Pestalotiopsin A. Side chain installation and exhaustive probing of olefin metathesis as a possible tool for elaborating the cyclononene ring

Article abstract of DOI:10.1021/jo070862j

(Chemical Equation Presented) A program directed toward an asymmetric synthesis of pestalotiopsin A is described. The routing begins with the dextrorotatory cyclobutanol 37, which is combined with the enantiomerically defined building blocks ent-15 and 16

Full text of DOI:10.1021/jo070862j

Pestalotiopsin A. Side Chain Installation and Exhaustive Probing of
Olefin Metathesis as a Possible Tool for Elaborating the
Cyclononene Ring
Leo A. Paquette,* Shuzhi Dong, and Gregory D. Parker
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette.1@osu.edu
ReceiVed April 24, 2007
A program directed toward an asymmetric synthesis of pestalotiopsin A is described. The routing begins
with the dextrorotatory cyclobutanol 37, which is combined with the enantiomerically defined building
blocks ent-15 and 16. These units are incorporated via stereocontrolled 1,2-nucleophilic addition and
anti-aldol coupling, respectively. With these straightforward reactions accomplished, the sequel involved
the introduction of terminal double bonds in anticipation of the fact that the (E)-cyclononene substructure
could be realized by ring-closing metathesis. This central issue was evaluated with several diene substrates
and catalysts, all to no avail. Cross-metathesis experiments involving 59 and 65 with the functionalized
heptene 60 revealed a marked difference in the inability to engage interaction with the ruthenium catalyst.
This awkwardness could not be skirted.
SCHEME 1. Retrosynthetic Analysis
Introduction
The previous report in this issue outlines three strategies
potentially suited to an asymmetric synthesis of the immuno-
suppressant known as pestalotiopsin A (1).1 Either 2, 3, or 4
(Scheme 1) was considered to be a potential precursor of 1.
Should a workable pathway to 1 be developed from any one of
these building blocks, the road would be opened to access the
enantiomer as well, with the ultimate goals being determination
of the absolute configuration of the target via synthesis and
broader-based pharmacologic evaluation. As matters have turned
out, a successful preparative route to 1 has so far proven elusive.
Details of the reaction sequences that have nevertheless
advanced our quest are presented herein.
Results and Discussion
Demise of the [4.2.0] Bicyclic Lactone Approach. The first
avenue to be pursued involved lactone 2 where the need existed
to invert configuration at the vinyl substituted carbon. This
objective was initially pursued by cleaving the unsaturated
substituent in 2 via ozonolysis to arrive at aldehyde 5 (Scheme
2). We soon came to recognize that 5 is a very labile substance.
(1) Paquette, L. A.; Parker, G. D.; Tei, T.; Dong, S. J. Org. Chem. 2007,
72, 7125.
10.1021/jo070862j CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/15/2007
J. Org. Chem. 2007, 72, 7135-7147
7135

Paquette et al.
SCHEME 2. Assessment of C-14 Installation
group did not survive. An alternative one-pot procedure involv-
ing IBX and DMSO in toluene3 did not lead to incorporation
of a double bond as in 13, whose fate was to serve as the
precursor to 14 via catalytic hydrogenation. The developments
summarized above prompted us to consider the utilization of
intermediates 3 and 4, the availability of which offered the
prospect of reasonable convergency.
Preliminary Assessment of the Core Buildup. To realize
these sub-goals, suitable side chain fragments were required.
From among several options, we came to favor 15 and 16.
Following their proper incorporation, medium-ring formation
was envisioned to be realizable.
Our approach to 15 and its aldol coupling to 3 are detailed
in Scheme 4. The known allylic alcohol 174 was arrived at by
sequential O-benzylation of 3-butyn-1-ol,5 hydroxymethylation
with paraformaldehyde and n-butyllithium,6 and reduction with
Red-Al.7 The key Sharpless asymmetric epoxidation was
accomplished with (-)-diisopropyl tartrate under standard
conditions at -20 °C.8 Conversion of 18 to the corresponding
SCHEME 3. Issue of Ring Unsaturation
1
Mosher ester confirmed by H NMR that a single enantiomer
had been formed.9 The subsequent acquisition of iodo epoxide
19 was cleanly realized through the agency of triphenylphos-
phine and iodine in the presence of imidazole.10 To position
ourselves to produce 15, 19 was subjected to the action of
n-butyllithium in THF,11 and the resulting vinyl carbinol 20 was
treated with potassium hydride in the presence of dimethyl
sulfate. Dihydroxylation of 21 followed by diol cleavage
delivered the lower side chain smoothly.
Installation of the lower side chain in 3 was initiated by
deprotonation with sodium hexamethyldisilazide in THF at -78
°C. Capture of the resulting enolate anion with aldehyde 15
proceeded stereoselectively to deliver anti-aldol 23 as the major
characterizable product. The stereochemical assignment to 23
was established by sodium borohydride reduction to give triol
24 (alongside a lesser amount of the elimination product 25)
and subsequent conversion of 24 into the corresponding cyclic
acetal 26 (Scheme 5).12 A vicinal coupling constant of 12.3 Hz
for the 1,3-dioxanyl ring protons confirmed the trans disposition
of its pendant groups. Consequently, the stereocontrol operating
While NMR spectroscopy of the crude product indicated the
transformation to have been successful, the material decomposes
when absorbed on silica gel or when subjected to the mildest
reagent combination for generating a cyclic acetal such as 6. In
an effort to reach comparable advancement in fewer steps, 1,4-
addition2 of the 1,3-dithianyl anion to enone 7 was also
investigated. Unfortunately, C-C bond formation proved not
to be effective under a variety of conditions. Another possible
solution that was entertained involved the regioselective ozo-
nolysis of 9. In fact, the nonequivalence of its two olefinic sites
can be relied upon to produce 10 following exposure to ozone.
However, yields in excess of 43% could not be realized and
lability issues persisted.
As a consequence, attention was redirected to lactone 11.
Initially, we sought to introduce an intracyclic double bond
patterned after the organoselenium approach applied earlier.1
In light of this analogy, it was disappointing to learn that
treatment of 11 with LDA and phenylselenenyl chloride at -78
°C gave no reaction, while the corresponding reaction at -20
°C led to decomposition (Scheme 3). When alternate recourse
was made to activation of the system as the silyl ketene acetal
in advance of quenching with PhSeCl, the MOM protecting
(3) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L. J. Am.
Chem. Soc. 2002, 124, 2245.
(4) (a) Dias, L. C.; DeOliveira, L. G. Org. Lett. 2004, 6, 2587. (b) Deba,
T.; Yakushiji, F.; Shindo, M.; Shishido, K. Synlett 2003, 1500.
(5) (a) Yadav, J. S.; Srihari, P. Tetrahedron: Asymmetry 2004, 15, 81.
(b) Giessert, A. J.; Brazis, N. J.; Diver, S. T. Org. Lett. 2003, 5, 3819.
(6) (a) Razon, P.; N’Zoutani, M.-A.; Dhulut, S.; Bazzenine-Lafollee, S.;
Pancrazi, A.; Ardisson, J. Synthesis 2005, 109. (b) Schomaker, J. M.;
Pulgam, V. R.; Borham, B. J. Am. Chem. Soc. 2004, 126, 13600.
(7) (a) Zhou, X.-T.; Carter, R. G. Chem. Commun. 2004, 2138. (b)
Ishihara, J.; Ishizaka, T.; Suzuki, T.; Hatakeyama, S. Tetrahedron Lett. 2004,
45, 7855.
(8) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S.-Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(9) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543.
(10) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1980,
2866.
(11) Marshall, J. A.; Sedrani, R. J. Org. Chem. 1991, 56, 5496.
(12) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem.
Res. 1998, 31, 9.
(2) (a) Brown, C. A.; Yamaichi, A. Chem. Commun. 1979, 100. (b)
Ziegler, F. E.; Fang, J. M.; Tam, C. C. J. Am. Chem. Soc., 1982, 104, 7174.
7136 J. Org. Chem., Vol. 72, No. 19, 2007

Pestalotiopsin A: Elaboration of the Cyclononene Ring
SCHEME 4. Enantioselective Aldol Coupling of 15 to Bicyclic Lactone 3
SCHEME 5. Proof of Stereochemistry of 23
during the formation of 23 likely results from convex-face
approach to the bicyclo[3.2.0]heptane framework with adoption
of a chelated chairlike transition state as depicted in 22.
In accord with the retrosynthetic plan, we next set for
ourselves the task of attaching a suitable upper chain segment
stereoselectively onto an intermediate cyclobutane derivable
from 4.1 To this end, advantage was taken of two relevant
aspects of strategy level design. It was reasoned that cyclobu-
tanol 4 would be straightforwardly amenable to oxidation to
give 28 and that the ketone carbonyl so introduced would
experience nucleophilic attack from the R-face to avoid
encounter with the bulky OTBS substituent (Scheme 6). At the
experimental level, the hydrogenolysis step to provide alcohol
4 and perruthenate oxidation of the latter to generate 28
proceeded quantitatively. Advantage was subsequently taken of
the ready availability of highly enantioenriched (S)-4-bromo-
2-methylpent-4-en-1-ol.13 Following conversion to the PMB
ether 16 and metalation with tert-butyllithium, coupling to
provide 29 proceeded well. The successful testing of this critical
reaction conformed nicely to the expected stereoselectivity as
deduced by COSY/NOESY correlations between H-3 and H-4,
in addition to a NOESY interaction involving H-4 and a vinyl
proton.
Advanced Side-Chain Construction. Following arrival at
29, the plan entailed subsequent elaboration of the bicyclic
lactone core. However, selective deprotection of a MOM ether
in the presence of an acid labile PMB ether can be challenging.
For example, B-bromocatecholborane, which has been reported
to allow the survival of a primary PMB ether while unmasking
a secondary MOM substituent,14 proved sufficiently reactive to
remove both groups in 29 within 5 min at -100 °C to generate
a triol. In contrast, conditions involving pyridinium tosylate in
tert-butyl alcohol at reflux15 proved mild enough for our
purposes. Possible dehydration of the allylic tertiary alcohol16
in 30 was largely suppressed by making recourse to this solvent
(Scheme 7). Oxidation of 30 with TPAP and NMO resulted in
the smooth generation of lactone 31.
(14) Paquette, L. A.; Gao, Z.; Ni, Z.; Smith, G. F. J. Am. Chem. Soc.
1998, 120, 2543.
(15) Ghosh, A. K.; Wang, Y.; Kim, J. T. J. Org. Chem. 2001, 66,
8973.
(16) Chang, N.-C.; Chang, C.-K. J. Org. Chem. 1996, 61, 4967.
(13) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988,
110, 2506.
J. Org. Chem, Vol. 72, No. 19, 2007 7137

