The total synthesis of (±)-arisugacin A

Article abstract of DOI:10.1016/S0040-4020(02)01524-7

A 20-step total synthesis of (±)-arisugacin A with an overall yield of 2.1% is described here in detail. This synthesis features a formal [3+3] cycloaddition reaction of α,β-unsaturated iminium salts with 6-aryl-4-hydroxy-2-pyrones through a highly stereoselective 6π-electron electrocyclic ring-closure of 1-oxatriene. A strategic dihydroxylation-deoxygenation protocol leading to the desired angular C12a-OH was developed to serve as a critical step in leading to the final total syntheses of arisugacin A. This synthetic endeavor also led to an interesting and unexpected retro-aldol-aldol sequence in the AB-ring.

Full text of DOI:10.1016/S0040-4020(02)01524-7

Tetrahedron 59 (2003) 311–324
The total synthesis of (6)-arisugacin A
Richard P. Hsung, † Kevin P. Cole, Luke R. Zehnder, Jiashi Wang, Lin-Li Wei,
Xiao-Fang Yang and Heather A. Coverdale
,
*
Department of Chemistry, University of Minnesota, 207 Pleasant Street S.E., Minneapolis, MN 55455-0431, USA
Received 4 October 2002; accepted 21 November 2002
This paper is dedicated to Professor Gilbert Stork on the occasion of his 80th birthday
Abstract—A 20-step total synthesis of (^)-arisugacin A with an overall yield of 2.1% is described here in detail. This synthesis features a
formal [3þ3] cycloaddition reaction of a,b-unsaturated iminium salts with 6-aryl-4-hydroxy-2-pyrones through a highly stereoselective
6p-electron electrocyclic ring-closure of 1-oxatriene. A strategic dihydroxylation–deoxygenation protocol leading to the desired angular
C12a–OH was developed to serve as a critical step in leading to the final total syntheses of arisugacin A. This synthetic endeavor also led to
an interesting and unexpected retro-aldol–aldol sequence in the AB-ring. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Arisugacin A (1), isolated from Penicillium Sp. Fo-4259 by
˜
Omura, is a potent and selective inhibitor of acetylcholin-
esterase with an IC50 of 1 nM,1 thereby possessing
significance in treatment of dementia diseases such as
Alzheimer’s disease.2 Given its biological relevance and
unique meroterpenoidal structure (a hybrid of polyketide
and terpenoid) that resembles other important natural
products such as the territrems (3)3 and pyripyropenes,4 we
have investigated a number of different synthetic routes
seeking an efficient synthesis of arisugacin A.5–8 In particular,
we have been developing a formal [3þ3] cyclo-addition
method9 – 11 that involves condensing a,b-unsaturated
iminium salts 7 with 6-aryl-4-hydroxy-2-pyrones such as 8
through a stereoselective 6p-electron electrocyclic ring-
closure12 of the 1-oxatriene intermediate 10 (Fig. 1).
In this tandem Knoevenagel condensation–pericyclic ring-
closure sequence,13 two s-bonds and a new stereocenter
adjacent to the oxygen atom are formed, leading to a
convergent synthesis of the advanced pentacyclic inter-
mediate 67,8 in a highly stereoselective manner (C6a in 6).
We have applied this stepwise cycloaddition to total
syntheses of pyranoquinoline alkaloids14 and expanded it
to synthesis of dihydropyridines using vinylogous amides.15
˜
Recently, Omura’s group and ours independently communi-
cated total syntheses of (^)-arisugacin A featuring this
Keywords: arisugacin A; formal [3þ3] cycloaddition; iminium salts;
stereoselective pericyclic ring-closure; retro-aldol–aldol sequence.
*
Corresponding author. Tel.: þ1-612-625-3045; fax: þ1-612-626-7541;
e-mail: hsung@chem.umn.edu
A recipient of 2001 Camille Dreyfus Teacher-Scholar and 2001–2003
McKnight New Faculty Awards.
†
Figure 1.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01524-7

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R. P. Hsung et al. / Tetrahedron 59 (2003) 311–324
cycloaddition step (7þ8!6),9 there are two major uncer-
tainties that could render this effort completely futile. First,
sterically congested a,b-unsaturated iminium salts such as 7
can impede the formal [3þ3] cycloaddition.9 Secondly, and
more significantly, in our hands,14b there had been no
successful stereoselective examples of this particular formal
cycloaddition using chiral a,b-unsaturated iminium salts
except in one isolated case.10b Thus, the ability to control
the stereochemistry at C6a through this key formal [3þ3]
cycloaddition reaction remained speculative.
However, because the 6p-electron electrocyclic ring-
closure of the respective 1-oxatriene 10 has been found to
be reversible,9,15a a favorable diastereoselectivity could still
be achieved leading to the thermodynamically more stable
isomer 6 in which the C6a methyl is b in the event that 11 is
the initial major product. The pentacycle 6 is more favored
than its C6a-epimer 11 (the C6a methyl is a) by about
2.40 kcal mol21 using PM3 calculations (Spartane). In
addition, calculations showed that the natural product
arisugacin A (1) itself is more stable with a b-C6a-methyl
than 12 (C6a methyl is a) by ca. 4.79 kcal mol21 (Fig. 2).
Figure 2.
stepwise cycloaddition reaction.16–18 We report here the
full details of our success in applying the formal [3þ3]
cycloaddition to a total synthesis of (^)-arisugacin A.
2.1. The epoxy diol route
Encouraged by this calculation, the racemic ester 13 was
prepared readily in 5 steps from a-ionone in 65% overall
yield via a known sequence used in the synthesis of
forskolin (Scheme 1).19 The subsequent intramolecular
Diels–Alder reaction of 13 in refluxing anhydrous n-decane
gave the tricyclic lactone 14 in 65% yield.20 Epoxidation of
14 using buffered m-CPBA led to the a-epoxy lactone 9 in
60% yield. The corresponding b-epoxy isomer was also
isolated in 10–20% yield but can be readily separated from
the a-epoxy isomer 9. The relative stereochemistry of 9 was
assigned using nOe experiments.
2. Results and discussion
Although the proposed route in Figure 1 is quite feasible
based on our understanding of the key formal [3þ3]
It is noteworthy that stereochemical control of the two new
stereogenic centers at C4a and C12b ultimately stems
from the stereochemistry at C1 through the intramolecular
Diels–Alder reaction. Hence, an optically pure 13 should
lead to an enantioselective preparation of the a-epoxy
lactone 9, thereby ultimately leading to an enantioselective
synthesis of arisugacin A (1). LAH reduction of the a-epoxy
lactone 9 led to the epoxy diol 15 in 78% yield with the
epoxide remained intact when carried out at low tempera-
ture. Standard functional group manipulations provided the
aldehyde 16 in 4 steps with an overall yield of 50%.
