl,
Et3N, CH2Cl2, 0 °C, then NaI, acetone, reflux, 78%. Overall 31%
from 9 to 16 over six steps.
anomeric effect at the level of the pyranone unit that
favors the placement of the furan oxygen at the axial
position.
While exposure to DBU caused equilibration of 15 to
the methyl-equatorial diastereomer, we found that this
operation was best postponed. Accordingly, the free OH
in 15 was converted into an iodide in preparation for
ketal hydrolysis and base-promoted cyclization to a
tricyclic intermediate. This latter step could not be
effected cleanly when the ring C ketone was present,
necessitating an intermediate NaBH4 reduction of 16 to
a carbinol, which fortunately required no protection. It
is worthy of note that this reduction proceeded stereo-
selectively to give the axial alcohol 17 through equatorial
delivery of hydride, in contrast with the normal behavior
of NaBH4. Seemingly, approach of the reducing agent
to the carbonyl group from the normally more favorable
axial trajectory is impeded due to molecular shape. A
similar phenomenon was observed earlier and confirmed
by us during reduction of late intermediate 2. Base
treatment of 17 provided exclusively the cis-fused isomer
of tricyclic intermediate 18, which was oxidized to 19 with
RuO4 (Sharpless conditions)10 and esterified to a an
essentially 1:1:1:1 mixture of diastereomers of 2, de-
scribed in Scheme 5 as compound 20. The tandem
oxidative cleavage of the vinyl group/carbinol oxidation
was not as efficient as previously observed in simpler
model compounds (cf. Scheme 8). Compensating for the
disappointing yield of this step, exposure of 20 to DBU
caused equilibration of the two peripheral stereogenic
centers to the thermodynamic relative configuration, as
apparent from a change in the isomer ratio to a substan-
(7) This principle had been partly validated during earlier synthetic
work on 1, particularly with respect to the stereochemistry of the
spiroacetal, but not for entirestereochemical array of 2, as shown here.
(8) For outstanding reviews see: (a) Snider, B. B. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
London, Springer-Verlag: Berlin, Germany, 1986. (b) Santelli, M;
Pons, J . M. Lewis Acids and Selectivity in Organic Synthesis; CRC
Press: Boca Raton, FL, 1996; Ch. 2. Fortunately, our enelike reaction
tolerates a good range of spectator functionality. Recent example of
carbonyl-ene reaction in terpene synthesis and bibliography: Snider,
B. B.; Vo, N. H.; O’Neil S. V.; Foxman, B. M. J . Am. Chem. Soc. 1996,
118, 7644.
(9) Theoretically, an intermediate of the type 13 could have been
prepared starting with addition of the kinetic enolate of 3-methyl-4-
[(tert-butyldimethylsilyl)oxy]-2-butanone to 9. However, reaction of
this enolate with 9 proceeded poorly, while addition to simple aldehydes
was uneventful. The reasons for this remain unclear.
(10) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936.

7808 J . Org. Chem., Vol. 62, No. 22, 1997
Ciufolini et al.
Sch em e 5a
Sch em e 7
Sch em e 8a
a
(a) MeOH, -10 °C; (b) HCOOH, rt, 1 h, 96% a-b; (c) tBuOK,
THF, 0 °C; (d) 5 mol % RuCl3‚3H2O, 2 equiv of KIO4, CCl4:MeCN:
H2O (2:2:3) 35% c-d; (e) MeI, K2CO3, DMF, rt, 2 h; (f) DBU, THF,
rt, 12 h, 60% e-f. Overall 20% from 16 to 2 over six steps.
Sch em e 6a
a
(a) MeOH, CH2Cl2, 0 °C; (b) THF-tBuOH, rt, 67% a-b; (c)
cat. RuCl3, KIO4, aqueous MeCN, CCl4, 56%.
described above. First, conversion of 5 to 7 was dictated
by the propensity of model analogues of 17 wherein an
ester was present in lieu of the vinyl group, e.g., 23, to
produce only cyclopropanes 24 upon base treatment
under a variety of conditions (Scheme 7). This forced
conversion of the ester to an alternative functionality.
Consideration of overall efficiency, as well as precedent,5a
induced us to select a vinyl unit as a latent ester group.