Paquette et al.
SCHEME 6. Upper Side Chain Incorporation
SCHEME 7. Pathway to Deoxygenated Lactone 34
SCHEME 8. Attachment of the Lower Side Chain
At this point, the OTBS substituent in 31 was expected to
contribute little to the diastereoselectivity of the pending aldol
reaction. Consequently, deoxygenation was undertaken by
sequential desilylation, thiocarbonate formation,17 and tin hy-
dride reduction. The notably crowded environment of the
hydroxyl group in 32 required the adoption of forcing conditions
to form O,O-thiocarbonate 33 (alongside a trace amount of the
isomeric O,S-thiocarbonate) and to bring about the targeted
delivery of 34. Initial attempts to bring about reductive removal
of the thiocarbonate functionality resulted in reversion to starting
alcohol 32 (use of less than 0.1 equiv AIBN) or formation of
an unknown side product (use of more than 1 equiv AIBN).
After extensive optimization studies, it was uncovered that the
heating of 33 with Bu3SnH (4 equiv) and AIBN (0.6 equiv) in
benzene at reflux generated 34 in essentially quantitative yield.
When 34 was next treated with NaHMDS followed by
aldehyde 15, 36 was obtained efficiently (Scheme 8). In its 1H
NMR spectrum, no coupling was observed between H-4 and
H-5, thereby indicating the dihedral angle to approximate 90°.
Added confirmation of this anti relationship was derived from
NOESY correlations involving H-4/H-6â and H-5/H-6R. The
configuration of C-1′′ was deduced by comparison with 23 and
the work of Tadano.18 As in the earlier examples, the stereo-
selectivity of this aldol coupling can be attributed to conse-
quences brought on by the bicyclo[3.2.0]heptane core that forces
aldehyde 15 to approach from the convex face and C-C bond
formation to proceed via the sodium enolate-chelated chairlike
transition state 35 with the lower side chain (R2) pointing away
from the upper side chain (R1).
(18) Takao, K.; Saegusa, H.; Tsujita, T.; Washizawa, T.; Tadano, K.
Tetrahedron Lett. 2005, 46, 5815.
(17) Drescher, M.; Ohler, E.; Zbiral, E. Synthesis 1991, 362.
7138 J. Org. Chem., Vol. 72, No. 19, 2007

Pestalotiopsin A: Elaboration of the Cyclononene Ring
SCHEME 9. Preparation of Aldol Diastereomer 38
the lower side chain. While the coformation of 48 and 49 could
not be remedied by the incremental addition of excess reagents
because of competing dehydration of the secondary carbinol,
the problem was rectified by the chromatographic separation
of 49 and its resubmission to the original selenylation conditions.
Diene 50 was subsequently generated efficiently (90%) by
reaction of 48 with 30% hydrogen peroxide and pyridine in THF
at -40 °C to room temperature.26
Synthesis of RCM Precursors. Concurrent with the work
reported above, significant quantities of (+)-37 were prepared
in parallel fashion1 and transformed as well into the diastere-
omeric aldol 3819 (Scheme 9). With the availability of this
material in quantity, our synthesis was redirected to accom-
modate this modification which shares the same stereogenic
center on the upper side chain, but demands a change to ent-
15. Since the absolute configuration of 1 remains unknown,
acquisition of its enantiomer via 38 would be equally revealing
and diagnostic.
Exploration of RCM Reactions. The availability of 50 set
the stage for exploring the feasibility of ring closing metathesis
(RCM) to construct the unsaturated nine-membered ring. The
development of catalysts that combine high activity with
excellent functional group tolerance has been key to the
widespread application of olefin metathesis in organic synthe-
sis.27 In spite of the generally superb application profile of the
ruthenium carbene 51, its limited thermal stability and low
activity toward substituted double bonds are major drawbacks.28
Exchange of one PCy3 in 51 with a sterically demanding
N-heterocyclic carbene leads to the second generation metathesis
catalyst 52, which displays increased stability and superior
reactivity toward polysubstituted and electron-deficient olefins.29
The phosphine-free catalyst 53, which has been developed
by the Hoveyda group, is a remarkably robust complex that
promotes olefin metathesis by a “release-return” mechanism.30
Its lower initiation activity compared to 52 renders 53 less
advantageous for more challenging metatheses involving the
formation of a trisubstituted double bond.31 However, its
robustness is beneficial for extended reaction times at elevated
temperatures. Follow-up studies aimed at improving this state
The greatly diminished reactivity of the hydroxyl functionality
in 38 was soon recognized.20 This inertness caused us not to be
concerned with a protection strategy en route to 40 (Scheme
10). The first and shorter of two pathways from 38 entailed
initial removal of the pair of PMB groups and subsequent
ozonolytic cleavage of the double bond to afford the triol in
high yield. Alternatively, application of the Johnson-Lemieux
protocol21 resulted in arrival at keto lactone 42 in advance of
the dual deprotection step with TFA.22 The employment of
standard dihydroxylation conditions involving a catalytic amount
of OsO4 in the presence of NMO suffered from a quite slow
reaction rate (>7 days) as a direct result of steric crowding in
the vicinity of the vinyl group. The process was appreciably
accelerated upon use of 2 equiv of pyridine23 but never
proceeded to completion unless recourse was made to stoichio-
metric levels of OsO4. Gratifyingly, these complications were
resolved when the Sharpless dihydroxylation protocol, with
DABCO as promoter, was resorted to.24 Under biphasic condi-
tions with K3Fe(CN)6 as the reoxidant, only one stereoisomer
of 41 was isolated quantitatively.
1
The availability of 40, whose complex H NMR spectrum
indicated the existence of an equilibrium with 40′, was projected
to allow serial application of the Mitsunobu-type aryl selenyl-
ation with o-nitrophenyl selenocyanate and tributylphosphine
(Scheme 11) followed by Grieco olefination upon exposure to
hydrogen peroxide.25 However, the predominant formation of
the 2-cyanotetrahydrofuran 44 demonstrated that prior formation
of acetonide 46 was warranted in order to bypass oxonium ion
generation.20 Subsequent to 2-fold PMB deprotection to generate
47, its exposure to ArSeCN (3.6 equiv) and Bu3P (3.6 equiv)
resulted only in partial conversion to 48 (Scheme 12). This
observation provided indication that the terminal hydroxyl group
in the upper side chain is more crowded than its counterpart in
of affairs have been undertaken by several research groups. For
example, Grela and co-workers introduced an electron-
withdrawing nitro group para to the 2-isopropoxybenzylidene
unit for the purpose of destabilizing the oxygen-metal interac-
tion, thereby facilitating access to the propagating 14-electron
(19) Dong, S. Ph.D. Dissertation, The Ohio State University, 2007.
(20) Dong, S.; Paquette, L. A. Heterocycles 2007, 72, 111.
(21) Pappo, R.; Alen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J. Org.
Chem. 1956, 21, 478.
(26) Pyridine was applied to avoid epoxidation of the resulting 2,2-
disubstituted olefin. See: (a) Grieco, P. A.; Yokoyama, Y.; Gilman, S.;
Nishizawa, M. J. Org. Chem. 1977, 42, 1977. (b) Clayden, J.; Knowles, F.
E.; Baldwin, I. R. J. Am. Chem. Soc. 2005, 127, 2412.
(27) Reviews: (a) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int.
Ed. 2003, 42, 4592. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001,
34, 18. (c) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3013. (d) Grubbs,
R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (e) Schuster, M.; Blechert,
S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2037.
(22) Yan, L.; Kahne, D. Synlett 1995, 523.
(23) (a) Criegee, R.; Marchand, B.; Wannowlus, H. Justus Liebigs Ann.
Chem. 1942, 550, 99. (b) Schroder, M. Chem. ReV. 1980, 80, 187 and
references therein.
(24) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu,
D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768. (b) Dong, S.; Paquette, L.
A. J. Org. Chem. 2005, 70, 1580.
(28) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100.
(25) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485.
(29) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
J. Org. Chem, Vol. 72, No. 19, 2007 7139

Paquette et al.
SCHEME 10. Availability of Triol 40
SCHEME 11. Phenylselenylation of Triol 40
species.32 The faster catalytic cycle initiation exhibited by 54
causes this catalyst to exhibit much improved capacity in ring-
closing, cross, and enyne metathesis while retaining excellent
air and thermal stability. More recently, Zhan and co-workers
adopted a similar strategy and introduced the sulfonamide 55,
which displays even higher reactivity than the Grela catalyst.33
To avail ourselves of several RCM substrates, 50 was
transformed via 56 into keto diene 45 as well as to the MOM-
protected lactone 57 (Scheme 13). The initial ring closure trials
involved 45 and 50 (0.002 or 0.01 M) with 52, 53, and 55 as
the catalyst at 20 °C or more elevated temperatures (40 and 80
°C). In each example, the diene was fully recovered without
any evidence of competing dimerization. Recourse to toluene
at reflux for several hours resulted in substrate decomposition,
but permitted recovery of the Hoveyda catalyst 53. The co-
addition of titanium isopropoxide15 to prevent chelation of the
catalyst with reactants bearing a homoallylic alcohol, if opera-
tive, offered no improvement. Subsequently, the secondary
hydroxyl in 50 was protected as its MOM ether, a small, robust
substituent that was not expected to impede close approach of
the olefinic termini. The exposure of 57 to 55 in toluene (0.01
M) at 80 °C did result in the generation of a new substance,
but it proved to be the isomer 58 and not a product of metathesis.
(30) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 791. (b) Garber, S. B.; Kingsbury, J.
S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168.
(31) (a) Wakamatsu, H.; Blechert, S. Angew. Chem., Int. Ed. 2002, 41,
794. (b) Wakamatsu, H.; Blechert, S. Angew. Chem., Int. Ed. 2002, 41,
2403.
(32) (a) Grela, K.; Harutyunyan, S.; Michrowska, A. Angew. Chem., Int.
Ed. 2002, 41, 4038. (b) Grela, K.; Kim, M. Eur. J. Org. Chem. 2003, 963.
(c) Michrowska, A.; Bujok, R.; Harutyunyan, S.; Sashuk, V.; Dolgonos,
G.; Grela, K. J. Am. Chem. Soc. 2004, 126, 9318. (d) Bieniek, M.; Bujok,
R.; Cabaj, M.; Lugan, N.; Lavigne, G.; Arlt, D.; Grela, K. J. Am. Chem.
Soc. 2006, 128, 13652.
1
The Z-configuration of this product follows from its H NMR
features.
Although the desired RCM product was not obtained, the
formation of 58 clearly demonstrated involvement of the meta-
thesis catalyst.34,35 Interestingly, when monolefin 59, which was
derived from monoselenide 49, was treated with alkene 6036
and the Zhan catalyst under cross metathesis conditions, the
coupling product 61 was obtained (Scheme 14). Accordingly,
(33) Zhan, Z. J. US Patent No. US20070043180A1.
7140 J. Org. Chem., Vol. 72, No. 19, 2007

Pestalotiopsin A: Elaboration of the Cyclononene Ring
SCHEME 12. Arrival at Diene 50
SCHEME 13. Preparation of Additional RCM Substrates
SCHEME 14. Cross-Metathesis Involving 59 and 60
the olefinic center of the lower side chain, when bearing a
homoallylic alcohol, is capable of participation in Ru-promoted
metathesis as long as propagation is initiated in the other reaction
partner. We do not imply that the secondary OH group is
responsible for the formation of 61, but only that it does not
suppress the process.
The metathesis reactivity of the olefinic functionality in the
upper side chain was probed in similar fashion. The preparation
of 65 originated with the regioselective removal of the less
hindered PMB ether by the treatment of 46 with 1.5 equiv of
DDQ (Scheme 15). Masking of the primary hydroxyl in 62 as
the TBDPS ether 63 was followed by treatment with excess
DDQ to generate 64. Subsequent Grieco olefination produced
monoalkene 65 efficiently. However, attempts to apply the same
(34) (a) Schmidt, B. Eur. J. Org. Chem. 2004, 1865. (b) Schmidt, B. J.
Mol. Catal. A 2006, 254, 53.
J. Org. Chem, Vol. 72, No. 19, 2007 7141