However, under our conditions9 as well as a variety of other
conditions,21,22 the formal [3þ3] cycloaddition reaction of
the iminium salt 17 with the pyrone 8 failed to provide any
desired pentacycle 18. This failure prompted us to think that
17 could be sterically too demanding, thereby obstructing
the reaction pathway.8
Molecular models revealed that if either the C1 carbon were
sp2 hybridized or the C1 hydroxyl group were unprotected,
such a steric congestion could be alleviated. We chose the
former option as shown in Scheme 2. Acetylation of the diol
15 followed by Dess–Martin periodinane (DMP) oxidation
afforded the ketone 19 in 90% overall yield. Deacetylation
of 19 led to the formation of the lactol 20, and PCC
Scheme 1.

R. P. Hsung et al. / Tetrahedron 59 (2003) 311–324
313
Scheme 2.
oxidation successfully unraveled the lactol 20 and gave the
desired keto aldehyde 21 in 71% yield. Attempts to go from
15 to 21 directly via a double Swern oxidation were not
fruitful.
Scheme 4.
minor isomer 11 (C6a methyl being a) from the reaction
that led to 6 could be cleanly separated and equilibrated
completely to the major isomer 6 (with C6a methyl being b)
when subjected again to the reaction conditions, thereby
supporting our assertion made earlier.
The keto aldehyde 21 proved to be quite suitable for
constructing the pentacycle 6. The iminium intermediate 22
was generated from 21 using 0.5–1.0 equiv. piperidinium
acetate in the presence of Na2SO4 at 808C for 1 h (Scheme
3). The subsequent reaction of 22 with the pyrone 8 in
EtOAc at 808C for 20 h led to the isolation of the pentacycle
6 in 65% yield with a diastereomeric ratio of 94:6. The
angular methyl at C6a was established as b for the major
isomer of 6 and a for the minor isomer (11) by using nOe
experiments.
2.2. Problems with the epoxy diol route
The above 13-step preparation of the pentacycle 6 in 9%
overall yield from a-ionone firmly establishes the feasibility
of the formal [3þ3] cycloaddition reaction as an approach to
arisugacin A (1) and its family members as well as structural
analogs. However, a major challenge lay ahead that led to
a 14-month investigation involving installation of the C12a
hydroxyl group in the C-ring. The sequence of epoxidation–
reduction was met with difficulties because ring opening
of the C12a–C12 epoxide in 25 by various nucleophilic
oxygen species precluded the addition of hydride (Scheme
4). The desired product 26 was never isolated.
By using the pyrone 2323 under the same conditions, the
pentacycle 24 was obtained in 72% yield with a dia-
stereomeric ratio of 91:9 also in favor of the same major
isomer. The compound 24 contains the desired E-ring
leading to territrem B (3). The high diastereoselectivity
obtained in these reactions here is likely a result of the
reversible 6p-electron electrocyclic ring-closure.9,15a The
To solve this problem, bisoxygenation or dihydroxylation of
the model tetracycle 27 was carried out followed by removal
of the more activated secondary oxygen functionality in 28
or 29 using reductive methods that we had developed
for these specific systems (Scheme 4).24,25 The effort in
developing this methodology (27 to 30) turned out to be
significant not only in this synthetic endeavor but also
for future total syntheses employing the formal [3þ3]
cycloaddition reaction.
Based on our model study (27 to 30),24,25 the C12–C12a
olefin in the C-ring of epoxy pentacycle 6 was subjected to a
variety of epoxidation and dihydroxylation conditions but
all failed (see supplementary materials for more details on
various conditions). The only discernable product arising
from these attempts was the diol 31 in only 8–21% yield
when using m-CPBA, but this result was also difficult to
reproduce (Scheme 5). Attempts to hydroborate the same
C12–C12a olefin in 6 using BH3–SMe2 gave exclusively
the alcohol 33 with b-C1–OH based on nOe experiments.
The alcohol 33 was also obtained when 6 was reduced using
Dibal-H or NaBH4.
Epoxidation of 33 using m-CPBA buffered with NaHCO3
led to the hexacycle 34 in 21% overall yield starting from 6.
Scheme 3.

314
R. P. Hsung et al. / Tetrahedron 59 (2003) 311–324
Scheme 5.
Stereochemistry of the hexacycle 34 was assigned using
nOe experiments. This indicates that not only epoxidation of
the C12–C12a olefin had taken place, but also the ring
opening of the C12–C12a epoxide had occurred. This
presumably took place through a vinyl oxocarbenium
intermediate that was trapped intramolecularly by the
b-C1–OH leading to the new furan ring, although such an
event could also take place without involving the proposed
zwitterion. Furthermore, C4a–C5 epoxide in the B-ring had
surprisingly ring-opened at the same time.
Reductive removal of the 3-chlorobenzoyl group (Bz p ) in
34 using Dibal-H (63% yield) led to a free alcohol at C5 that
was subjected to xanthate formation (CS2, MeI, 52%
yield).21 However, the subsequent Barton’s deoxygenation
proceeded only in very low yield in removing the C5 oxygen
functionality of 34. Ultimately, there were other additional
problems associated with ring opening of the C4a–C5
epoxide (see supplementary materials), thereby completely
suffocating this route. The most significant result turned out
to be the hindsight recognition that the C1–OH group has to
Scheme 7.
be beta to allow successful functionalization of the C12–
C12a olefin in the C-ring.
2.3. The triol route
To avoid the C4a–C5 epoxide issue, a new route to the keto
enal “37-a” was pursued (Scheme 6). The triol 35 could be
attained via LAH reduction of 15, and acylation of 35 would
lead to the acetate 36 whose stereochemistry was corrobo-
rated by X-ray analysis. The subsequent TPAP oxidation of
36 followed by deacylation and PCC oxidation led to the
keto-enal “37-a” in 73% overall yield.
It was not readily apparent that the assignment of keto enal
“37-a” was incorrect until we pursued the subsequent
formal [3þ3] cycloaddition of the alleged “37-a” with the
pyrone 8. The reactions of keto enal “37-a” with 8 could
only proceed at high temperatures using the more reactive
piperidinium hydrochloride salt21 leading to the pentacycle
39 with low yield and poor diastereoselectivity (Scheme 7).
An X-ray structural analysis disturbingly showed while the
connectivity was correct, it was not the keto enal “37-a” but
37-b that had led to the wrong pentacycle 39 (see
Scheme 6.