We also explored perhydrobenzofuranone 28 and 29
as alternative advanced intermediates for 1. The route
to these compounds also relies on our ene reaction, as
briefly outlined in Scheme 8. It was hoped that formation
of a kinetic enolate of the type 30 from 28 or 29 would
allow connection of a forerunner to the spirocyclic seg-
ment of 1. Unfortunately, enolization of 28/29 in a
controlled manner was found to be extremely problem-
atic. In particular, 28 displayed a strong inclination to
undergo self-aldolization, carbonyl reduction even under
Corey-Gross conditions,14 and a miscellany of other
complex transformations. While these difficulties were
not entirely unexpected for an R-alkoxy ketone such as
28,5m,15 their gravity bordered on the extreme, and it
seriously undermined our attempts to connect the future
spiroacetal moiety by aldol-type operations.
a
(a) DMSO, rt; (b) MeOH, 0 °C, 76% a-b; (c) PhCHdCHCOCl,
4-DMAP, CH2Cl2, rt, 71%. Overall 54% from 2 to (()-1 over three
steps, 1.4% from 3 to (()-1 over 21 steps.
tial 1:45:2.5:1.5 in favor of the most energetically favor-
able 2.11 This intermediate was readily advanced to (()-
phyllanthocin by minor permutations/modifications of
known procedures. Thus, reaction of 2 with the Corey-
Chaykowsky ylide12 proceeded efficiently to afford fura-
none epoxide 23. The high degree of chemoselectivity
observed in this reaction may be attributed to increased
electrophilicity of the furanone vs the pyranone carbonyl,
as a result of an inductive effect generated by the pair of
spiroacetal oxygen substituents at the furanone R-posi-
tion. The elevated stereoselectivity appears to be a
consequence of molecular shape: the sulfur ylide attacks
preferentially from the convex face of the strongly
puckered molecule of 2. Molecular shape is also likely
to be responsible for selective formation of axial carbinol
22 upon reduction of pyranone 21 with NaBH4 (12:1
diastereoselectivity).13 Finally, cinnamoylation of 22
afforded fully synthetic (()-1, mp 113-115 °C (Scheme
6).
Both 28 and 29 condensed in a satisfactory manner
with aromatic aldehydes under aqueous basic conditions,
whereupon an enolate of the type 30 presumably forms
reversibly and in minute concentrations. However, non-
enolizable aliphatic aldehydes suitable for delivery of the
spiroacetal moiety of 1, e.g., 31 and 32, produced exceed-
ingly poor results in this reaction. Isoxazole aldehyde
33, a carrier of a latent variant of the desired spiro group,
condensed efficiently with 29, but the resultant 34
In closing, it seems worthwhile to recount some im-
portant early observations that ultimately led to the
formulation of the successful route to phyllanthocin
16
resisted reductive ring cleavage with Mo(CO)6 under
mild conditions, whereas more forcing conditions pro-
(11) This ratio was determined by scrutiny of the 1H NMR spectra
of 20 and 2, hardcopies of which are provided as Supporting Informa-
tion.
(12) Corey, E. J .; Chaykowsky, M. J . Am. Chem. Soc. 1965, 87, 1353.
(13) While NaBH4 is normally selective for the equatorial alcohol
in reduction of six-membered cyclic ketones, a well-documented steric
effect is responsible for the opposite selectivity in the present system
(ref. 5).
(14) Corey, E. J .; Gross, A. W. Tetrahedron Lett. 1984, 25, 495.
(15) An excellent survey of the unpredictable behavior of R-alkoxy
ketones toward enolate formation may be found in: Gleave, D. M.
Doctoral Dissertation, University of Saskatchewan, 1993.
(16) Nitta, M.; Kobayashi, T. J . Chem. Soc., Chem. Commun. 1982,
877.

Enelike Reactions of Aldehydes with Vinyl Ethers
J . Org. Chem., Vol. 62, No. 22, 1997 7809
Sch em e 9a
mL) containing 1.5 g of powdered NaHCO3. When the reaction
was completed (TLC), Me2S (7.5 mL) was added, and the
mixture was warmed to rt, washed with brine, dried (Na2SO4),
and concentrated. The residue was chromatographed (40%
EtOAc/hexanes) to give 7.12 g (53% over two steps) of 3,
colorless, viscous oil. 1H: 9.78 (t, 1H, J ) 0.4 Hz), 4.38 (dt,
1H, J ) 15.9, 1.9 Hz), 4.23 (ddd, 1H, J ) 15.9, 2.3, 6.5 Hz),
3.06 (ddt, 1H, J ) 18.7, 3.7, 0.4 Hz), 2.95 (m, 1H), 2.69 (ddt,
1H, J ) 18.7, 8.2, 0.4 Hz), 2.53 (m, 1H), 1.90 (m, 1H). 13C:
199.1, 178.6, 66.9, 44.2, 33.9, 28.8. IR: 3422, 1761, 1718. MS
(CI): 129 (MH+). HRMS (CI): calcd for C6H9O3 129.0552
(MH+). Found 129.0551.