Paquette et al.
SCHEME 16. Recourse to Lactol Functionality
SCHEME 15. Attempted Cross-Metathesis Involving 59 and
60
transformed into a series of dienes by Grieco olefination.
Construction of the (E)-cyclononene ring via RCM proved to
be challenging, although not entirely without analogy,40 leading
to the conclusion that a different ring-closing strategy must be
adopted in the future.41
Experimental Section
(1S,6S,7S)-7-Benzyloxy-8,8-dimethyl-3-oxo-2-oxabicyclo[4.2.0]-
oct-4-ene-5-carbaldehyde (10). A stirred solution of 9 (7 mg, 25
µmol) in methanol/CH2Cl2 (1:1) (0.5 mL) was cooled to -78 °C
and treated with ozone for 2 min. N2 gas was bubbled through the
reaction mixture until the blue color had completely dispersed, and
dimethyl sulfide (25 µL) was added. The reaction mixture was
warmed to rt, stirred for 4 h, and partitioned between CH2Cl2 (10
mL) and water (5 mL). The combined organic extracts were washed
with brine (2 mL), and dried. The solvent was evaporated under
reduced pressure to leave a residue that was purified by column
chromatography on silica gel (eluting with an increasing proportion
of ethyl acetate in hexanes from 20 to 30%) to give 10 (3 mg,
43%) as a colorless oil: IR (film, cm-1) 1726, 1697, 1607; 1H NMR
(300 MHz, CDCl3) δ 9.77 (s, 1H), 7.41-7.27 (m, 5H), 6.51 (d, J
) 0.8 Hz, 1H), 4.77 (d, J ) 8.2 Hz, 1H), 4.67 (d, J ) 12.1 Hz,
1H), 4.43 (d, J ) 12.1 Hz, 1H), 3.65 (d, J ) 5.4 Hz, 1H), 3.43 (m,
1H), 1.26 (s, 3H), 1.16 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
192.0, 162.2, 149.9, 137.7, 129.6, 128.4, 127.8, 127.4, 85.2, 79.5,
71.5, 47.2, 34.3, 21.8, 21.1; HRMS (ES) m/z (M + Na)+ calcd
286.1200, obsd 286.1220; [R]2D0 +69.7 (c 0.3, CHCl3).
{(2R,3R)-3-[2′-(4′′-Methoxybenzyloxy)ethyl]oxiranyl}-
methanol (18). A stirred solution of D-(-)-diisopropyl tartrate (0.96
g, 4.10 mmol) in anhydrous CH2Cl2 (40 mL) was treated with 4 Å
molecular sieves (1 g) under nitrogen. After 10 min, the reaction
mixture was cooled to -20 °C and treated with titanium isopro-
poxide (0.99 g, 3.47 mmol). After 30 min, a solution of 17 (700
mg, 3.15 mmol) in anhydrous CH2Cl2 (10 mL) was added, and the
reaction mixture was stirred for a further 90 min. TBHP (5.56 mL,
9.46 mmol) was added, and the resultant mixture was stirred for
12 h at -20 °C, quenched with dimethyl sulfide (0.67 mL), and
warmed to 0 °C. After 1 h, the reaction mixture was filtered through
Celite, which was rinsed with CH2Cl2 (50 mL). The filtrate was
treated with 10% aqueous tartaric acid solution (10 mL), stirred
for 30 min, and separated into layers. The aqueous phase was
cross metathesis conditions described above to generate 66
failed. The efficient recovery of 65 from all of the runs clearly
reflected its lack of reactivity, which in turn impeded us from
exploring relay ring-closing metathesis (RRCM) strategies for
elaboration of the cyclononene ring.37
To lessen the conformational constraints introduced by the
acetonide functionality, it was necessary to generate the diol
without perturbing the MOM ether. Heating 57 with PPTS in
methanol induced the concomitant deprotection of both sites;
nor did the use of triflic acid in trifluoroethanol and THF at 0
°C38 exhibit reasonable chemoselectivity. The most well-suited
conditions were identified to be ferric chloride on silica gel with
CHCl3 as reaction medium39 (Scheme 16). Nevertheless, special
care had to be exercised as too little reagent was ineffective,
while too much resulted in dual cleavage and double bond
migration. Cleavage of the 1,2-diol was successfully ac-
complished with NaIO4 in aqueous methanol, and the resulting
keto lactone 68 was reduced with excess Dibal-H to produce
69. Neither of these advanced intermediates gave evidence of
entering into RCM.
In summary, the upper and lower side chains have been
incorporated via stereo-controlled nucleophilic addition and anti-
aldol reactions, respectively. Several of these potential precursors
to pestalotiopsin A possessing all of the framework carbons were
(35) The observation of isomerization products does not necessarily mean
that the metathesis catalyst interacts directly with the alkene. Impurities in
the metathesis catalyst (Fu¨rstner, A.; Ackermann, L.; Gabor, B.; Goddard,
R.; Lehmann, C. W.; Mynott, R.; Stelzer, F.; Thiel, O. R. Chem. Eur. J.
2001, 7, 3236) or decomposition products thereof (Hong, S. H.; Day, M.
W.; Grubbs. R. H. J. Am. Chem. Soc. 2004, 126, 7414) might be responsible.
Attempts to suppress this side reaction with additives have been probed
(Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem. Soc.
2005, 127, 17160).
(36) Clive, D. L. J.; Yeh, V. S. C. Synth. Commun. 2000, 320, 3267.
(37) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H.
J. Am. Chem. Soc. 2004, 126, 10210.
(38) (a) Kobayashi, S.; Reddy, R. S.; Sugiura, Y.; Sasaki, D.; Miyagawa,
N.; Hirama, M. J. Am. Chem. Soc. 2001, 123, 2887. (b) Holcombe, J. L.;
Livinghouse, T. J. Org. Chem. 1986, 51, 111.
(40) (a) Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene,
B.; Yusuff, N.; Wood, J. L. J. Am. Chem. Soc. 2004, 126, 16300. (b) Li,
Y.; Hale, K. J. Org. Lett. 2007, 9, 1267.
(41) For an example of an alternative tactic as applied to a synthesis of
punctaporonin B, consult: Kende, A. S.; Kaldor, I.; Aslanian, R. J. Am.
Chem. Soc. 1988, 110, 6265.
(39) Kim, K. S.; Song, Y. H.; Lee, B. H.; Hahn, C. S. J. Org. Chem.
1986, 51, 404.
7142 J. Org. Chem., Vol. 72, No. 19, 2007