R. P. Hsung et al. / Tetrahedron 59 (2003) 311–324
315
1
shifted olefinic H in the C-ring (7.43 ppm), whereas the
same olefinic 1H in 39-cis is at the expected region
1
(6.09 ppm). The H in 40 experiences diamagnetic aniso-
tropic effect due to its close proximity to the A-ring
carbonyl oxygen.26
When the pentacyle 40 was treated with 2.0 equiv. of LDA
followed by addition of PhSeCl, 40 was found to have
isomerized completely to the pentacycle 39 likely via a
similar retro-aldol–aldol sequence. The propensity of 40 to
epimerize to 39 back to implies that 39 could actually be the
thermodynamically more stable structure.
2.4. The final total synthesis
Advanced pentacycles 42 and 40 provided new opportuni-
ties in achieving a total synthesis of (^)-arisugacin A (1).
However, attempts at oxidizing the C-ring olefin in 42 using
various protocols all failed (see supplementary materials).
These failures suggest that the stereochemistry of the
C1–OH group likely plays a significant role sterically.
Given our earlier success in epoxidizing the epoxy
pentacycle 32 having the b-C1–OH (see Scheme 5), the
pentacycle 40 was subjected to directed reduction using
NMe4B(OAc)3H in AcOH to give exclusively the diol 43 in
94% yield with b-C1–OH (Scheme 9, also see supple-
mentary materials).26
Scheme 8.
Dihydroxylation24,25 of 43 using a stoichiometric amount of
OsO4 in pyridine gave the desired tetraol 44 in 83% yield as
a single diastereomer. The removal of the C12–OH in 44
using the Et3SiH protocol24,25 gave an undesired hexacycle
structurally similar to 34.27 Hydrogenation of 44 using
Ac2O as solvent24,25 gave instead the triol acetate 45 in 93%
yield, suggesting that acylation of the C1–OH had taken
place. The triol acetate 45 could also be obtained
quantitatively using Ac2O and DMAP, providing exclusive
acylation at the b-C1–OH.
supplementary materials) and not the desired pentacycle 40
with trans-fused AB-ring.26 It is reasonable to propose that a
retro-aldol–aldol sequence had occurred during preparation
of 37 at the stage of deacylation of 38 using K2CO3/MeOH
(see the box in Scheme 7). Calculations (AM1-Spartane)
showed that cis-fused decalin motif in 37-a is actually more
stable than 37-a by ,1.5 kcal mol21 presumably due to the
severe interactions between the two axial methyl groups in
the trans-decalin motif of 37-a.
On the other hand, the desired pentacycle 40 was calculated
(AM1-Spartane) to be more stable than 39 by
,1.0 kcal mol21, but attempts using K2CO3/MeOH or
DBU to equilibrate 39 to 40 via another retro-aldol–aldol
sequence all failed (see supplementary materials).26
To avoid this unexpected retro-aldol–aldol predicament,
desired pentacycle 40 was prepared via yet another route. As
shown in Scheme 8, the triol 35 was oxidized using Ley’s
TPAP oxidation without protecting either the C1- or C4a-
hydroxyl group to give the diol enal 41 in 70% yield. This
chemoselectivity likely was a result of a shorter reaction
time in favor of the more reactive primary allyl alcohol. The
diol enal 41 was surprisingly stable and did not lactolize
unless it was subjected to elevated temperatures or acidic
conditions.26
Reaction of the diol enal 41 with 8 under the standard [3þ3]
conditions led to the desired pentacyle 42 essentially as a
single diastereomer with an improved 50% yield. Subse-
quent oxidation of 42 using Ley’s TPAP afforded the
pentacycle 40 in 95% yield. The relative stereochemistry
was unambiguously confirmed using X-ray analysis. The
X-ray structure of 40 also explains the unusually downfield
Scheme 9.

316
R. P. Hsung et al. / Tetrahedron 59 (2003) 311–324
trometers using CDCl3 (except where noted) with TMS or
residual solvent as standard. Melting points were deter-
mined using a Laboratory Devices MEL-TEMP and are
uncorrected/calibrated. Infrared spectra were obtained using
NaCl plates on a Midac M2000 FTIR. TLC analysis was
performed using Aldrich 254 nm polyester-backed plates
˚
(60 A, 250 mm) and visualized using UV and vanillin or
KMnO4 stains. Low resolution mass spectra were obtained
using an Agilent 1100 series LS/MSD and are APCI. High
resolution mass spectral analyses performed at University of
Minnesota Department of Chemistry Mass Spectrometry
Laboratory. X-Ray analyses performed at University of
Minnesota Department of Chemistry X-ray facility. All
spectral data obtained for new compounds are reported here.
Scheme 10.
Subsequent removal of the C12–OH in 45 using Et3SiH and
12 equiv. of TFA gave 46 in 89% yield.24,25 The reductive
cleavage was selective for the more reactive allylic C-12
hydroxyl group. Such chemoselectivity is also possible due
to the assistance from the pyranyl oxygen atom for the C-12
hydroxyl group is essentially situated in the gamma position
of an enol-ether. Deacylation of 46 gave the desired triol 47
in 90% yield.
4.1.1. Ketone 6. A heterogeneous mixture of enal 21
(8.2 mg, 33 mmol), pyrone 8 (10.0 mg, 40 mmol), Na2SO4
(3.0 mg) and piperidinium acetate (3.0 mg, 21 mmol) in dry
ethyl acetate (1.5 mL) was sealed in a 3 mL vial and heated
to 908C. After 18 h, the mixture was filtered through a pad of
silica, concentrated, and purified by flash chromatography
(60% EtOAc in hexanes) to afford the title compound
(10.3 mg, 65%) as a bright yellow solid in a diastereomeric
ratio of 94:6 with the desired isomer being major.
Ley’s TPAP oxidation of the triol 47 led to the pentacycle
48 in 90% yield (Scheme 10). To circumvent the retro-
aldol–aldol that was observed earlier for 40, protocols such
as DDQ and IBX29 were examined to install the double
bond in the A-ring but were not successful. Schlosser’s base,
prepared from deprotonating diisopropyl amine with n-BuLi
in the presence of KOt-Bu, proved to be effective in the
selenation using PhSeBr. This outcome is presumably due to
some counter cation effect since LDA or KHMDS did not
work well. Subsequent oxidative elimination of the selenide
intermediate using H2O2 led to (^)-arisugacin A (1) in 67%
yield for the two steps. The synthetic sample matched
6: 1H NMR (500 MHz, CDCl3) d 0.87 (s, 3H), 1.17 (s, 3H),
1.43 (s, 3H), 1.53 (s, 3H), 1.66–1.72 (m, 1H), 1.97–2.03
(m, 1H), 2.38–2.45 (m, 2H), 2.80–2.86 (m, 2H), 3.32 (d,
1H, J¼4.5 Hz), 3.93 (s, 3H), 3.94 (s, 3H), 6.10 (s, 1H), 6.38
(s, 1H), 6.90 (d, 1H, J¼8.5 Hz), 7.29 (s, 1H), J¼2.0 Hz),
7.38 (dd, 1H, J¼2.0, 8.5 Hz); 13C NMR (75 MHz, CDCl3) d
22.8, 25.1, 26.7, 28.6, 33.8, 35.2, 36.3, 36.9, 52.4, 52.9,
56.0, 56.1, 66.6, 77.9, 96.2, 101.5, 108.3, 111.0, 112.9,
119.1, 124.6, 132.4, 149.2, 151.5, 160.2, 161.5, 163.7,
211.8; IR (film) cm21 1271, 1515, 1550, 1714, 2944, 2968;
mass spectrum (EI): m/e (%relative intensity) 478 (M)þ
(50), 463 (M2CH3)þ (100), 435 (32), 165 (99), 149 (69), 69
(86); m/e calcd for C28H30O7 478.1992; found 478.1999.