En e P r od u ct 5. Silica gel (1 g) was added to a mixture of
aldehyde 3 (6.5 g, 51 mmol), 2-MP (4, 30 mL, 6 equiv), CH2Cl2
(60 mL), AcOH (10 µL, 0.2 mol %), Yb(fod)3 (100 mg, 0.2 mol
%). After stirring at rt for 10 h, the mixture was diluted with
Et2O (200 mL), washed (saturated aqueous NaHCO3), dried
(Na2SO4), and concentrated to give 13.9 g (100%) of 5, light
yellow oil, 1.5:1 mixture of unassigned diastereomers. 1H
(C6D6): 4.33 (m, 1H), 4.14 (m, 1H), 3.97 (m, 1H), 3.92 (d, 1H,
J ) 1.7 Hz), 3.85 (d, 1H, J ) 1.7 Hz), 3.70 (m, 1H), 3.52 (m
1H), 3.20 (s, 3H), 3.00 (s, 3H),2.72- 2.10 (m, 3H), 1.60 (m, 2H),
1.30 (s, 6H). 13C (C6D6): 179.5, 161.9, 101.4, 84.1, 68.4, 66.5,
55.0, 49.4, 42.4, 36.8, 36.3, 30.6, 25.8, 25.6. IR: 1773, 1653.
MS (CI): 273 (MH+), 255, 241, 183, 73. HRMS (CI): calcd for
C14H25O5: 273.1702 (MH+), obsd 273.1695.
a
(a) Aqueous EtOH, rt, 90%; (b) EtOH, reflux, 91%.
Wittig P r od u ct 6. DIBAL (1.5 M in toluene, 28.7 mL, 43
mmol) was added to a solution of 5 (10.5 g, 38.6 mmol) in 150
mL dry THF at -78 °C. Stirring was continued for 1 h, and
then MeOH was added dropwise until bubbling stopped
(CAUTION: flammable gases released). The mixture was
diluted with Et2O (400 mL), washed (saturated aqueous
NaHCO3), dried (Na2SO4), and concentrated. Chromatography
(50% EtOAc/hexanes) gave 7.9 g (75%) of the lactol, colorless
oil. 1H (C6D6): 5.37 (m, 1H), 4.25 (m, 2H), 4.05 (m, 1H), 3.98
(d, 1H, J ) 2.1 Hz), 3.85 (d, 1H, J ) 2.1 H), 3.77 (m, 1H), 3.68
(m, 1H), 3.20 (s, 3H), 3.13 (s, 3H), 2.80 (m, 1H), 2.44-1.70 (m,
4H), 1.38 (s, 3H), 1.27 (s, 3H). 13C (C6D6): 162.3, 104.2, 101.5,
99.2, 83.2, 69.3, 67.2, 54.8, 49.4, 43.7, 42.4, 35.0, 25.80, 25.75
ppm. IR: 3410, 1671. MS (CI): 257 (MH+ - H2O), 225, 185,
167, 141, 113, 73. HRMS (CI): calcd for C14H25O4: 257.1753
(MH+ - H2O), obsd 257.1745. BuLi (2.5M in hexane, 24 mL,
60 mmol) was added to a suspension of Ph3PMe+ I- (23.6 g,
58.5 mmol) in THF (150 mL) at 0 °C, followed, 30 min later,
by a solution of lactol (5.34 g, 19.5 mmol) in THF (35 mL).
After stirring for 1 h, the mixture was diluted with ether (250
mL), washed with H2O (150 mL), dried (Na2SO4), and concen-
trated. The residue was treated with petroleum ether (200
mL), the precipitate was filtered off, and the solution was
concentrated. Chromatography gave 4.2 g (79%) of alcohol 6,
colorless oil. 1H: 5.61 (m, 1H), 5.07 (m, 2H), 4.00 (m, 1H),
3.93 (d, 1H, J ) 1.9 Hz), 3.89 (d, 1H, J ) 1.9 Hz), 3.66 (m,
2H), 3.49 (s, 3H), 3.23 (s, 3H), 2.65 (dd, 1H, J ) 13.5 and 4.3
Hz), 2.37 (dd, 1H, J ) 14.1 and 5.7 Hz), 2.29 (dd, 1H, J ) 14.1
and 5.3 Hz), 2.24 (dd, 1H, J ) 13.5 and 4.7 Hz), 1.65-1.56 (m,
3H), 1.34 (s, 3H), 1.33 (s, 3H). 13C: 161.5, 142.7, 115.1, 101.1,
82.9, 67.7, 60.9, 54.7, 49.3, 41.3, 40.9, 38.0, 37.7, 25.3, 25.2.
IR: 3406, 1658. MS (CI): 255 (MH+ - H2O), 241, 223, 209,
moted complex reactions. Attempted hydration of the
enone double bond in 34 with aqueous acid induced
instead an interesting rearrangement to furanone 35,
wherein the enone double bond has formally migrated
to a remote position inside the furanoid ring. We propose
the mechanism of Scheme 9 to account for this notewor-
thy rearrangement. Fortunately, the merger of the
future spiro and bicyclic units by the method detailed in
Scheme 4 resolved all such difficulties.