Pestalotiopsin A: Elaboration of the Cyclononene Ring
extracted with CH2Cl2 (2 × 50 mL), and the combined organic
extracts were dried. The solvent was evaporated under reduced
pressure to yield the crude product, which was purified by column
chromatography on silica gel (eluting with 20-30% ethyl acetate
in hexanes) to provide 18 (683 mg, 91%) as a colorless oil: IR
(film, cm-1) 3430, 1613, 1586; 1H NMR (300 MHz, CDCl3) δ 7.25
(d, J ) 8.6 Hz, 2H), 6.88 (d, J ) 8.6 Hz, 2H), 4.45 (s, 2H), 3.90-
(ddd, J ) 12.5, 5.5, 2.7 Hz, 1H), 3.81 (s, 3H), 3.62 (m, 1H), 3.58
(t, J ) 5.9 Hz, 2H), 3.09 (ddd, J ) 6.7, 5.5, 2.7 Hz, 1H), 2.97 (dt,
J ) 6.7, 2.5 Hz, 1H), 1.99-1.65 (m, 2H), 1.62 (dd, J ) 7.3, 5.5
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 159.2, 130.3, 129.3 (2 C),
113.8 (2 C), 72.8, 66.5, 61.7, 58.4, 55.3, 53.7, 32.0; [R]1D9 +27.0 (c
1.5, CHCl3) (lit. [R]1D9 +27.7 (c 0.9, CHCl3).
7.24 (d, J ) 8.4 Hz, 2H), 6.88 (d, J ) 8.4 Hz, 2H), 4.47-4.36 (m,
2H), 3.80 (s, 3H), 3.78 (m, 1H), 3.60-3.53 (m, 2H), 3.44 (s, 3H),
2.08-1.83 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 203.1, 159.2,
130.2, 129.3 (2 C), 113.8 (2 C), 83.0, 72.6, 64.7, 58.3, 55.3,
30.6; HRMS (ES) m/z (M + Na)+ calcd 261.1103, obsd,
261.1107;[R]1D9 +20.4 (c 1.0, CHCl3).
(1S,4S,5S,6S)-6-Benzyloxy-4-[(2R,3R)-1-hydroxy-2-methoxy-
4-(4-methoxybenzyloxy)butyl]-7,7-dimethyl-2-oxabicyclo[3.2.0]-
heptan-3-one (23). A stirred solution of 3 (100 mg, 0.41 mmol) in
anhydrous THF (8 mL) was cooled to -78 °C under N2 and treated
with NaHMDS (0.49 mL, 1.0 M in THF, 0.49 mmol). After 2 h, a
solution of 15 (193 mg, 0.81 mmol) in THF (2 mL) was added.
The reaction mixture was warmed to rt over 4 h, treated with
saturated NH4Cl solution (10 mL), and extracted with ethyl acetate
(3 × 10 mL). The combined organic extracts were washed with
brine (10 mL), dried, and evaporated under reduced pressure to
leave a residue that was purified by column chromatography on
silica gel (eluting with an increasing proportion of ethyl acetate in
hexanes from 0 to 50%) to give 23 (72 mg, 37%) as a colorless
oil: IR (film, cm-1) 3432, 1767, 1612; 1H NMR (500 MHz, CDCl3)
δ 7.38-7.28 (m, 5H), 7.22 (d, J ) 8.5 Hz, 2H), 6.88 (d, J ) 8.5
Hz, 2H), 4.48 (d, J ) 11.5 Hz, 1H), 4.45 (s, 2H), 4.44 (d, J ) 11.5
Hz, 1H), 4.34 (d, J ) 6.5 Hz, 1H), 3.99 (dd, J ) 3.0, 1.0 Hz, 1H),
3.80 (s, 3H), 3.70-3.64 (m, 2H), 3.61 (dt, J ) 9.0, 2.5 Hz, 1H),
3.55 (d, J ) 5.5 Hz, 1H), 3.48 (ddd, J ) 9.5, 6.5, 3.0 Hz, 1H),
3.37 (s, 3H), 2.88 (s, 1H), 2.87 (t, J ) 6.0 Hz, 1H), 2.00-1.88 (m,
2H), 1.20 (s, 3H), 1.13 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
178.5, 159.5, 137.9, 129.5, 129.3, 128.5, 127.8, 127.6, 113.9, 84.4,
82.0, 79.1, 74.6, 73.1, 71.7, 65.6, 56.8, 55.2, 47.9, 44.4, 43.9, 29.3,
21.6, 19.9; HRMS (ES) m/z (M + Na)+ calcd 507.2359, obsd,
507.2373; [R]1D9 -98.5 (c 0.2, CHCl3).
(3R,4S)-3-(tert-Butyldimethylsilyloxy)-4-(2-(methoxymethoxy)-
ethyl)-2,2-dimethylcyclobutanone (28). A stirred solution of 4 (70
mg, 0.22 mmol) and N-methylmorpholine N-oxide monohydrate
(44 mg, 0.33 mmol) in 10% MeCN/CH2Cl2 (10 mL) was treated
with 4 Å molecular sieves (110 mg) under N2. After 5 min, TPAP
(4 mg, 0.011 mmol) was added, and the reaction mixture was stirred
for a further 30 min and passed through a pad of silica gel which
was rinsed with ethyl acetate (20 mL). The solvent was evaporated
under reduced pressure to yield the crude product, which was
purified by column chromatography on silica gel (elution with
5-10% ethyl acetate in hexanes) to yield 28 (69.5 mg, 100%) as
a colorless oil: IR (film, cm-1) 1777, 1462, 1111, 1043; 1H NMR
(300 MHz, CDCl3) δ 4.61 (s, 2H), 4.18 (d, J ) 7.7 Hz, 1H), 3.62-
3.51 (m, 3H), 3.34 (s, 3H), 1.93-1.83 (m, 2H), 1.20 (s, 3H), 1.03
(s, 3H), 0.91 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 217.2, 96.4, 70.1, 65.8, 62.6, 57.2, 55.2, 25.8 (3
C), 24.0, 22.8, 18.2, 16.1, -4.7, -5.1; HRMS (ES) m/z (M + Na)+
calcd 339.1968, obsd 339.1967; [R]2D1 -1.7 (c 1.57, CHCl3).
(2S,3R)-2-Iodomethyl-3-[2′-(4′′-methoxybenzyloxy)ethyl]ox-
irane (19). A solution of 18 (500 mg, 2.1 mmol) in anhydrous
THF (20 mL) was cooled to 0 °C under N2 in the dark and treated
with triphenylphosphine (716 mg, 2.73 mmol) and imidazole (429
mg, 6.30 mmol). A solution of iodine (693 mg, 2.73 mmol) in
anhydrous THF (5 mL) was added over 1 h, and the reaction
mixture was allowed to warm slowly to rt over a further 1 h,
quenched with saturated Na2S2O3 solution (25 mL), and extracted
with ether (3 × 30 mL). The combined organic extracts were
washed with brine (20 mL) and then dried. The solvent was
evaporated under reduced pressure to leave a residue that was
purified by column chromatography on silica gel (eluting with
0-10% ethyl acetate in hexanes) to give 19 (550 mg, 75%) as a
1
colorless oil: IR (film, cm-1) 1613, 1586, 1514; H NMR (300
MHz, CDCl3) δ 7.26 (d, J ) 8.5 Hz, 2H), 6.89 (d, J ) 8.5 Hz,
2H), 4.50 (s, 2H), 3.89 (s, 3H), 3.57 (m, 2H), 3.24 (m, 1H), 3.10-
3.02 (m, 2H), 2.98 (ddd, J ) 6.5, 5.1, 1.7 Hz, 1H), 1.87 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 159.3, 130.3, 129.3 (2 C), 113.8 (2
C), 72.8, 66.4, 60.4, 58.3, 55.3, 32.2, 4.9; [R]1D9 -4.3 (c 1.1,
CHCl3) (lit. [R]19 -4.3 (c 1.04, CHCl3).
D
(R)-5-(4-Methoxybenzyloxy)pent-1-en-3-ol (20). A stirred solu-
tion of 19 (8.3 g, 23.9 mmol) in anhydrous THF (300 mL) was
cooled to -78 °C under N2 and treated with n-butyllithium (19.6
mL, 31.0 mmol, 1.58 M in hexanes). After 2 h, the reaction mixture
was warmed to -30 °C over 1 h and treated with water (150 mL).
The aqueous layer was extracted with ether (3 × 500 mL), and the
combined organic extracts were washed with brine (200 mL) and
then dried. The solvent was evaporated under reduced pressure to
leave a residue that was purified by column chromatography on
silica gel (eluting with 10-20% ethyl acetate in hexanes) to give
20 (5.14 g, 97%) as a colorless oil: IR (film, cm-1) 3414, 1613,
1
1586; H NMR (300 MHz, CDCl3) δ 7.25 (d, J ) 8.6 Hz, 2H),
6.88 (d, J ) 8.6 Hz, 2H), 5.87 (ddd, J ) 17.3, 10.3, 5.5 Hz, 1H),
5.27 (dd, J ) 17.3, 1.4 Hz, 1H), 5.10 (dd, J ) 10.3, 1.4 Hz, 1H),
4.45 (s, 2H), 4.33 (s, 1H), 3.81 (s, 3H), 3.81-3.56 (m, 2H), 2.88
(d, J ) 3.1 Hz, 1H), 1.92-1.73 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 159.3, 140.5, 130.0, 129.3 (2 C), 114.3, 113.8 (2 C),
(1R,3R,4S)-3-(tert-Butyldimethylsilyloxy)-1-((S)-5-(4-methoxy-
benzyloxy)-4-methylpent-1-en-2-yl)-4-(2-(methoxymethoxy)ethyl)-
2,2-dimethylcyclobutanol (29). To a stirred solution of (S)-1-(4-
methoxybenzyloxy)-2-methyl-4-bromopent-4-ene (16) (0.61 g, 2.05
mmol) in THF (10 mL) at -78 °C was added tert-butyllithium
(2.25 mL, 1.75 M in pentane, 3.93 mmol) slowly. After 15 min, a
solution of 28 (0.54 g, 1.71 mmol) in THF (13 mL) was added
slowly against the wall of the reaction flask. After 3 h at -78 °C,
saturated NH4Cl solution (10 mL) was added. The aqueous layer
was separated and extracted with Et2O (3 × 10 mL). The combined
organic layers were dried and concentrated in vacuo. Purification
of the residue by column chromatography (elution with 5-20%
EtOAc in hexanes) gave 29 (0.65 mg, 71%, 80% borsm) as a
colorless oil, along with starting material 28 (0.060 g, 11%), and
the epimer of 28 (0.083 g, 16%): IR (film, cm-1) 3450, 1614, 1513,
73.0, 72.0, 68.1, 55.3, 36.3; [R]1D9 -9.2 (c 1.0, CHCl3) (lit. [R]19
D
-8.5 (c 0.98, CHCl3).
(R)-2-Methoxy-4-(4′-methoxybenzyloxy)butyraldehyde (15).
A stirred solution of 21 (500 mg, 2.12 mmol) in 1:1 THF/pH 7
buffer (30 mL) was treated with NMO‚H2O (573 mg, 4.24 mmol)
and potassium osmate (78 mg, 0.21 mmol). After 24 h, sodium
bisulfite (2.2 g, 21.2 mmol) was added, and the reaction mixture
was extracted with ethyl acetate (2 × 50 mL). The combined
organic extracts were washed with brine (20 mL) and dried
(MgSO4), and the solvent was evaporated under reduced pressure
to give the crude diols. A stirred solution of these diols (2.12 mmol)
in 5:1 THF/pH 7 buffer (30 mL) was treated with NaIO4 (906 mg,
4.24 mmol) and stirred for 24 h. The reaction mixture was diluted
with brine (25 mL) and extracted with 10% Et2O/hexanes (3 × 30
mL). The combined organic extracts were washed with brine (20
mL), dried, and freed of solvent under reduced pressure to provide
15 (492 mg, 98%) as a colorless oil: IR (film, cm-1) 1733, 1612,
1
1462; H NMR (500 MHz, CDCl3) δ 7.26 (d, J ) 8.5 Hz, 2 H),
6.86 (d, J ) 8.5 Hz, 2 H), 4.96 (s, 1 H), 4.89 (s, 1 H), 4.59 (ABq,
J ) 6.5 Hz, ∆ν ) 9.3 Hz, 2 H), 4.43 (s, 2 H), 3.80 (s, 3 H), 3.74
(d, J ) 5.5 Hz, 1 H), 3.49 (dt, J ) 6.4, 1.3 Hz, 2 H), 3.36-3.33
1
1586; H NMR (300 MHz, CDCl3) δ 9.66 (d, J ) 1.5 Hz, 1H),
J. Org. Chem, Vol. 72, No. 19, 2007 7143