1
spectroscopically [co-spectra of H NMR in pyridine-d5]
and analytically [TLC: in 2:1 EtOAc/hexane: 2:1 ether/
hexane; 1:9 acetone/CHCl3] with (þ)-arisugacin A.
3. Conclusions
4.1.2. Ester 13. The allylic alcohol (100.0 mg, 590 mmol),
2-butynoic acid (75.0 mg, 1.5 equiv.) and DCC (200.0 mg,
1.6 equiv.) were dissolved in CH2Cl2 (10.0 mL) and cooled
to 08C. DMAP (20.0 mg) in CH2Cl2 (3.0 mL) was added
dropwise, and the reaction placed in the refrigerator
overnight. The resulting mixture was filtered through a
coarse frit to remove precipitated N,N0-dicyclohexyl urea.
The liquid portion was washed with 1 M HCl (5 mL), brine
(5 mL), and dried (Na2SO4). Removal of solvent in vacuo,
followed by silica gel chromatography (7% EtOAc in
hexanes) afforded the ester (132.0 mg, 96%) as a clear oil.
We have described here a 20-step total synthesis of
(^)-arisugacin A with an overall yield of 2.1%. This
synthesis features a formal [3þ3] cycloaddition reaction of
a,b-unsaturated iminium salts with 6-aryl-4-hydroxy-2-
pyrones through a highly stereoselective 6p-electron
electrocyclic ring-closure of 1-oxatriene. A strategic
dihydroxylation–deoxygenation protocol leading to the
desired angular C12a–OH was developed to serve as a
critical step in the final total synthesis of arisugacin A. Our
synthetic endeavor also led to an interesting observation of
an unexpected retro-aldol–aldol sequence in the AB-ring.
13: Rf¼0.63 (10% EtOAc in hexanes); 1H NMR (300 MHz,
CDCl3) d 0.98 (s, 3H), 1.03 (s, 3H), 1.40 (ddd, 1H, J¼3.3,
6.6, 13.2 Hz), 1.64 (m, 1H), 1.69 (s, 3H), 1.78 (dddd, 1H,
J¼3.3, 4.2, 6.6, 14.1 Hz), 1.92 (dddd, 1H, J¼3.3, 4.8, 10.8,
14.4 Hz), 1.98 (s, 3H), 5.02 (dd, 1H, J¼2.7, 18.0 Hz), 5.28
(dd, 1H, J¼4.5, 4.5 Hz), 5.31 (dd, 1H, J¼2.4, 11.4 Hz), 6.17
(dqdd, 1H, J¼1.2, 1.2, 11.4, 17.4 Hz).
4. Experimental
4.1. General
All reactions performed in flame-dried glassware under
nitrogen atmosphere. Solvents were distilled prior to use.
Reagents were used as purchased (Aldrich, Acros), except
4.1.3. Lactone 14. Ester 13 (12.4 g, 52.9 mmol) was
dissolved in n-decane (750 mL) in a 1 L flask. A condenser
was attached and the system purged with nitrogen. The
solution was heated to reflux (1808C) for 28 h. After
where noted. Chromatographic separation were performed
using Bodman 60 A SiO2. H and 13C NMR spectra were
˚
1
obtained on Varian VI-300, VX-300, and VI-500 spec-

R. P. Hsung et al. / Tetrahedron 59 (2003) 311–324
317
cooling, solvent was removed under high vacuum
(0.1 mmHg, 408C) and the residue was purified by flash
silica gel chromatography (10% EtOAc in hexanes) to
afford the lactone (7.29 g, 59%) as a clear oil along with
recovered ester (1.43 g, 12%).
(film) cm21 1437, 2907, 2846, 2990, 3370; mass spectrum
(EI): m/e (%relative intensity) 216 (M22H2O)þ (31), 177
(100), 161 (41), 149 (98), 135 (49), 123 (86), 107 (79), 91
(61), 81 (63), 55 (53).
4.1.6. Aldehyde 16. Acetic anhydride (1.0 mL) was added
dropwise to a solution of diol 15 (54.0 mg, 214 mmol) in
pyridine (4 mL) at rt. After 24 h, the solution was diluted
with CH2Cl2 (30 mL), washed with saturated NaHCO3
(30 mL), dried (Na2SO4), and concentrated under vacuum
(ca. 1 mmHg) to remove solvents. Flash chromatography
(1:6 EtOAc/hexanes) afforded the monoacetylated inter-
mediate (60.2 mg, 96%) as a white solid.
14: Rf¼0.48 (20% EtOAc in hexanes); 1H NMR (500 MHz,
CDCl3) d 1.14 (s, 3H), 1.16 (ddd, 1H, J¼4.5, 7.0, 18.0 Hz),
1.20 (s, 3H), 1.21 (s, 3H), 1.43 (ddd, 1H, J¼3.5, 13.5,
13.5 Hz), 1.59 (ddd, 1H, J¼4.5, 14.0, 14.0 Hz), 1.90 (dddd,
1H, J¼3.5, 3.5, 3.5, 13.0 Hz), 2.25 (s, 3H), 2.78 (dd, 1H,
J¼6.0, 21.0 Hz), 2.91 (d, 1H, J¼21.0 Hz), 4.30 (dd, 1H,
J¼5.0, 12.5 Hz), 5.66 (dd, 1H, J¼2.0, 6.5 Hz).