In summary, this work demonstrates the viability of
our enelike methodology in the synthesis of at least
moderately complex organic structures.17 Even in terms
of length (23 linear steps from butyrolactone as the
longest linear sequence), the present synthesis is com-
parable to several known alternatives (only the Burke
synthesis5c is significantly shorter), but it starts with
structurally simpler materials. This provides an indica-
tion of the synthetic potential of our enelike reaction,
further applications of which will be described in due
course.
Exp er im en ta l Section 18
Ald eh yd e 3. BuLi (2.5 M in hexane, 42 mL, 105 mmol)
was added to a cold (-78 °C) solution of iPr2NH (10.6 g, 105
mmol) in THF (200 mL, Ar). After 30 min, γ-butyrolactone
(9.04 g, 105 mmol) was added. Stirring at -78 °C was
continued for 45 min before addition of allyl bromide (12.7 g,
105 mmol). The reaction mixture was warmed to -20 °C,
quenched with saturated aqueous NaHCO3, and extracted
(EtOAc). The combined extracts were dried (Na2SO4) and
concentrated to give 11.5 g of 2-allylbutyrolactone as a colorless
oil. Ozonized oxygen was bubbled through a cold (-78 °C)
solution of this material in CH2Cl2 (150 mL) and MeOH (20
183, 151, 113, 73. HRMS (CI): calcd for C15H27O3 (MH+
-
H2O) 255.1960, obsd 255.1955. Anal. Calcd for C15H28O4: C
66.14%, H 10.36%, Found: C 65.92%, H 10.34%.
Silyl Eth er 7. A cold (0 °C) solution of 3 (4.2 g, 15.4 mmol),
imidazole (4.2 g, 62 mmol), and TBDMSCl (2.6 g, 16.9 mmol)
in 30 mL of DMF was stirred for 30 min, and then it was
diluted with ether (100 mL) and washed with H2O. The ether
layer was dried (Na2SO4) and concentrated to a colorless oil,
5.7 g, 96% yield. 1H: 5.56 (m, 1H), 5.02 (m, 2H), 4.21 (m, 2H),
3.99 (d, 1H, J ) 1.5 Hz), 3.86 (d, 1H, J ) 1.5 Hz), 3.59 (m,
2H), 3.21 (s, 3H), 3.14 (s, 3H), 2.89 (dd, 1H, J ) 13.5 and 4.4
Hz), 2.59 (dd, 1H, J ) 13.7 and 6.8 Hz), 2.37 (dd, 1H, J ) 13.7
and 6.8 Hz), 2.22 (dd, 1H, J ) 13.5 and 9.0 Hz), 1.42-1.35 (m,
3H), 1.36 (s, 3H), 1.32 (s, 3H), 0.91(s, 9H), 0.04 (s, 6H). 13C:
162.6, 143.6, 115.3, 101.3, 83.1, 69.1, 61.4, 54.7, 49.3, 42.8, 41.9,
39.3, 37.9, 26.5, 26.1, 26.0, 18.9, -4.72 ppm. IR: 1652. MS
(CI): 355 (MH+ - CH3OH), 297, 257, 165, 89. HRMS (CI):
calcd for C20H39O3Si (MH+ - CH3OH) 355.2669, found 355.2663.
(17) For an asymmetric variant of this chemistry see: Carreira, E.;
Lee, W.; Singer,R. A. J . Am. Chem. Soc. 1995, 117, 3649.
(18) Unless otherwise indicated: (a) NMR spectra (ppm, δ, 1H )
250; 13C ) 62.5 MHz, 25 °C) were recorded in CDCl3. Splitting: “s”
(singlet), “d”, “dd”, etc. (doublet, doublet of doublets, etc.), “t” (triplet),
“q” (quartet), “m” (multiplet), “app” (apparent), “br” (broad), or “c”
(complex). (b) FTIR spectra (cm-1) were obtained from films on NaCl
plates. (c) Low and high res mass spectra (m/e) were obtained in the
CI (CH4) or EI (70 eV) mode. All sensitive reactions were carried out
under Ar. MeOH: dried over 4 Å mol sieves; EtOAc, MP: dist at atm.
press; CH2Cl2, Et3N, iPr2NH: dist from CaH2 at atm press.; THF: dist
from Na/Ph2CO. Elemental analyses were performed by Galbraith-
Laboratories, Knoxville, TN.

7810 J . Org. Chem., Vol. 62, No. 22, 1997
Ciufolini et al.
Anal. Calcd for C21H42O4Si: C 65.24%, H 10.95%. Found: C
65.31%, H 10.90%.