Paquette et al.
(m, 1 H), 3.35 (s, 3 H), 3.22 (dd, J ) 9.1, 6.9 Hz, 1 H), 2.97 (dd,
J ) 14.0, 6.4 Hz, 1 H), 2.78 (s, 1 H), 2.25 (dd, J ) 15.2, 5.2 Hz,
1 H), 2.17-2.11 (m, 1 H), 1.88-1.82 (m, 1 H), 1.69-1.56 (m, 2
H), 0.99 (s, 3 H), 0.94 (d, J ) 6.6 Hz, 3 H), 0.93 (s, 3 H), 0.92 (s,
9 H), 0.04 (s, 3 H), 0.03 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ
159.0, 147.6, 131.0, 129.1 (2 C), 113.7 (2 C), 111.1, 96.5, 84.1,
76.1, 75.9, 72.5, 66.4, 55.3 (2 C), 46.4, 39.6, 36.0, 31.8, 25.9 (3
C), 24.2, 23.0, 18.3, 17.4, 16.9, -4.6, -5.0; HRMS (ES) m/z (M
+ Na)+ calcd 559.3431, obsd 559.3445; [R]2D1 -21.2 (c 0.52,
CHCl3).
(1R,5S,6R)-6-(tert-Butyldimethylsilyloxy)-1-((S)-5-(4-methoxy-
benzyloxy)-4-methylpent-1-en-2-yl)-7,7-dimethyl-2-oxabicyclo-
[3.2.0]heptan-3-one (31). A stirred solution of 30 (16.5 mg, 0.034
mmol) and N-methylmorpholine N-oxide monohydrate (13.6 mg,
0.10 mmol) in 10% MeCN/CH2Cl2 (2 mL) was treated with 4 Å
molecular sieves (20 mg) under N2. After 5 min, TPAP (0.6 mg,
1.7 µmol) was added, and the reaction mixture was stirred for a
further 90 min and passed through a pad of silica gel which was
rinsed with ethyl acetate (10 mL). The solvent was evaporated under
reduced pressure to leave a residue that was purified by column
chromatography on silica gel (elution with 5-20% ethyl acetate
in hexanes) to yield 31 (16.1 mg, 99%) as a colorless oil: IR (film,
cm-1) 1778, 1611, 1461, 1250, 1122; 1H NMR (500 MHz, CDCl3)
δ 7.26 (d, J ) 8.5 Hz, 2 H), 6.87 (d, J ) 8.5 Hz, 2 H), 5.02 (s, 1
H), 4.97 (s, 1 H), 4.42 (ABq, J ) 11.7 Hz, ∆ν ) 14.0 Hz, 2 H),
3.80 (s, 3 H), 3.74 (d, J ) 6.9 Hz, 1 H), 3.36 (t, J ) 7.3 Hz, 1 H),
3.30 (dd, J ) 9.2, 5.8 Hz, 1 H), 3.23 (dd, J ) 9.2, 6.6 Hz, 1 H),
2.64 (dd, J ) 17.7, 1.0 Hz, 1 H), 2.43 (dd, J ) 17.7, 8.8 Hz, 1 H),
2.29 (dd, J ) 15.9, 5.0 Hz, 1 H), 2.13-2.08 (m, 1 H), 1.72 (dd, J
) 15.6, 9.0 Hz, 1 H), 1.04 (s, 3 H), 0.98 (s, 3 H), 0.92 (d, J ) 6.7
Hz, 3 H), 0.91 (s, 9 H), 0.02 (s, 6 H); 13C NMR (75 MHz, CDCl3)
δ 177.2, 159.0, 143.9, 130.8, 129.2 (2 C), 113.7 (2 C), 112.6, 94.9,
75.4, 72.5, 72.2, 55.3, 47.4, 38.3, 36.4, 31.5, 28.6, 25.8 (3 C), 24.0,
18.3, 17.1, 16.8, -4.8, -5.1; HRMS (ES) m/z (M + Na)+ calcd
511.2856, obsd 511.2856; [R]2D5 -12.0 (c 0.25, CHCl3).
O-(1R,5S,6R)-1-((S)-5-(4-Methoxybenzyloxy)-4-methylpent-1-
en-2-yl)-7,7-dimethyl-3-oxo-2-oxabicyclo[3.2.0]heptan-6-yl O-p-
Tolyl Carbonothioate (33). A stirred solution of 32 (24 mg, 0.064
mmol) in anhydrous CH3CN (1 mL) was treated with DMAP (23
mg, 0.19 mmol) and O-p-tolyl chlorothionoformate (29 µL, 0.19
mmol) under N2. The cloudy reaction mixture was vigorously stirred
for 24 h, and more DMAP (23 mg, 0.19 mmol) and O-p-tolyl
chlorothionoformate (29 µL, 0.19 mmol) were added. After a further
day, the reaction mixture was quenched with water (5 mL), and
extracted with Et2O (3 × 10 mL). The combined organic extracts
were washed with brine (5 mL), then dried. The solvent was
evaporated under reduced pressure, and the residue was purified
by column chromatography on silica gel (elution with 5-30% ethyl
acetate in hexanes) to afford 33 (27 mg, 81%) as a pale yellow oil:
IR (film, cm-1) 1778, 1611, 1506, 1267, 1194; 1H NMR (400 MHz,
CDCl3) δ 7.26 (d, J ) 8.5 Hz, 2 H), 7.21 (d, J ) 8.3 Hz, 2 H),
6.97 (d, J ) 8.3 Hz, 2 H), 6.88 (d, J ) 8.5 Hz, 2 H), 5.12 (d, J )
9.6 Hz, 1 H), 5.11 (s, 1 H), 5.05 (s, 1 H), 4.43 (ABq, J ) 11.8 Hz,
∆ν ) 13.7 Hz, 2 H), 3.81 (s, 3 H), 3.67 (dt, J ) 7.3, 2.1 Hz, 1 H),
3.33-3.23 (m, 2 H), 2.71-2.57 (m, 2 H), 2.37 (s, 3 H), 2.33 (dd,
J ) 15.7, 4.7 Hz, 1 H), 2.15-2.09 (m, 1 H), 1.75 (dd, J ) 15.6,
9.1 Hz, 1 H), 1.19 (s, 3 H), 1.17 (s, 3 H), 0.93 (d, J ) 6.6 Hz, 3
H); 13C NMR (75 MHz, CDCl3) δ 195.0, 175.9, 159.1, 151.1, 143.1,
130.2 (2 C), 129.7, 129.2 (2 C), 128.3, 121.2 (2 C), 113.7 (2 C),
113.5, 94.0, 81.8, 75.3, 72.6, 55.3 (2 C), 47.7, 37.3, 36.4, 31.6,
29.7, 23.9, 17.0, 16.8; HRMS (ES) m/z (M + Na)+ calcd 547.2130,
obsd 547.2127; [R]2D0 -3.0 (c 0.30, CHCl3).
chromatography on silica gel (elution with an increasing proportion
of ethyl acetate in hexanes from 0 to 20%) to furnish 34 (12 mg,
99%) as a colorless oil: IR (film, cm-1) 1777, 1613, 1248, 1097;
1H NMR (500 MHz, CDCl3) δ 7.26 (d, J ) 8.5 Hz, 2 H), 6.87 (d,
J ) 8.5 Hz, 2 H), 5.03 (s, 1 H), 4.97 (s, 1 H), 4.43 (ABq, J ) 11.9
Hz, ∆ν ) 13.3 Hz, 2 H), 3.80 (s, 3 H), 3.30 (dd, J ) 9.2, 5.9 Hz,
1 H), 3.24 (dd, J ) 9.2, 6.5 Hz, 1 H), 3.15 (dd, J ) 16.0, 7.6 Hz,
1 H), 2.60 (dd, J ) 17.8, 7.6 Hz, 1 H), 2.38 (d, J ) 17.8 Hz, 1 H),
2.30 (dd, J ) 15.6, 4.7 Hz, 1 H), 2.17-2.10 (m, 1 H), 1.87 (dd, J
) 11.8, 8.8 Hz, 1 H), 1.72 (dd, J ) 15.6, 9.0 Hz, 1 H), 1.48 (dd,
J ) 11.8, 7.6 Hz, 1 H), 1.15 (s, 3 H), 1.03 (s, 3 H), 0.92 (d, J )
6.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 177.2, 159.0, 143.8,
129.7, 129.2 (2 C), 113.7 (2 C), 112.9, 97.2, 75.4, 72.6, 55.3, 41.7,
36.1, 35.3, 31.5, 31.4, 29.7, 25.0, 22.9, 17.0; HRMS (ES) m/z (M
+ Na)+ calcd 381.2042, obsd 381.2030; [R]2D4 -33.3 (c 0.64,
CHCl3).
(1S,4S,5R)-4-((1R,2R)-1-Hydroxy-2-methoxy-4-(4-methoxy-
benzyloxy)butyl)-1-((S)-5-(4-methoxybenzyloxy)-4-methylpent-
1-en-2-yl)-7,7-dimethyl-2-oxabicyclo[3.2.0]heptan-3-one (36). To
a stirred solution of NaHMDS (0.19 mL, 0.85 M in toluene, 0.16
mmol) in THF (0.8 mL) at -78 °C under N2 was slowly added
lactone 34 (53.2 mg, 0.15 mmol) in THF (0.4 mL). After 20 min,
a solution of aldehyde 15 (39 mg, 0.16 mmol) in THF (0.2 mL)
was added. The reaction mixture was stirred at -78 °C for 2 h,
quenched with a saturated NH4Cl solution (10 mL), and extracted
with ether (3 × 10 mL). The combined organic extracts were
washed with brine (5 mL), then dried. The solvent was evaporated
under reduced pressure to leave a residue that was purified by
column chromatography on silica gel (elution with an increasing
proportion of ethyl acetate in hexanes from 5 to 40%) to yield 36
(70 mg, 79%, 96% borsm) as a colorless oil, along with recovered
34 (9.6 mg, 18%): IR (film, cm-1) 1760, 1613, 1514, 1248, 1094;
1H NMR (500 MHz, CDCl3) δ 7.26-7.21 (m, 4 H), 6.88-6.85
(m, 4 H), 5.01 (s, 1 H), 4.96 (s, 1 H), 4.44-4.39 (m, 4 H), 3.80 (s,
3 H), 3.79 (s, 3 H), 3.67-3.60 (m, 3 H), 3.56-3.50 (m, 1 H), 3.35
(s, 3 H), 3.32 (dd, J ) 9.2, 5.7 Hz, 1 H), 3.22 (dd, J ) 9.2, 6.7 Hz,
1 H), 3.01 (t, J ) 7.9 Hz, 1 H), 2.79 (d, J ) 3.8 Hz, 1 H), 2.26
(dd, J ) 15.7, 4.6 Hz, 1 H), 2.14-2.09 (m, 1 H), 1.96-1.88 (m,
3 H), 1.72 (dd, J ) 15.7, 9.0 Hz, 1 H), 1.49 (dd, J ) 12.2, 6.8 Hz,
1 H), 1.13 (s, 3 H), 0.99 (s, 3 H), 0.91 (d, J ) 6.6 Hz, 3 H); 13C
NMR (100 MHz, CDCl3) δ 177.7, 159.3, 159.0, 144.1, 130.9, 129.9,
129.4 (2 C), 129.2 (2 C), 113.9 (2 C), 113.7 (2 C), 112.7, 96.0,
79.2, 75.6, 73.2, 72.9, 72.5, 65.8, 57.2, 55.3, 51.1, 41.7, 37.7, 36.2,
36.0, 31.3 (2 C), 28.9, 25.7, 23.4, 17.1; HRMS (ES) m/z (M +
Na)+ calcd 619.3247, obsd 619.3280; [R]D23 -46.6 (c 0.38, CHCl3).
(1R,4R,5S)-4-((1S,2S)-1,4-Dihydroxy-2-methoxybutyl)-1-((S)-
5-hydroxy-4-methylpent-1-en-2-yl)-7,7-dimethyl-2-oxabicyclo-
[3.2.0]heptan-3-one (39). To a solution of aldol adduct 38 (30 mg,
0.05 mmol) in CH2Cl2 (6 mL) and pH 7 buffer (0.3 mL) was added
DDQ (69 mg, 0.30 mmol). The green mixture was stirred at 0 °C
for 30 min and at rt for 4 h. The resulting orange suspension was
washed with saturated NaHCO3 solution (10 mL). The aqueous
phase was extracted with CH2Cl2 (5 × 10 mL), and the combined
organic extracts were dried and evaporated. The residue was
chromatographed over silica gel eluting with 2-7% MeOH/CH2-
Cl2 to give triol 39 (17 mg, 100%) as a colorless oil: IR (film,
cm-1) 3404, 1747, 1454, 1077; 1H NMR (500 MHz, CDCl3) δ 5.13
(s, 1 H), 5.08 (s, 1 H), 3.82-3.62 (series of m, 4 H), 3.53-3.41
(series of m, 2 H), 3.42 (s, 3 H), 3.08 (t, J ) 8.0 Hz, 1 H), 2.86 (d,
J ) 3.8 Hz, 1 H), 2.10 (dd, J ) 13.8, 6.4 Hz, 1 H), 2.01-1.87
(series of m, 5 H), 1.53 (dd, J ) 12.1 7.0 Hz, 1 H), 1.14 (s, 3 H),
1.01 (s, 3 H), 0.92 (d, J ) 6.4 Hz, 3 H); 13C NMR (125 MHz,
CDCl3) δ 177.7, 144.7, 113.7, 96.1, 80.2, 73.4, 67.5, 59.1, 57.4,
51.1, 41.8, 37.5, 36.5, 36.2, 34.2, 31.7, 25.7, 23.2, 17.5; HRMS
(ES) m/z (M + Na)+ calcd 379.2097, obsd 379.2111; [R]2D3 +98.5
(c 0.41, CHCl3).
(1S,5R)-1-((S)-5-(4-Methoxybenzyloxy)-4-methylpent-1-en-2-
yl)-7,7-dimethyl-2-oxabicyclo[3.2.0]heptan-3-one (34). A solution
of 33 (18 mg, 0.034 mmol), tributyltin hydride (38 µL, 0.14 mmol),
and AIBN (3.4 mg, 0.021 mmol) in freshly distilled benzene (6
mL) was degassed thoroughly with argon. The reaction mixture
was heated at 90 °C for 5 h, cooled, and purified by column
(1R,4R,5S)-4-((1S,2S)-1,4-Dihydroxy-2-methoxybutyl)-1-((S)-
4-hydroxy-3-methylbutanoyl)-7,7-dimethyl-2-oxabicyclo[3.2.0]-
7144 J. Org. Chem., Vol. 72, No. 19, 2007