4.1.4. Lactone 9. Lactone 14 (175.0 mg, 0.753 mmol) was
dissolved in CH2Cl2 (3 mL) and cooled to 08C. Solid
m-CPBA (77%, 254.0 mg, 1.13 mmol) was then added in
one portion and the solution placed in the refrigerator for 2
d. Precipitated m-chlorobenzoic acid was removed by
filtration through a coarse fritted funnel, and the filtrate
diluted with chilled CH2Cl2 (25 mL). The filtrate was then
washed successively with cold 1 M NaOH (5 mL), H2O
(5 mL), and brine (5 mL). Drying (Na2SO4), concentration
in vacuo, and flash chromatography (20% EtOAc in
hexanes) afforded the b-epoxide (10–20% dependant on
trial) and the desired a-epoxide (109.0 mg, 59%) as a
colorless oil.
Monoacetylated intermediate: 1H NMR (300 MHz, CDCl3)
d 0.80 (s, 3H), 1.18 (s, 3H), 1.19 (s, 3H), 1.15–1.24 (m, 1H),
1.75–1.80 (m, 1H), 2.01 (s, 3H), 1.92–2.07 (m, 2H), 2.48
(s, 2H), 2.55 (d, 1H, J¼6.3 Hz), 3.14 (t, 1H, J¼1.8 Hz), 4.00
(s, 1H), 4.78 (d, 1H, J¼2.1 Hz); 13C NMR (75 MHz,
CDCl3) d 20.2, 21.1, 23.5, 25.4, 26.8, 26.9, 31.3, 32.4, 34.7,
45.2, 51.0, 60.7, 66.2, 72.0, 130.1, 132.4, 170.9; IR
(film) cm21 1243 m, 1725 vs, 2916 m, 2988 s, 3524 brs;
mass spectrum (EI): m/e (%relative intensity) 294 (M)þ (5),
279 (M2CH3)þ (29), 261 (27), 234 (M2AcOH)þ (5), 219
(17), 216 (M2H2O2AcOH)þ (14), 201 (19), 173 (23), 159
(54), 149 (48), 135 (100), 119 (52), 107 (33), 91 (35), 81
(46), 69 (22), 55 (32).
1
9: Rf¼0.20 (20% EtOAc in hexanes); H NMR (500 MHz,
To a solution of the mono-acetylated intermediate
(described above) (17.8 mg, 60.5 mmol) in CH2Cl2
(2.0 mL) at rt was added 2,6-lutidine (8 drops) and TESOTf
(6 drops) sequentially. After 4 h, the solution was filtered
through a pad of silica, concentrated, and the crude residue
purified by flash chromatography (1:13 EtOAc/hexanes) to
afford the TES ether/acetate (20.1 mg, 81%) as a colorless
oil.
CDCl3) d 0.81, (s, 3H), 1.21 (s, 3H), 1.32 (s, 3H), 1.37 (ddd,
1H, J¼1.5, 14.0, 14.0 Hz), 1.55 (dddd, 1H, J¼2.5, 12.0,
12.0, 14.0 Hz), 1.67 (ddd, 1H, J¼2.5, 5.0, 14.0 Hz), 1.98
(dddd, 1H, J¼2.5, 5.0, 5.5, 12.5 Hz), 2.16 (s, 3H), 2.60 (dd,
1H, J¼3.0, 18.0 Hz), 2.73 (d, 1H, J¼18.5 Hz), 3.10 (d, 1H,
J¼3.5 Hz), 4.16 (dd, 1H, J¼5.5, 11.5 Hz); 13C NMR
(75 MHz, CDCl3) d 19.3, 25.3, 25.7, 26.8, 29.8, 33.4,
34.7, 44.8, 48.3, 66.3, 84.1, 126.8, 146.0, 168.7; mass
spectrum (EI): m/e (%relative intensity) 248 (M)þ (65), 149
(31), 121 (39), 105 (40), 91 (41), 84 (100); m/e calcd for
C15H20O3 248.1412; found 248.1409.
1
TES ether/acetate: H NMR (300 MHz, CDCl3) d 0.63 (q,
6H, J¼7.7 Hz), 0.79 (s, 3H), 0.96 (t, 9H, J¼7.8 Hz), 1.11–
1.15 (m, 1H), 1.16, (s, 3H), 1.17 (s, 3H), 1.67 (s, 3H), 1.65–
1.72 (m, 1H), 2.01 (s, 3H), 1.90–2.11 (m, 2H), 2.46 (s, 2H),
2.96 (t, 1H, J¼2.1 Hz), 4.13 (t, 1H, J¼1.8 Hz), 4.70 (d, 1H,
J¼12.6 Hz), 4.79 (d, 1H, J¼12.6 Hz).
4.1.5. Diol 15. To a solution of lactone 9 (113.0 mg,
455 mmol) in ether (10 mL) at 2788C was added a solution
of LAH (1 M in THF, 1.80 mL, 1.80 mmol). After 2 h at
2788C, the solution was allowed to warm to rt and
quenched with saturated ammonium chloride (10 mL).
The organic layer was separated, and the aqueous phase
extracted with EtOAc (3£10 mL). The combined organic
extracts were washed with saturated NaHCO3 (10 mL),
brine (10 mL), and dried (Na2SO4). Concentration, followed
by flash chromatography (gradient, 25–50% EtOAc in
hexanes) afforded the title diol (71.2 mg, 62%) as a white
solid.
To a solution of the TES ether (described above) (20.1 mg,
49.2 mmol) in methanol (2.5 mL) at rt was added a solution
of K2CO3 (35.0 mg, 253 mmol) in H2O (0.5 mL). After 2 d,
the reaction mixture was diluted with ether (20 mL), washed
with brine (20 mL), dried (Na2SO4), concentrated, and the
residue subjected to flash chromatography (10% EtOAc in
hexanes) to afford the deacetylated intermediate (15.6 mg,
87%) as a white solid.