5.56 (m,1H), 5.05 (m, 2H), 4.08 (m, 1H), 3.62-3.55 (br, 4H),
3.19 (s, 3H), 3.17 (s, 3H), 3.10 (s, 3H), 2.76-2.52 (m, 2H), 2.37-
1.97 (m, 3H), 1.78-1.55 (m, 3H), 1.59 (s, 3H), 1.44 (s, 3H), 1.11
(d, 3H, J ) 5.4 Hz), 0.99 (s, 9H), 0.03 (s, 6H). 13C: 183.4, 143.1,
115.8, 103.1, 102.1, 96.4, 82.2, 67.7, 66.9, 61.2, 50.0, 49.4, 48.8,
41.3, 39.6, 39.3, 38.4, 30.3, 26.51, 26.47, 25.13, 25.10, 18.8, 16.9,
Alcoh ol 8. Purified MCPBA (2.3 g, 13.5 mmol) in CH2Cl2
(7 mL) was added to a cold (0 °C) mixture of silyl ether 7 (3.5
g, 9 mmol), powdered K2CO3 (200 mg), dry MeOH (5 mL), and
CH2Cl2 (20 mL). After 2 h of vigorous stirring, the mixture
was diluted with CH2Cl2 (50 mL), washed (1 N aqueous
NaOH), dried (Na2SO4), and concentrated. Chromatography
gave 2.85 g (73%) of 8 as a colorless oil. 1H: 5.50 (m,1H), 5.05
(m, 2H), 4.12 (m,1H), 3.90 (dd, 1H, J ) 12.0 and 9.5 Hz), 3.76
(dd, 1H, J ) 12.0 and 5.3 Hz), 3.63 (m, 2H), 3.19 (s, 3H), 3.12
(s,3H), 3.03 (s,3H), 2.19-1.93 (m, 4H), 1.77-1.38 (m, 3H), 1.35
(s, 3H), 1.23 (s, 3H), 0.99 (s, 9H), 0.07 (s, 6H). 13C: 142.0,
115.7, 101.9, 101.4, 68.4, 62.4, 60.6, 49.0, 48.1, 40.0, 38.8, 37.9,
37.5, 36.7, 26.0, 25.4, 25.2, 18.3, -5.22. IR: 3462, 1638. MS
(EI): 403 (MH+ - CH3OH), 331, 313, 255, 185, 155, 129, 73.
HRMS (EI): calcd for C21H43O5Si (MH+ - CH3OH) 403.2880,
obsd 403.2876. Anal. Calcd for C22H46O6Si: C 60.79%, H
10.67%. Found: C 60.63%, H 10.63%.
Ald eh yd e 9. Alcohol 8 (3.5 g, 8.1 mmol) in CH2Cl2 (10 mL)
was added at rt to a slurry of NMO (1.9 g, 16.1 mmol), TPAP
(100 mg, 0.3 mmol), and 4 Å mol sieve (1.8 g) in CH2Cl2 (100
mL). After stirring for 2 h, the mixture was filtered (Celite)
and concentrated. The resulting dark oil was treated with
hexane (30 mL), and the dark ppt was filtered off. Concentra-
tion of the filtrate gave 3.5 g (100%) of the sensitive aldehyde,
light yellow oil. 1H (C6D6): 9.29 (s, 1H), 5.39 (m, 1H), 4.94
(m,2H), 3.88 (m, 1H), 3.53 (m, 2H), 3.12 (s, 3H), 3.03 (s, 3H),
3.02 (s, 3H), 2.19-1.91 (m, 4H), 1.59-1.24 (m, 3H), 1.38 (3,
3H), 1.18 (s, 3H), 0.93 (s, 1H), 0.01 (s, 6H). 13C (C6D6): 197.1,
142.9, 115.8, 101.9,101.6, 67.6, 60.9, 50.1, 48.9, 48.8, 40.6, 39.6,
38.7, 38.3, 26.5, 25.6, 25.3, 18.8, -4.9. IR: 1751, 1669. MS
(CI): 401 (MH+ - CH3OH), 375, 343, 311, 179, 115, 73. HRMS
(CI): calcd for C21H41O5Si (MH+ - CH3OH) 401.2723, obsd
401.2715. Anal. Calcd for C22H44O6Si: C 61.07%, H 10.25%.
Found: C 61.40%, H 10.10%.
14.6, -4.8, -4.9. IR: 2220, 1689. MS (CI): 597 (MH+
-
CH3OH), 555, 539, 403, 313, 185, 73. HRMS (CI): calcd for
C32H61O6Si2 (MH+ - CH3OH) 597.4007, obsd 597.3997.