Pestalotiopsin A: Elaboration of the Cyclononene Ring
heptan-3-one (40). Triol 39 (17 mg, 0.048 mmol) was dissolved
in CH2Cl2 (2 mL) and cooled to -78 °C. Ozone was bubbled into
the reaction mixture until a pale blue color persisted, followed by
O2 for 10 min. The reaction mixture was quenched with PPh3 (63,
0.24 mmol), allowed to warm to rt, and stirred overnight. The
solvent was removed in vacuo, and the residue was purified by
flash chromatography on silica gel (eluting with 2-7% MeOH/
CH2Cl2) to give 40 (16.9 mg, 99%) as a pale oil. Compound 40 is
(5 mL). The aqueous layer was extracted with EtOAc (10 × 5 mL).
The combined organic extracts were washed with brine (5 mL)
and then dried. The solvent was removed to leave a residue, which
was purified by flash chromatography on silica gel (eluting with
2-7% MeOH/CH2Cl2) to yield 40 (16.9 mg, 99%) as a pale oil.
Selenylation of 40. To a stirring solution of 40 (10.3 mg, 0.029
mmol) and o-nitrophenyl selenocyanate (33 mg, 0.14 mmol) in THF
(0.3 mL) under N2 at rt was added tri-n-butylphosphine (36 µL,
0.14 mmol). After being stirred for 3 h, the solvent was removed
in vacuo. The crude product was purified by column chromatog-
raphy on silica gel (eluting with 10-40% EtOAc/hexanes) to give
43 (4 mg, 20%) and 44 (8 mg, 53%) as yellow oils. Compound 43
was used directly and not characterized.
1
characterized by complex H and 13C NMR spectra indicating the
existence of lactols and keto alcohol. Therefore the NMR data are
not reported: IR (film, cm-1) 3404, 1770, 1712, 1087; HRMS (ES)
m/z (M + Na)+ calcd 381.1889, obsd 381.1893.
(1R,4R,5S)-1-((2S,4S)-1,2-Dihydroxy-5-(4-methoxybenzyloxy)-
4-methylpentan-2-yl)-4-((1S,2S)-1-hydroxy-2-methoxy-4-(4-meth-
oxybenzyloxy)butyl)-7,7-dimethyl-2-oxabicyclo[3.2.0]heptan-3-
one (41). To a solution of 38 (30 mg, 0.05 mmol) in 1 mL of
t-BuOH-H2O (l:l, 0.5 mL of each) was added DABCO (6 mg,
0.05 mmol), K2OsO2(OH)4 (4 mg, 0.01 mmol), K3Fe(CN)6 (50 mg,
0.15 mmol), K2CO3 (21 mg, 0.15 mmol), and NaHCO3 (13 mg,
0.15 mmol). After vigorous stirring at rt for 1 day, Na2SO3 (71
mg, 0.5 mmol) was added and stirring was maintained overnight.
The reaction mixture was extracted with EtOAc. The combined
organic extracts were dried and evaporated to give the crude
product, which was purified by flash chromatography on silica gel
(1-3% MeOH/CH2Cl2) to afford 41 (31 mg, 99%) as a colorless
oil: IR (film, cm-1) 3363, 1760, 1514, 1248, 1089; 1H NMR (400
MHz, CDCl3) δ 7.24 (d, J ) 8.6 Hz, 4 H), 6.87 (d, J ) 8.6 Hz, 4
H), 4.53 (d, J ) 11.6 Hz, 1 H), 4.43 (s, 4 H), 4.40 (d, J ) 11.6 Hz,
1 H), 3.79 (s, 6 H), 3.70-3.53 (series of m, 5 H), 3.44 (dd, J )
9.2, 4 Hz, 1 H), 3.39 (s, 3 H), 3.13-3.06 (m, 1 H), 2.82 (s, 1 H),
1.98 (dd, J ) 11.8, 9.4 Hz, 1 H), 1.92-1.86 (m, 1 H), 1.72 (dd, J
) 15.0, 7.8 Hz, 1 H), 1.61-1.56 (m, 3 H), 1.45 (dd, J ) 11.8, 6.6
For 44: IR (film, cm-1) 3456, 1777, 1511, 1332, 1097; 1H NMR
(500 MHz, CDCl3) δ 8.32 (d, J ) 8.0 Hz, 1 H), 7.64 (d, J ) 8.0
Hz, 1 H), 7.55 (t, J ) 8.0 Hz, 1 H), 7.33 (t, J ) 8.0 Hz, 1 H), 4.12
(dd, J ) 8.0, 6.5 Hz, 1 H), 3.87 (d, J ) 7.5, 4.5 Hz, 1 H), 3.69-
3.66 (m, 2 H), 3.50 (s, 3 H), 3.16-2.97 (series of m, 4 H), 2.59-
2.54 (m, 1 H), 2.45 (dd, J ) 12.5, 8.0 Hz, 1 H), 2.30 (dd, J )
12.5, 10.0 Hz, 1 H), 2.17-2.07 (series of m, 3 H), 1.64-1.58 (m,
1 H), 1.26 (s, 3 H), 1.18-1.14 (m, 6 H); 13C NMR (100 MHz,
CDCl3) δ 177.2, 156.3, 143.7, 133.7, 129.1, 126.5, 125.3, 120.3,
90.5, 80.7, 79.5, 77.2, 76.7, 72.7, 68.6, 57.8, 50.8, 41.8, 40.9, 38.8,
36.7, 34.3, 29.7, 25.5, 25.2, 22.7, 20.6, 17.4; HRMS (ES) m/z (M
+ Na)+ calcd 575.1272, obsd 575.1258; [R]2D3 +31.9 (c 0.16,
CHCl3).
Selenoxide Elimination within 43. To a solution of 43 (4 mg,
0.0055 mmol) in THF (0.5 mL) was added 30% aqueous hydrogen
peroxide (4 µL) at 0 °C. Stirring was maintained for 1 d at rt. The
reaction mixture was diluted with H2O (1 mL) and extracted with
ether (3 × 2 mL). The combined organic extracts were washed
with brine, dried, and concentrated. The residue was purified by
column chromatography on silica gel (eluting with 10-30% EtOAc/
Hz, 1 H), 1.23 (s, 3 H), 1.12 (s, 3 H), 0.89 (d, J ) 6.8 Hz, 3 H; 13
C
hexanes) to give 45 (2 mg, 99%) as a colorless oil: IR (film, cm-1
)
NMR (100 MHz, CDCl3) δ 178.1, 159.4, 159.2, 130.2, 129.8, 129.6,
129.5, 129.4, 129.3, 129.2, 127.8, 113.9, 113.7, 96.1, 78.8, 76.8,
75.5, 73.2, 73.1, 72.8, 67.2, 66.1, 57.5, 55.3, 55.2, 50.4, 43.3, 41.9,
40.6, 39.6, 36.4, 29.7, 28.8, 26.5, 19.6; HRMS (ES) m/z (M + Na)+
calcd 653.3302, obsd 653.3306; [R]2D3 +13.6 (c 1.73, CHCl3).
3496, 1780, 1716, 1651, 1121, 1089; 1H NMR (400 MHz, CDCl3)
δ 5.60-5.56 (m, 1 H), 5.44 (d, J ) 10.0 Hz, 1 H), 5.41 (d, J )
16.8 Hz, 1 H), 4.94 (s, 1 H), 4.77 (s, 1 H), 3.77 (t, J ) 8.4 Hz, 1
H), 3.54 (d, J ) 8.4 Hz, 1 H), 3.30-3.24 (m, 5 H), 3.16 (d, J )
16.4 Hz, 1 H), 2.98 (s, 1 H), 2.03 (dd, J ) 12.0, 9.2 Hz, 1 H), 1.74
(s, 3 H), 1.58 (dd, J ) 12.0, 7.2 Hz, 1 H), 1.15 (s, 3 H), 1.10 (s,
3 H); 13C NMR (100 MHz, CDCl3) δ 203.8, 176.8, 137.9, 135.7,
122.5, 115.5, 94.8, 82.4, 77.2, 74.0, 56.4, 49.0, 48.2, 42.3, 37.0,
35.3, 29.7, 24.5, 22.9, 22.8; HRMS (ES) m/z (M + Na)+ calcd
345.1678, obsd 345.1677; [R]2D3 +84.3 (c 0.07, CHCl3).
(1R,4R,5S)-4-((1S,2S)-1-Hydroxy-2-methoxy-4-(4-methoxy-
benzyloxy)butyl)-1-((S)-4-(4-methoxybenzyloxy)-3-methylbu-
tanoyl)-7,7-dimethyl-2-oxabicyclo[3.2.0]heptan-3-one (42). A
stirred solution of 41 (20 mg, 0.032 mmol) in 5:1 THF/pH 7 buffer
(1.8 mL) was treated with NaIO4 (30 mg, 0.14 mmol) and stirred
for 48 h. The reaction mixture was diluted with brine (5 mL) and
extracted with Et2O (3 × 5 mL). The combined organic extracts
were washed with brine (5 mL), then dried. The solvent was
evaporated under reduced pressure to give a residue, which was
purified by flash chromatography on silica gel (10-40% EtOAc/
hexanes) to afford 42 (16 mg, 84%) as a colorless oil: IR (film,
cm-1) 3443, 1775, 1712, 1613; 1H NMR (500 MHz, CDCl3) δ 7.22
(d, J ) 8.6 Hz, 2 H), 7.18 (d, J ) 8.6 Hz, 2 H), 6.93 (d, J ) 8.6
Hz, 2 H), 6.86 (d, J ) 8.6 Hz, 2 H), 4.38 (s, 4 H), 3.81 (s, 3 H),
3.80 (s, 3 H), 3.73 (dd, J ) 3.4, 1.4 Hz, 1 H), 3.66-3.57 (m, 2 H),
3.46-3.41 (m, 2 H), 3.34 (s, 3 H), 3.27 (dd, J ) 9.1, 5.8 Hz, 1 H),
3.22-3.18 (m, 2 H), 2.80 (s, 1 H), 2.53-2.42 (m, 2 H), 2.33-
2.29 (m, 1 H), 1.98 (dd, J ) 12.1, 9.2 Hz, 1 H), 1.90-1.87 (m, 2
H), 1.54 (dd, J ) 12.1, 7.6 Hz, 1 H), 1.12 (s, 3 H), 1.07 (s, 3 H),
0.83 (d, J ) 6.7 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 205.4,
177.7, 159.5, 159.1, 153.6, 130.7, 129.5 (2 C), 129.3, 129.2 (2 C),
114.1 (2 C), 113.7 (2 C), 94.9, 78.7, 74.7, 74.5, 73.1, 72.5, 65.2,
56.9, 55.3 (2 C), 49.2, 43.3, 42.5, 37.0, 36.7, 28.8, 28.3, 24.6, 23.1,
17.2; HRMS (ES) m/z (M + Na)+ calcd 621.3040, obsd 621.3031;
[R]2D3 +21.5 (c 0.62, CHCl3).
Acetonide 46. A solution of 41 (50 mg, 0.079 mmol) in 2,2-
dimethoxypropane (3 mL) was treated with PPTS (2 mg, 0.008
mmol) and stirred for 1 h at 80 °C. The solvent was removed, and
the crude product was purified by column chromatography on silica
gel (eluting with 20-40% EtOAc/hexanes) to give 46 (43 mg, 81%)
as a colorless oil: IR (film, cm-1) 3395, 1766, 1613, 1513, 1248,
1
1094; H NMR (500 MHz, CDCl3) δ 7.24-7.22 (m, 4 H), 6.87-
6.84 (m, 4 H), 4.41 (s, 2 H), 4.40 (s, 2 H), 4.34 (s, 1 H), 4.01 (d,
J ) 8.8 Hz, 1 H), 3.92 (d, J ) 8.8 Hz, 1 H), 3.79 (s, 6 H), 3.60-
3.52 (m, 4 H), 3.39 (s, 3 H), 3.30 (d, J ) 6.2 Hz, 2 H), 2.82 (s, 1
H), 2.79-2.76 (m, 1 H), 2.29-2.25 (m, 1 H), 2.00-1.94 (m, 2 H),
1.88-1.85 (m, 1 H), 1.79 (dd, J ) 15.0, 5.2 Hz, 1 H), 1.67 (dd, J
) 15.0, 5.4 Hz, 1 H), 1.45 (dd, J ) 12.6, 5.2 Hz, 1 H), 1.42 (s, 3
H), 1.36 (s, 3 H), 1.12 (s, 3 H), 1.10 (s, 3 H), 1.00 (d, J ) 6.7 Hz,
3 H); 13C NMR (125 MHz, CDCl3) δ 178.1, 159.2, 159.0, 130.9,
130.3, 129.4 (2 C), 129.2 (2 C), 113.8 (2 C), 113.6 (2 C), 109.2,
94.8, 86.3, 79.3, 75.8, 73.8, 72.7, 72.5, 70.9, 66.1, 57.9, 55.3 (2
C), 51.6, 42.4, 40.2, 39.1, 36.6, 29.8, 28.8, 27.1, 26.8, 26.3, 25.8,
19.9; HRMS (ES) m/z (M + Na)+ calcd 693.3615, obsd 693.3637;
[R]2D3 +25.9 (c 0.83, CHCl3).
(1R,4R,5S)-4-((1S,2S)-1,4-Dihydroxy-2-methoxybutyl)-1-((S)-
4-hydroxy-3-methylbutanoyl)-7,7-dimethyl-2-oxabicyclo[3.2.0]-
heptan-3-one (40). Compound 42 (16 mg, 0.027 mmol) was treated
with TFA (0.05 mL) in CH2Cl2 (0.5 mL) at rt. After 5 min, the
reaction mixture was quenched with saturated NaHCO3 solution
Removal of PMB Groups from 46. The reaction was carried
out according to the procedure described for the preparation of 39
starting with 46 (35 mg, 0.052 mmol) and DDQ (71 mg, 0.31
mmol). The usual workup and silica gel chromatography (2-7%
J. Org. Chem, Vol. 72, No. 19, 2007 7145