1
Deacetylated intermediate: H NMR (300 MHz, CDCl3) d
15: mp¼147.5–148.08C; Rf¼0.13 (50% EtOAc in hex-
0.66 (q, 6H, J¼8.1 Hz), 0.81 (s, 3H), 0.98 (t, 9H, J¼7.8 Hz),
1.12 (s, 3H), 1.12–1.19 (m, 1H), 1.37 (s, 3H), 1.74 (s, 3H),
1.70–1.82 (m, 1H), 1.87–1.97 (m, 1H), 2.03–2.14 (m, 1H),
2.39 (d, 1H, J¼18.0 Hz), 2.49 (dd, 1H, J¼3.1, 18.0 Hz),
2.98 (t, 1H, J¼0.9 Hz), 4.11 (s, 2H), 4.27 (dd, 1H, J¼2.1,
3.6 Hz).
1
anes); H NMR (300 MHz, CDCl3) d 0.84 (s, 3H), 1.14 (s,
3H), 1.20 (s, 3H), 1.27 (m, 1H), 1.78 (s, 3H), 1.80–1.94 (m,
2H), 2.05 (ddd, 1H, J¼2.4, 4.2, 15.0 Hz), 2.44 (d, 1H,
J¼18.6 Hz), 2.53 (dd, 1H, J¼2.7, 18.6 Hz), 3.23 (dd, 1H,
J¼2.4, 2.4 Hz), 3.69 (brs, 1H), 4.01 (d, 1H, J¼12.3 Hz),
4.12 (dd, 1H, J¼3.9, 3.9 Hz), 4.23 (d, 1H, J¼12.0 Hz); 13C
NMR (75 MHz, CDCl3) d 19.9, 23.2, 25.5, 26.5, 26.8, 31.2,
32.1, 35.0, 45.2, 52.0, 57.7, 66.7, 73.5, 128.6, 134.4; IR
To a solution of the alcohol (15.6 mg, 42.6 mmol)
(described above) in CH2Cl2 (3.0 mL) was added a mixture

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R. P. Hsung et al. / Tetrahedron 59 (2003) 311–324
of NaHCO3 (11.0 mg, 131 mmol) and Dess–Martin period-
inane (55.0 mg, 130 mmol). After 2.5 h at rt, the reaction
was quenched with 2-propanol, filtered through a pad of
silica, concentrated, and the residue purified via flash
chromatography (5% EtOAc in hexanes) to afford enal 16
(11.3 mg, 73%) as a white solid.
25.9, 28.1, 33.5, 34.8, 35.2, 37.2, 53.3, 54.4, 68.4, 134.8,
141.5, 191.8, 209.4; IR (film) cm21 1378, 1420, 1627, 1678,
1712, 1737, 2942, 2966; mass spectrum (EI): m/e (%relative
intensity) 233 (M2CH3)þ (29), 205 (8), 189 (12), 175 (80),
161 (27), 147 (36), 133 (100), 119 (65), 105 (81), 91 (48), 77
(44), 55 (73).
16: 1H NMR (300 MHz, CDCl3) d 0.56 (q, 6H, J¼7.8 Hz),
0.80 (s, 3H), 0.94 (t, 9H, J¼7.8 Hz), 1.17 (s, 3H), 1.15–1.18
(m, 1H), 1.30 (s, 3H), 1.60–1.68 (m, 1H), 2.00 (s, 3H),
1.92–2.11 (m, 2H), 2.56 (s, 2H), 3.03 (t, 1H, J¼1.0, 2.1 Hz),
4.77 (t, 1H, J¼2.4 Hz), 10.03 (s, 1H).
4.1.10. Ketone 24. A heterogeneous mixture of enal 21
(4.4 mg, 18 mmol), pyrone 23 (6.0 mg, 22 mmol), Na2SO4
(3.0 mg) and piperidinium acetate (1.5 mg, 11 mmol) in dry
ethyl acetate (1.5 mL) was sealed in a 3 mL vial and heated
to 908C. After 18 h, the mixture was filtered through a pad of
silica, concentrated, and purified by flash chromatography
(60% EtOAc in hexanes) to afford the title compound
(6.5 mg, 72%) as a bright yellow solid in a diastereomeric
ratio of 85:15 with the desired isomer being major.
4.1.7. Ketone 19. To a solution of the monoacetylated
intermediate (see above) (56.2 mg, 191 mmol) in CH2Cl2
(15 mL) at rt was added NaHCO3 (70.0 mg, 0.825 mmol)
and Dess–Martin periodinane (350.0 mg, 0.825 mmol).
After 2 h, the reaction was quenched with 2-propanol,
concentrated, and filtered through a silica pad. The residue
was subjected to flash chromatography (25% EtOAc in
hexanes) to afford 19 (52.4 mg, 94%) as a light tan solid.
24: 1H NMR (500 MHz, CDCl3) d 0.88 (s, 3H), 1.18 (s, 3H),
1.54 (s, 3H), 1.56 (s, 3H), 1.65–1.75 (m, 1H), 1.97–2.05
(m, 1H), 2.38–2.42 (m, 2H), 2.78–2.89 (m, 2H), 3.33 (d,
1H, J¼6.4 Hz), 3.90 (s, 3H), 3.91 (s, 6H), 6.11 (s, 1H), 6.41
(s, 1H), 6.99 (s, 2H); 13C NMR (75 MHz, CDCl3) d 22.9,
25.1, 26.7, 28.6, 33.8, 35.6, 36.3, 37.0, 52.4, 52.9, 56.4,
61.0, 66.6, 78.0, 97.1, 102.0, 102.9, 112.8, 126.6, 132.7,
141.2, 147.3, 153.5, 161.3, 163.4, 211.7; IR (film) cm21
1129, 1504, 1551, 1582, 1717, 2919, 2962; mass spectrum
(EI): m/e (%relative intensity) 508 (M)þz (43), 493
(M2CH3)þ (100), 465 (55), 291 (6), 228 (13), 195 (33),
173 (9), 157 (11), 149 (90), 91 (11), 69 (20), 57 (27); m/e
calcd for C29H32O8 508.2097; found 508.2090.
19: 1H NMR (300 MHz, CDCl3) d 0.88 (s, 3H), 1.23 (s, 3H),
1.69 (s, 3H), 1.80–1.87 (m, 2H), 1.97 (s, 3H), 2.43 (td, 1H,
J¼4.8, 14.4 Hz), 2.54 (s, 2H), 2.70 (ddd, 1H, J¼4.0, 7.5,
14.4 Hz), 2.54 (s, 1H), 4.74 (s, 2H); 13C NMR (75 MHz,
CDCl3) d 20.0, 20.9, 23.4, 26.0, 28.9, 32.8, 34.5, 35.6, 37.4,
53.1, 53.5, 60.9, 67.4, 128.8, 130.6, 170.9, 213.0.
4.1.8. Lactol 20. To a solution of ketone 19 (51.1 mg,
175 mmol) in methanol (5.0 mL) at rt was added a solution
of K2CO3 (70.0 mg, 506 mmol) in H2O (1.0 mL). After
20 h, the solution was poured into brine (30 mL) and
extracted (CH2Cl2, 3£30 mL). The combined extracts were
dried (Na2SO4) and concentrated. The resulting tan solid
(44.2 mg, 99%) was used without further purification.
4.1.11. Diol 31. A solution of pentacycle 6 (33.5 mg,
70 mmol) in 2 mL CH2Cl2 was cooled to 2108C and solid
m-CPBA (35.5 mg, 77%, 160 mmol) was added along with
5.0 mg of K2CO3. The mixture was stirred and allowed to
warm to rt over a period of 2 h at which time an additional
15.0 mg of m-CPBA was added. An additional 10.0 mg was
added after another 5 h along with 5.0 mg of K2CO3. Four
hours after the final addition, the mixture was diluted with
CH2Cl2 (20 mL) and washed with saturated NaHCO3
(3£20 mL). The organic layer was then washed with
brine, dried (Na2SO4), and concentrated under reduced
pressure. The residue was subjected to silica gel flash
chromatography (gradient, 0–40% EtOAc in hexanes) to
afford 2.9 to 7.6 mg (8–21%) of diol 31 depending on the
trial.