Sp ir ok eta l 15. A mixture of ynone 12 (145 mg, 0.23 mmol),
MeOH (4 mL), and benzyltrimethylammonium hydroxide
(“Triton B”, 40 wt % in MeOH, 1.2 equiv) was stirred at rt for
10 h, and then it was diluted with ether (25 mL) and washed
(H2
O). The ether layer was dried (Na2SO4) and concentrated,
and the crude product 13 was dissolved in THF (3 mL)/water
(1.2 mL). Neat TFA (0.7 mL) was slowly added, and 2 h later
the mixture was neutralized (saturated aqueous NaHCO3) and
extracted (CH2Cl2). The extracts were dried (Na2SO4) and
concentrated to give 47 mg (62% over two steps) of diol 14. To
a solution of this diol in dry CH2Cl2 (4 mL) was added CSA (5
mg). After 12 h at rt, the mixture was washed (saturated
aqueous NaHCO3), dried (Na2SO4), and concentrated to give
34 mg (71%) of 15. 1H: 5.54 (m, 1H), 5.01 (m, 2H), 4.10-3.98
(m, 2H), 3.74-3.59 (m, 3H), 3.38 (s, 3H), 3.23 (s, 3H), 2.87-
2.35 (m, 4H), 2.16 (m, 1H), 1.78-1.46 (m, 5H), 0.98 (d, 3H, J
) 6.6 Hz). 13C: 207.0, 141.9, 116.1, 108.8, 106.9, 74.8, 73.1,
65.5, 60.9, 50.5, 49.4, 47.2, 44.7, 38.4, 37.9, 36.0, 9.2. IR: 3458,
2936, 1717, 1454, 1387, 1325, 1287, 1173, 130, 1063, 982, 920.
MS (EI): 297 (MH+ - CH3OH), 265, 200, 185, 155, 127, 115,
101, 88. HRMS (EI): calcd for C16H25O5 (MH+ - CH3OH)
297.1702, obsd 297.1695.
F u r a n on e 17. To a cold (0 °C) solution of 15 (135 mg, 0.41
mmol) and Et3N (280 µL, 5 equiv) in CH2Cl2 (7 mL) was added
MsCl (40 µL, 1.2 equiv). After 30 min, the mixture was washed
(saturated aqueous NaHCO3), dried (Na2SO4), and concen-
trated. The crude mesylate and NaI (200 mg, 1.3 mmol) in
acetone (10 mL) was refluxed for 7 h and then cooled, filtered
(Celite), and partitioned between ether (20 mL) and water (10
Alk yn e 10. A solution of commercial 2-methyl-1,3-pro-
panediol (8.1 g, 90 mmol), TBDMS-Cl (13.6 g, 90 mmol), and
imidazole (6.8 g, 100 mmol) in DMF (80 mL) was stirred at 0
°C for 30 min and then it was diluted with ether (250 mL),
washed with water, dried (Na2SO4), and concentrated. Chro-
matography (10% EtOAc/hexane) gave 8.6 g (47% yield,
colorless oil) of the mono-TBS ether derivative. This material
(8.5 g, 42 mmol) was dissolved in CH2Cl2 (100 mL) and treated
with PDC (23.5 g, 1.5 equiv) at rt. After 4 h, the mixture was
filtered and concentrated, and the residue was chromato-
graphed (20% EtOAc/hexane) to give 6.9 g (81% yield, colorless
oil) of the expected aldehyde. A solution of this aldehyde in
CH2Cl2 (20 mL) was introduced into a cold (0 °C) preformed
slurry of Corey-Fuchs reagent, which had been prepared by
the addition of a solution of CBr4 (22.7 g, 68.4 mmol) in CH2Cl2
(40 mL) into a cold (0 °C) suspension of Zn powder (4.5 g,
68.7mmol) and Ph3P (17.9g, 68.3 mmole) in CH2Cl2 (200 mL),
followed by stirring for 20 min. The reaction mixture was
stirred at rt for 1 h, and then it was poured into petroleum
ether (1 L), filtered to remove the precipitate, and concentrated
to give the dibromo olefin (oil). A cold (-78 °C) solution of
this oil in THF (60 mL) was treated with BuLi (2.5 M in
hexane, 28 mL, 70 mmol), and after 30 min the mixture was
quenched with saturated aqueous NaHCO3 and extracted with
Et2O. The ether extract was concentrated and the residue
chromatographed (100% hexane) to give 4.3 g (63% over two
steps) of alkyne 10 as a colorless oil. 1H: 3.70 (dd, 1H, J )
9.5, 5.3 Hz), 3.46 (dd, 1H, J ) 9.5, 7.1 Hz), 2.56 (m, 1H), 2.03
(d, 1H, J ) 2.4 Hz), 1.18 (d, 1H, J ) 6.7 Hz), 0.90 (s, 9H), 0.06
(s, 6H). 13C: 86.6, 69.2, 67.3, 29.2, 26.1, 18.5, 17.4, -5.2.