Paquette et al.
MeOH/CH2Cl2) gave 47 (22.2 mg, 99%) as a colorless oil: IR (film,
cm-1) 3400, 1758, 1238, 1060; 1H NMR (400 MHz, CDCl3) δ 4.05
(d, J ) 9.0 Hz, 1 H), 3.95 (d, J ) 9.0 Hz, 1 H), 3.79-3.73 (m, 3
H), 3.61-3.56 (m, 2 H), 3.47 (dd, J ) 10.4, 5.6 Hz, 1 H), 3.43 (s,
3 H), 3.92-3.85 (m, 2 H), 2.21-2.16 (m, 1 H), 2.08 (dd, J ) 12.6,
9.6 Hz, 1 H), 1.93-1.88 (m, 2 H), 1.83 (dd, J ) 15.2, 7.2 Hz, 1
H), 1.66 (dd, J ) 15.2, 4.8 Hz, 1 H), 1.52 (dd, J ) 12.6, 5.6 Hz,
1 H), 1.50 (s, 3 H), 1.49 (s, 3 H), 1.16 (s, 3 H), 1.13 (s, 3 H), 0.98
(d, J ) 6.7 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 178.1, 109.5,
94.8, 86.1, 81.0, 73.3, 71.5, 68.2, 59.3, 57.7, 51.8, 42.2, 41.1, 39.1,
36.3, 31.9, 31.8, 27.2, 26.7, 26.3, 25.7, 19.6; HRMS (ES) m/z (M
+ Na)+ calcd 453.2464, obsd 453.2476; [R]2D3 +22.3 (c 1.31,
CHCl3).
Selenylation of 47. The reaction was carried out according to
the procedure described for the preparation of 43 starting with 47
(22.2 mg, 0.052 mmol), ArSeCN (42 mg, 0.186 mmol), and Bu3P
(46 µL, 0.186 mmol). The usual workup and silica gel chroma-
tography (10-50% EtOAc/ hexanes) gave 48 (32 mg, 78%) and
49 (6.3 mg, 20%) as yellow oils.
For 48: IR (film, cm-1) 3379, 1770, 1513; 1H NMR (400 MHz,
CDCl3) δ 8.29 (dd, J ) 8.0, 1.2 Hz, 1 H), 8.24 (dd, J ) 8.0, 1.2
Hz, 1 H), 7.67 (dd, J ) 8.0, 1.2 Hz, 1 H), 7.61 (dd, J ) 8.0, 1.2
1 H), 7.56 (dt, J ) 8.0, 1.2 Hz, 1 H), 7.48 (dt, J ) 8.0, 1.2 Hz, 1
H), 7.32-7.26 (m, 2 H), 4.57 (s, 1 H), 4.04 (d, J ) 8.8 Hz, 1 H),
3.96 (d, J ) 8.8 Hz, 1 H), 3.74 (dd, J ) 7.6, 4.0 Hz, 1 H), 3.60-
3.55 (m, 1 H), 3.49 (s, 3 H), 3.35-3.31 (m, 1 H), 3.03-2.86 (series
of m, 4 H), 2.78 (dd, J ) 12.0, 8.0 Hz, 1 H), 2.52-2.47 (m, 1 H),
2.17-2.04 (m, 3 H), 1.90-1.88 (m, 2 H), 1.51 (s, 3 H), 1.45 (s, 3
H), 1.44-1.38 (m, 1 H), 1.19-1.08 (m, 9 H); 13C NMR (100 MHz,
CDCl3) δ 177.5, 147.1, 146.9, 133.9, 133.6, 133.3, 129.9, 129.0,
126.5, 126.3, 125.4, 125.3, 109.6, 94.6, 86.2, 81.2, 73.0, 71.6, 58.0,
52.1, 44.2, 42.3, 39.0, 36.3, 35.3, 28.8, 28.2, 27.4, 26.7, 26.3, 25.7,
23.3, 20.6; HRMS (ES) m/z (M + Na)+ calcd 821.1243, obsd
821.1235; [R]2D3 +24.8 (c 0.50, CHCl3).
For 49: IR (film, cm-1) 3376, 1761, 1513; 1H NMR (400 MHz,
CDCl3) δ 8.29 (dd, J ) 8.0, 1.2 Hz, 1 H), 7.62 (d, J ) 8.0 Hz, 1
H), 7.51 (dt, J ) 8.0, 1.2 Hz, 1 H), 7.31 (dt, J ) 8.0, 1.2 Hz, 1 H),
4.54 (s, 1 H), 4.02 (s, 2 H), 3.76-3.49 (series of m, 4 H), 3.48 (s,
3 H), 3.04-2.82 (series of m, 4 H), 2.24-2.04 (series of m, 3 H),
1.84 (dd, J ) 15.2, 7.6 Hz, 1 H), 1.66 (dd, J ) 15.2, 4.4 Hz, 1 H),
1.52 (s, 3 H), 1.51-1.46 (m, 1 H), 1.42 (s, 3 H), 1.12 (s, 6 H),
0.99 (d, J ) 6.7 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 177.8,
151.0, 133.6, 129.0, 126.5, 125.3, 115.1, 109.4, 94.7, 86.2, 81.5,
77.2, 72.7, 71.5, 68.3, 58.0, 52.2, 42.1, 41.1, 39.1, 36.2, 31.7, 28.0,
27.3, 26.8, 26.2, 25.7, 19.7; HRMS (ES) m/z (M + Na)+ calcd
638.1844, obsd 638.1851; [R]2D3 +47.9 (c 0.14, CHCl3).
Selenoxide Elimination within 48. A solution of 48 (42 mg,
0.052 mmol) in THF (1.7 mL) was cooled to -40 °C and then
treated with pyridine (9 µL, 0.11 mmol) and 30% hydrogen peroxide
(33 µL, 0.32 mmol). The reaction mixture was allowed to warm to
rt, stirred for 12 h, and quenched with saturated NaHSO3 solution
(2 mL). The aqueous layer was extracted with ether (3 × 5 mL),
and the combined organic extracts were washed with brine, dried,
and evaporated. The residue was purified by column chromatog-
raphy on silica gel (eluting with 10-20% EtOAc/hexanes) to give
50 (18.6 mg, 90%) as a colorless oil: IR (film, cm-1) 3434, 1746,
1463; 1H NMR (500 MHz, CDCl3) δ 5.83-5.76 (m, 1 H), 5.37 (d,
J ) 10.3 Hz, 1 H), 5.29 (d, J ) 17.3 Hz, 1 H), 4.87 (s, 1 H), 4.78
(s, 1 H), 4.08 (s, 1 H), 4.03 (ABq, J ) 9.0 Hz, ∆ν ) 19.9 Hz, 2
H), 3.79 (t, J ) 5.8 Hz, 1 H), 3.74-3.71 (m, 1 H), 3.33 (s, 3 H),
2.85-2.79 (m, 2 H), 2.57 (d, J ) 14.2 Hz, 1 H), 2.44 (d, J ) 14.2
Hz, 1 H), 2.03 (dd, J ) 12.6, 9.6 Hz, 1 H), 1.88 (s, 3 H), 1.50 (dd,
J ) 12.6, 4.6 Hz, 1 H), 1.47 (s, 3 H), 1.40 (s, 3 H), 1.15 (s, 3 H),
1.12 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 178.6, 142.3, 135.0,
120.0, 115.6, 109.3, 94.3, 86.6, 83.8, 74.0, 70.1, 56.7, 51.5, 43.8,
42.0, 38.9, 35.3, 27.2, 26.9, 26.3, 26.0, 24.3; HRMS (ES) m/z (M
+ Na)+ calcd 417.2253, obsd 417.2250; [R]2D3 +15.2 (c 0.23,
CHCl3).
Attempted RCM Reaction of 57. To a solution of 57 (5 mg,
0.011 mmol) in degassed PhMe (1.0 mL, 0.01 M) at 80 °C was
added 55 (1.7 mg, 0.0023 mmol) in PhMe (0.2 mL). The stirred
reaction mixture was heated for 2 days before being cooled to rt.
Concentration in vacuo gave a dark oily residue which was purified
by column chromatography on silica gel (10-20% EtOAc in
hexanes) to afford 58 (4 mg, 80%) as a tan oil: IR (film, cm-1
)
1773, 1645, 1456; 1H NMR (500 MHz, CDCl3) δ 5.00 (q, J ) 6.9
Hz, 1 H), 4.88 (s, 1 H), 4.77 (d, J ) 6.8 Hz, 1 H), 4.74 (s, 1 H),
4.60 (d, J ) 6.8 Hz, 1 H), 4.25 (d, J ) 9.3 Hz, 1 H), 3.94 (ABq,
J ) 8.7 Hz, ∆ν ) 14.6 Hz, 2 H), 3.65 (s, 3 H), 3.40 (s, 3 H), 2.95
(dd, J ) 9.3, 3.2 Hz, 1 H), 2.69-2.65 (m, 1 H), 2.59 (d, J ) 14.2
Hz, 1 H), 2.39 (d, J ) 14.2 Hz, 1 H), 2.02 (dd, J ) 12.4, 9.7 Hz,
1 H), 1.90 (s, 3 H), 1.67 (d, J ) 6.9 Hz, 3 H), 1.49 (dd, J ) 12.4,
4.9 Hz, 1 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 1.21(s, 3 H), 1.13 (s, 3
H); 13C NMR (100 MHz, CDCl3) δ 176.9, 151.6, 142.9, 129.7,
128.3, 115.3, 113.6, 109.3, 93.4, 85.9, 77.2, 75.9, 69.9, 60.3, 55.7,
51.4, 42.5, 39.4, 34.6, 29.7, 27.7, 27.2, 26.5, 25.9, 24.5; HRMS
(ES) m/z (M + Na)+ calcd 461.2515, obsd 461.2520; [R]2D3 +25.4
(c 0.13, CHCl3).
Grieco Olefination of 49. To a solution of 49 (17 mg, 0.028
mmol) in THF (2 mL) was added 30% hydrogen peroxide (70 µL)
at 0 °C. Stirring was maintained for 1 day at rt. The reaction mixture
was diluted with H2O (2 mL) and extracted with ether (3 × 5 mL).
The combined organic extracts were washed with brine, then dried
and concentrated. The residue was purified by column chromatog-
raphy on silica gel (eluting with 30-70% EtOAc/hexanes) to give
59 (7 mg, 64%) as a colorless oil: IR (film, cm-1) 3390, 1755,
1
1644; H NMR (400 MHz, CDCl3) δ 5.84-5.74 (m, 1 H), 5.37
(dd, J ) 10.0, 1.2 Hz, 1 H), 5.29 (d, J ) 17.6 Hz, 1 H), 4.05 (d,
J ) 8.8 Hz, 1 H), 4.03 (s, 1 H), 3.92 (d, J ) 8.8 Hz, 1 H), 3.79 (t,
J ) 5.6 Hz, 1 H), 3.70 (t, J ) 6.8 Hz, 1 H), 3.60 (dd, J ) 10.4, 5.6
Hz, 1 H), 3.49 (dd, J ) 10.4, 5.6 Hz, 1 H), 3.32 (s, 3 H), 2.88-
2.80 (m, 2 H), 2.24-2.18 (m, 1 H), 2.04 (dd, J ) 12.4, 9.6 Hz, 1
H), 1.82 (dd, J ) 15.2, 7.6 Hz, 1 H), 1.67 (dd, J ) 10.8, 6.0 Hz,
1 H), 1.53-1.49 (m, 4 H), 1.39 (s, 3 H), 1.14 (s, 3 H), 1.12 (s, 3
H), 0.98 (d, J ) 6.7 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ
178.5, 135.0, 120.1, 109.5, 94.7, 85.7, 83.9, 77.2, 73.7, 71.6, 68.3,
56.7, 51.4, 41.9, 41.5, 39.0, 35.5, 31.9, 27.2, 26.9, 26.2, 25.7, 19.6;
HRMS (ES) m/z (M + Na)+ calcd 435.2359, obsd 435.2359;
[R]2D3 +30.0 (c 0.34, CHCl3).
Cross-Metathesis between 59 and 60. To a solution of 59 (5
mg, 0.012 mmol) and 60 (11.1 mg, 0.032 mmol) in degassed PhMe
(0.2 mL) was added 55 (1.8 mg, 0.0024 mmol). The reaction
mixture was heated at 45 °C for 2 d before being cooled to rt.
Concentration in vacuo gave a dark oily residue which was purified
by column chromatography on silica gel (1-3% MeOH in CH2-
Cl2) to afford 61 (6 mg, 67%) as a tan oil: IR (film, cm-1) 3451,
1
1762, 1653; H NMR (500 MHz, CDCl3) δ 7.67-7.65 (m, 4 H),
7.43-7.35 (m, 6 H), 5.70-5.64 (m, 1 H), 5.40 (dd, J ) 15.5, 8.5
Hz, 1 H), 4.04 (d, J ) 8.9 Hz, 1 H), 3.89 (d, J ) 8.9 Hz, 1 H),
3.82-3.79 (m, 2 H), 3.70-3.58 (m, 3 H), 3.52-3.48 (m, 1 H),
3.27 (s, 3 H), 2.84-2.80 (m, 1 H), 2.73 (dd, J ) 7.1, 2.9 Hz, 1 H),
2.21-2.17 (m, 1 H), 2.09-2.04 (m, 2 H), 2.01 (dd, J ) 12.5, 9.7
Hz, 1 H), 1.82 (dd, J ) 15.2, 7.7 Hz, 1 H), 1.68-1.51 (m, 3 H),
1.47 (s, 3 H), 1.46-1.34 (m, 8 H), 1.14 (s, 3 H), 1.12 (s, 3 H),
1.04 (s, 9 H), 0.97 (d, J ) 6.7 Hz, 3 H); 13C NMR (100 MHz,
CDCl3) δ 178.9, 137.7, 135.6 (4 C), 134.1 (2 C), 129.5 (2 C), 127.6
(4 C), 126.1, 109.5, 94.6, 85.6, 83.5, 77.2, 73.5, 71.7, 68.3, 63.9,
56.3, 51.5, 41.9, 39.0, 35.2, 32.4, 32.0, 29.0, 27.2, 27.0, 26.9 (3
C), 26.2, 25.7, 25.4, 19.7, 19.2, 11.2; HRMS (ES) m/z (M + Na)+
calcd 759.4268, obsd 759.4263; [R]2D3 +21.1 (c 0.18, CHCl3).
Regioselective Removal of PMB Group in 46. The reaction
was carried out according to the procedure described for the
preparation of 39 starting with 46 (32 mg, 0.048 mmol) and DDQ
(16 mg, 0.072 mmol). The usual workup and silica gel chroma-
tography (1-5% MeOH/CH2Cl2) gave 62 (16 mg, 62%; 100%
borsm) as a colorless oil, along with recovered 46 (12 mg, 38%):
7146 J. Org. Chem., Vol. 72, No. 19, 2007