20: 1H NMR (300 MHz, CDCl3) d 0.78 (s, 3H), 1.19 (s, 3H),
1.22 (s, 3H), 1.46–1.53 (m, 1H), 1.58 (s, 3H), 1.70–1.88
(m, 3H), 2.33 (dd, 1H, J¼3.0, 17.4 Hz), 2.51 (s, 1H), 2.52
(d, 1H, J¼17.7 Hz), 3.06 d, 1H, J¼3.0 Hz), 4.34 (s, 2H); 13C
NMR (75 MHz, CDCl3) d 20.1, 20.3, 26.4, 29.5, 31.6, 33.9,
34.0, 34.7, 49.6, 50.5, 65.0, 66.5, 106.5, 117.7, 137.4; mass
spectrum (EI): m/e (%relative intensity) 250 (M)þ (2), 193
(28), 162 (22), 149 (92), 129 (43), 107 (43), 97 (71), 91 (49),
69 (100), 55 (53); m/e calcd for C15H23O3 251.1647; found
251.1650.
31: Rf¼0.46 (65% EtOAc in hexanes); 1H NMR (300 MHz,
CDCl3) d 0.88 (s, 3H), 1.18 (s, 3H), 1.25 (m, 1H), 1.48 (s,
3H), 1.54 (s, 3H), 1.70 (m, 1H), 2.01 (m, 1H), 2.43 (d, 1H,
J¼16.8 Hz), 2.81 (ddd, 1H, J¼7.5, 11.7, 19.2 Hz), 2.99 (dd,
1H, J¼3.9, 16.8 Hz), 3.48 (d, 1H, J¼3.9 Hz), 3.92 (s, 3H),
3.94 (s, 3H), 3.95 (s, 1H), 6.11 (s, 1H), 6.92 (d, 1H, J¼
8.6 Hz), 7.36 (d, 1H, J¼2.1 Hz), 7.53 (dd, 1H, J¼2.1,
8.6 Hz); mass spectrum (CI): m/e (%relative intensity) 513
(10) (MþH)þ, 447 (7), 391 (14), 307 (73), 154 (100), 107
(74); m/e calcd for C28H33O9 513.2125; found 513.2130.
4.1.9. Aldehyde 21. To a solution of lactol 20 (21.0 mg,
83.4 mmol) in CH2Cl2 (3.0 mL) was added PCC (90.0 mg,
418 mmol). After 16 h at rt, additional PCC (45.0 mg,
209 mmol) was added. After an additional 3 h, the solution
was diluted with hexanes (2.0 mL), filtered through a pad of
silica, concentrated, and the residue subjected to flash
chromatography (1:5 EtOAc/hexanes) to afford the title
compound (8.2 mg, 32%) as a white solid and recovered
starting material (9.4 mg, 40%).
21: 1H NMR (300 MHz, CDCl3) d 0.87 (s, 3H), 1.39 (s, 3H),
1.78 (s, 3H), 1.81–1.90 (m, 1H), 1.97 (s, 3H), 1.96–2.04
(m, 1H), 2.45 (ddd, 1H, J¼5.7, 8.1, 15.3 Hz), 2.64 (s, 2H),
2.90 (ddd, 1H, J¼5.7, 8.7, 15.2 Hz), 3.24 (t, 1H, J¼2.1 Hz),
10.01 (s, 1H); 13C NMR (75 MHz, CDCl3) d 19.5, 23.4,
4.1.12. Alcohol 33. To a solution of pentacycle 6 (100 mg,
0.21 mmol) in THF (8 mL) was added a 2.0 M solution of
BH3·Me2S in THF (0.52 mL, 1.04 mmol) at 2788C. The
reaction mixture was stirred at 2788C for 1 h and warmed to
room temperature. The reaction was quenched with H2O

R. P. Hsung et al. / Tetrahedron 59 (2003) 311–324
319
(10 mL) and the normal aqueous workup was employed.
Flash chromatographic separation (gradient, 40–60% EtOAc
in hexanes) gave 33 (51.2 mg, 50%) as a yellow solid.
The xanthate: To a solution of triol (13.0 mg, 25.0 mmol) in
THF (3 mL) was added NaH (60% suspension in mineral
oil, 6.0 mg, 150 mmol) at 08C. After stirring for 30 min, CS2
(10 mL, 0.16 mmol) was added, and after an additional
30 min, iodomethane (10 mL, 0.16 mmol) was added. The
reaction was stirred at room temperature for 2 h and then
quenched with H2O (0.5 mL). After normal workup the
crude product was purified by flash chromatography to
afford the xanthate (7.9 mg, 52%) as a colorless oil.
33: Rf¼0.20 (66% EtOAc in hexanes); 1H NMR (500 MHz,
CDCl3) d 0.75 (s, 3H), 1.16 (s, 3H), 1.39 (s, 3H), 1.42 (s,
3H), 1.46 (td, 1H, J¼3.5, 13.5 Hz), 1.61 (dt, 1H, J¼3.5,
14 Hz), 1.74 (brs, 1H), 1.81–1.96 (m, 2H), 2.38 (d, 1H, J¼
17 Hz), 2.78 (dd, 1H, J¼4, 17 Hz), 3.15 (d, 1H, J¼4 Hz),
3.93 (s, 3H), 3.95 (s, 3H), 4.27 (dd, 1H, J¼5, 11 Hz), 6.39 (s,
1H), 6.60 (s, 1H), 6.90 (d, 1H, J¼8.5 Hz), 7.31 (d, 1H, J¼
2 Hz); 7.39 (dd, 1H, J¼2.5, 8.5 Hz); 13C NMR (125 MHz,
CDCl3) d 18.4, 25.9, 26.2, 26.3, 27.5, 34.0, 35.6, 36.0, 45.3,
51.5, 56.0, 56.1, 65.2, 72.6, 78.2, 96.4, 101.8, 108.2, 111.0,
111.7, 119.0, 124.2, 137.6, 149.2, 153.5, 159.8, 162.0,
163.5; mass spectrum (CI): m/e (% relative intensity) 481
(MþH)þ (100), 261 (10), 195 (9), 165 (26), 135 (12), 119
(30); m/e calcd for C28H33O7 481.2225; found 481.2226.