Yn on e 12. BuLi (2.5 M in hexane, 1.0 mL, 2.5 mmol) was
added to a cold (-78 °C) solution of alkyne 10 (464 mg, 2.34
mmol) in THF (5 mL, Ar). After stirring for 20 min, a solution
of aldehyde 9 (714 mg, 1.65 mmol) in THF (3 mL) was added,
and after 1 h, the reaction was quenched (saturated aqueous
NaHCO3) and extracted with EtOAc. The extracts were dried
(Na2SO4) and concentrated, and the crude alcohol 11 was
submitted to TPAP oxidation using the same protocol described
above for 8. Chromatography (20% EtOAc/hexanes) provided
920 mg (89% over two steps) of ynone 12, colorless oil. 1H:
mL). The ether layer was dried (Na2
SO4) and concentrated.
Flash chromatography gave 138 mg (78% over two steps) of
iodide 16. 1H: 5.40 (m, 1H), 5.09 (m, 2H), 4.04-3.97 (m, 2H),
3.77-3.72 (m, 1H), 3.40 (s, 3H), 3.28 (s, 3H), 3.20 (m, 1H), 3.07
(m, 1H), 2.65 (m, 2H), 2.47-2.37 (m, 2H), 2.11 (m, 1H), 1.90-
1.61 (m, 5H), 0.99 (d, 3H, J ) 6.5 Hz).
108.0, 107.0, 74.6, 65.5, 50.6, 49.4, 47.2, 44.9, 42.6, 38.8, 38.6,
- CH3OH), 386,
13C: 206.9, 140.1, 116.7,
36.0, 9.2, 4.6. IR: 1729. MS (EI): 407 (MH+
371, 330, 197, 183, 115, 101. HRMS (EI): calc for C16H24O4I
(MH+ - CH3OH) 407.0719, found 407.0712. Powdered NaBH4
(50 mg, 1.3 mmol) was added to a cold (0 °C) solution of 16
(113 mg, 0.26 mmol) in MeOH (5 mL) and THF (0.5 mL). After
30 min, the reaction was quenched (saturated aqueous NH4
Cl)
and extracted (EtOAc). The extracts were dried (Na2SO4) and
concentrated. The crude product was dissolved in HCOOH
(0.8 mL). After 1 h, the solution was neutralized (saturated
aqueous NaHCO3
) and extracted (CH2Cl2). The extracts were
dried (Na2SO4) and concentrated to give 100 mg (96% over two
steps) of furanone 17, colorless oil. 1H: 5.50 (m, 1H), 5.15 (m,
2H), 4.47 (m, 1H), 3.89 (m, 1H), 3.83-3.61 (m, 2H), 3.27 (m,
1H), 3.07 (m, 1H), 2.69-2.58 (m, 1H), 2.49-2.39 (m, 1H), 2.28
(m, 1H), 2.08-1.72 (m, 7H), 0.95-0.90 (m, 3H). 13C: 207.2,
140.1, 117.3, 98.9, 73.8, 67.5, 62.4, 42.5, 40.1, 39.2, 38.1, 35.1,
35.4, 13.3, 4.7. IR: 1762, 1649. MS (EI): 395 (MH+), 377,
366, 294, 263, 236, 195, 154, 131, 109. HRMS (EI): calcd for
C15H22O3I (MH+ - H2O) 377.0614, obsd 377.0608. Anal. Calcd
for C15
H23O4I: C 45.70%, H 5.88%. Found C 45.94%, H 5.92%.
Dik eto Ester 2. A THF solution of t-BuOK (67 mg, 0.60
mmol) was added to a cold (0 °C) solution of furanone 17 (80
mg, 0.20 mmol) in THF (4 mL, Ar atm). After 30 min, the
reaction was neutralized (saturated aqueous NH4Cl) and
extracted with ether. The extracts were dried (Na2SO4) and
concentrated, and the crude tricyclic compound 18 was dis-
solved in a mixture of CCl4 (2 mL), CH3CN (2 mL), H2O (3
mL), KIO4 (150 mg, 3 equiv), and RuCl3 (3 mg, 0.05 equiv).