Pestalotiopsin A: Elaboration of the Cyclononene Ring
IR (film, cm-1) 3382, 1762, 1514; 1H NMR (400 MHz, CDCl3) δ
7.24 (d, J ) 8.6 Hz, 2 H), 6.87 (d, J ) 8.6 Hz, 2 H), 4.42 (s, 2 H),
4.26 (s, 1 H), 4.09-4.05 (m, 2 H), 3.80 (s, 3 H), 3.65-3.42 (series
of m, 6 H), 3.39 (s, 3 H), 2.83-2.77 (m, 2 H), 2.14-2.10 (m, 1
H), 1.99 (dd, J ) 12.5, 9.7 Hz, 1 H), 1.94-1.84 (m, 2 H), 1.77
(dd, J ) 15.0, 6.4 Hz, 1 H), 1.67 (dd, J ) 15.0, 5.2 H, 1 H), 1.50-
1.47 (m, 4 H), 1.37 (s, 3 H), 1.18 (s, 3 H), 1.12 (s, 3 H), 0.99 (d,
J ) 6.7 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 178.4, 159.2,
130.3, 129.4 (2 C), 113.8 (2 C), 109.4, 94.6, 85.9, 79.5, 73.6, 72.8,
71.6, 68.4, 66.2, 57.8, 55.3, 51.4, 42.4, 41.0, 39.2, 36.5, 31.8, 29.9,
27.1, 26.8, 26.5, 25.7, 19.6; HRMS (ES) m/z (M + Na)+ calcd
573.3040, obsd 573.3036; [R]2D3 +25.9 (c 0.76, CHCl3).
(d, J ) 8.6 Hz, 2 H), 4.40 (s, 2 H), 4.31 (s, 1 H), 4.05 (d, J ) 8.9
Hz, 1 H), 3.87 (d, J ) 8.9 Hz, 1 H), 3.79 (s, 3 H), 3.62-3.47
(series of m, 6 H), 3.40 (s, 3 H), 2.84 (s, 1 H), 2.80-2.76 (m, 1
H), 2.19-2.15 (m, 1 H), 2.02-1.56 (series of m, 5 H), 1.46 (dd, J
) 12.3, 5.2 Hz, 1 H), 1.36 (s, 3 H), 1.35 (s, 3 H), 1.14 (s, 3 H),
1.11 (s, 3 H), 1.05 (s, 9 H), 1.00 (d, J ) 6.7 Hz, 3 H); 13C NMR
(100 MHz, CDCl3) δ 178.0, 159.2, 135.6 (4 C), 133.9 (2 C), 130.3,
129.5 (2 C), 129.3 (2 C), 127.6 (4 C), 113.8 (2 C), 109.3, 94.6,
86.3, 79.3, 77.2, 74.0, 72.6, 71.0, 69.5, 66.1, 57.8, 55.2, 51.7, 42.6,
39.2, 36.5, 31.1, 29.9, 29.7, 27.0 (3 C), 26.9, 26.8, 26.5, 26.0, 22.7,
19.5, 19.3; HRMS (ES) m/z (M + Na)+ calcd 811.4217, obsd
811.4221; [R]2D3 +14.7 (c 0.81, CHCl3).
TBDPS Protection of 62. A solution of 62 (20 mg, 0.036 mmol)
in CH2Cl2 (0.4 mL) was charged with Et3N (7 µL, 0.047 mmol)
and DMAP (0.5 mg, 0.004 mmol) at rt. TBDPSCl (12 µL, 0.044
mmol) was added dropwise into the reaction mixture under Ar.
The reaction mixture was stirred at rt for 1 d and quenched with
water (2 mL). The aqueous layer was extracted with CH2Cl2 (3 ×
5 mL), and the combined organic extracts was washed with brine,
dried, and evaporated. The residue was purified by column
chromatography on silica gel (10-30% EtOAc in hexanes) to afford
63 (27 mg, 94%) as a colorless oil: IR (film, cm-1) 3394, 1766,
Acknowledgment. This work was supported in part by the
Astellas USA Foundation for which we are appreciative. S.D.
thanks The Ohio State University for the award of a Presidential
Fellowship.
Supporting Information Available: Selected experimental
procedures and 1H/13C NMR spectra for all products. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
1513, 1464, 1249, 1112; H NMR (400 MHz, CDCl3) δ 7.67-
7.64 (m, 4 H), 7.43-7.34 (m, 6 H), 7.22 (d, J ) 8.6 Hz, 2 H), 6.85
JO070862J
J. Org. Chem, Vol. 72, No. 19, 2007 7147