This biphasic mixture was stirred vigorously for 2 h at rt, and
then it was extracted with CH2Cl2. The extracts were dried
(Na2SO4) and concentrated to give 20 mg (35% over two steps)

Enelike Reactions of Aldehydes with Vinyl Ethers
J . Org. Chem., Vol. 62, No. 22, 1997 7811
of acid 19. A mixture of this crude acid (14 mg, 0.05 mmol),
THF (0.5 mL), powdered K2CO3 (10 mg), and MeI (12 µL, 4
equiv) was stirred at rt for 4 h, and then it was diluted with
ether (5 mL), washed with H2O, dried (Na2SO4), and concen-
trated to give a mixture of four diastereomers of 2. A solution
of this material and DBU (50 µL) in 1 mL of dry THF was
stirred overnight, and then it was diluted with EtOAc, washed
(saturated aqueous NH4Cl), and concentrated. Prep TLC
provided 9 mg (60% over two steps) of diketo ester 2. 1H: 4.54
(m, 1H), 4.01 (dd, 1H, J ) 11.1 and 7.2 Hz), 3.79 (dd, 1H, J 1
) J 2 ) 11.1 Hz), 3.70 (s, 3H), 3.01 (d, 1H, J ) 14.5 Hz), 2.83-
2.74 (m, 2H), 2.60-2.46 (m, 3H), 2.35 (d, 1H, J ) 14.5 Hz),
2.04-1.71 (m, 4H), 1.03 (d, 3H, J ) 6.6 Hz). 13C: 208.2, 205.2,
175.7, 102.9, 72.1, 66.8, 52.1, 46.2, 45.0, 42.4, 36.7, 29.2, 26.3,
23.2, 9.3. IR: 1766, 1723. MS: 296 (M+), 265, 185, 140, 111.
HRMS (EI): calcd for C15H20O6 296.1260, obsd 296.1252. Anal.
Calcd for C15H20O6: C 60.80%, H 6.80%. Found C 60.71%, H
6.80%.
(()-P h ylla n th ocin 1. To a solution of ester 2 (5 mg, 17
µmol) in DMSO (0.3 mL) was added a solution of dimethy-
loxosulfonium methylide in DMSO (1.2 equiv). After 15 min,
the mixture was quenched (saturated aqueous NH4Cl) and
extracted with ether (10 mL). The extracts were washed with
water, dried (Na2SO4), and concentrated. A cold (0 °C) solution
of the resulting crude epoxide 21 in MeOH (1 mL) and THF
(0.1 mL) was treated with powdered NaBH4 (5 mg, 0.13 mmol),
and after 30 min, it was quenched with saturated aqueous
NH4Cl and extracted with ether. The extracts were dried
(Na2SO4) and concentrated to give 4 mg (76% over two steps)
of alcohol 22. A solution of this alcohol in 2 mL of CH2Cl2
containing DMAP (10 mg, 6 equiv) and cinnamoyl chloride (7
mg, 3 equiv) was refluxed for 4 h and then washed (H2O) and
concentrated. Preparative TLC provided and recrystallization
(1:9 ether/hexane) gave a 71% yield of (()-phyllanthocin,
colorless prisms, mp 113-115 °C. 1H: 7.77 (d, 1H, J ) 15.9
Hz), 7.56-7.52 (m, 2H), 7.40-7.36 (m, 3H), 6.49 (d, 1H, J )
15.9 Hz), 5.09 (br q, 1H, J ) 2.7 Hz), 4.39 (dd, 1H, J ) 6.5
and 3.8 Hz), 4.02 (dd, 1H, J 1 ≈ J 2 ) 11.3 Hz), 3.45 (dd, 1H, J
) 11.3 and 4.5 Hz), 3.28 (s, 3H), 2.95 (AB q, 2H, J ) 13.2 and
5.4 Hz), 2.42 (tt, 1H, J ) 11.9 and 3.4 Hz), 2.23 (br d, 1H, J )
14.5 Hz), 2.04 (dd, 1H, J ) 15.2 and 2.8 Hz), 1.98-1.85 (m,
2H), 1.72 (ddd, 1H, J ) 3.6, 12.3, 14.7 Hz), 1.63 (dd, 1H, J )
15.3 and 3.2 Hz), 1.60-1.37 (m, 2H), 1.33-1.19 (m, 2H), 0.88
(d, 3H, J ) 7.0 Hz). 13C: 176.1, 166.9, 144.5, 134.8, 130.0,
128.8, 128.0, 118.9, 101.9, 72.7, 71.1, 70.0, 63.4, 51.2, 50.2, 38.7,
37.0, 34.4, 33.1, 26.5, 22.4, 12.8. IR: 1736, 1709, 1643. MS
(EI): 442 (M+), 411, 392, 294, 263, 182, 148, 131, 113. HRMS
(EI): calcd for C25H30O7 (M+) 442.1992, obsd 442.1987. Anal.
Calcd for C25H30O7: C 67.86%, H 6.83%. Found C 67.78%, H
6.80%.
Ack n ow led gm en t. We gratefully acknowledge the
National Institutes of Health (CA-55268), the National
Science Foundation (CHE 95-26183), and the Robert A.
Welch Foundation (C-1007) for their generous support
of our research program. M.A.C. is a Fellow of the
Alfred P. Sloan Foundation, 1994-1998.
Su p p or tin g In for m a tion Ava ila ble: Hardcopy spectra of
compounds 20 and 2 before and after equilibration (5 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
the journal, and can be ordered from the ACS; see any current
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J O971151W