1
The xanthate: Rf¼0.31 (66% EtOAc in hexanes); H NMR
(500 MHz, CDCl3) d 1.00–1.09 (m, 1H), 1.05 (s, 3H), 1.09
(s, 3H), 1.47–1.52 (m, 1H), 1.68 (s, 3H), 1.81 (s, 3H), 2.02–
2.09 (m, 2H), 2.15 (d, 1H, J¼16 Hz), 2.62 (s, 3H), 2.65 (dd,
1H, J¼7.5, 17 Hz), 3.95 (s, 3H), 3.96 (s, 3H), 5.12 (dd, 1H,
J¼4, 11 Hz), 5.21 (s, 1H), 6.93 (d, 1H, J¼7 Hz), 7.30 (d,
1H, J¼2.5 Hz), 7.42 (dd, 1H, J¼2.5, 8.5 Hz).
4.1.15. Triol 35. Solid LAH (530.0 mg, 3.0 equiv.) was
cautiously added to THF (100 mL) at 08C. The diol 15
(1.17 g, 4.64 mmol) was dissolved in THF (20 mL) and
slowly added to the LAH suspension. A condenser was fitted
to the flask, the system purged with nitrogen, and the
solution heated to reflux overnight. The next day, the
reaction was cooled to 08C and excess hydride destroyed by
titration with 1 M HCl. Water (50 mL) was added, and the
biphase saturated with NaCl. Extraction with EtOAc
(4£35 mL), drying (Na2SO4) and evaporation of solvents
yielded crude 35 which was purified by silica gel
chromatography (50% EtOAc in hexanes) to afford pure
35 (870.0 mg, 74%) as a white solid. Range of the yield for
different trials was within 62–90%.
4.1.13. meta-Chlorobenzoate 34. To a solution of alcohol
33 (136.0 mg, 0.28 mmol) in CH2Cl2 (6 mL) was added
NaHCO3 (238.0 mg, 2.83 mmol) and m-CPBA (284.0 mg,
1.14 mmol) sequentially at 08C. The mixture was stirred
over 12 h and was then poured into 25 mL of sat aq NaCl
and extracted (CH2Cl2, 3£25 mL). The combined extracts
were then dried over Na2SO4. The crude product was
purified by flash chromatography (40% EtOAc in hexanes)
to afford 34 (76.4 mg, 41%) as a light yellow solid.
34: Rf¼0.22 (66% EtOAc in hexanes); 1H NMR (500 MHz,
CDCl3) d 1.00 (s, 3H), 1.03 (s, 3H), 1.17–1.24 (m, 1H),
1.71–1.77 (m, 1H), 1.75 (s, 3H), 1.77 (s, 3H), 1.81–1.87
(m, 1H), 1.96 (d, 1H, J¼15.5 Hz), 2.11 (dt, 1H, J¼2.5,
13.5 Hz), 2.38 (d, 1H, J¼4 Hz), 2.67 (dd, 1H, J¼7,
15.5 Hz), 3.69 (s, 1H), 3.94 (s, 3H), 3.96 (s, 3H), 4.66
(brd, 1H, J¼11 Hz), 5.00 (s, 1H), 5.55 (d, 1H, J¼7 Hz), 6.33
(s, 1H), 6.91 (d, 1H, J¼8.5 Hz), 7.30 (d, 1H, J¼2 Hz), 7.40
(dd, 1H, J¼2, 8.5 Hz), 7.45 (t, 1H, J¼8 Hz), 7.59 (ddd, 1H,
J¼1, 2, 8 Hz), 7.87 (td, 1H, J¼2, 8 Hz), 7.97 (t, 1H, J¼
2 Hz), mass spectrum (CI): m/e (% relative intensity) 653
(MþH)þ (100), 315 (15), 277 (16), 261 (13), 203 (12), 165
(48), 139 (89), 119 (36); m/e calcd for C35H38O10Cl
653.2154; found 653.2150.
35: mp¼135.5–137.58C; Rf¼0.42 (25% acetone in chloro-
form); 1H NMR (300 MHz, CDCl3) d 1.03 (s, 3H), 1.05 (s,
3H), 1.14 (m, 1H), 1.26 (m, 1H), 1.68–1.88 (m, 3H), 2.00–
2.14 (m, 3H), 2.18–2.30 (m, 1H), 3.46 (s, 1H), 4.00 (m, 1H),
4.06 (d, 1H, J¼11.7 Hz), 4.07 (brs, 1H), 4.31 (dd 1H, J¼7.2,
11.7 Hz), 5.23 (d, 1H, J¼7.2 Hz); 13C NMR (75 MHz,
CDCl3) d 19.2, 23.5, 24.6, 25.3, 25.7, 27.7, 28.7, 30.2, 38.0,
46.3, 57.4, 73.4, 78.0, 134.2, 135.5; IR (film) cm21 3356
brs, 2966 s, 1654 m; mass spectrum (EI): m/e (%relative
intensity) 236 (M2H2O)þ (35), 221 (40), 185 (33), 162
(55), 152 (47), 139 (61), 137 (69), 119 (61), 109 (66), 81
(100).
4.1.14. The xanthate. To a solution of m-chlorobenzoate 34
(28.0 mg, 43 mmol) in CH2Cl2 (3 mL) was added DIBAL-H
(1 M in hexanes, 0.2 mL, 0.2 mmol) at 2788C. The reaction
mixture was stirred at 2788C for 1 h and then warmed to
room temperature. The reaction was quenched with 1 M
HCl (10 mL) and extracted (CH2Cl2, 3£10 mL). After
normal workup, the crude product was purified via flash
chromatography (gradient, 40–60% EtOAc in hexanes) to
give the desired alcohol (14.2 mg, 63%) as a white solid.
4.1.16. Acetate 36. Triol 35 (650.0 mg, 2.56 mmol) was
dissolved in pyridine (30 mL) and acetic anhydride
(2.41 mL, 10 equiv.) was slowly added. The solution was
allowed to stir at room temperature overnight. Solvent,
excess acetic anhydride, and AcOH were removed by
vacuum distillation at room temperature to afford 36
(750.0 mg, 99%) as a white solid which was not further
purified.
1
The alcohol: Rf¼0.20 (66% EtOAc in hexanes); H NMR
(500 MHz, CDCl3) d 1.12 (s, 3H), 1.20 (td, 1H, J¼3,
13.5 Hz), 1.23 (s, 3H), 1.63–1.68 (m, 1H), 1.66 (s, 3H),
1.77–1.83 (m, 1H), 1.80 (s, 3H), 1.87 (d, 1H, J¼15 Hz),
2.06 (dt, 1H, J¼2.5, 14 Hz), 2.32 (brs, 1H), 2.52 (dd, 1H,
J¼6.5, 15 Hz), 3.69 (brs, 1H), 3.93 (s, 3H), 3.94 (s, 3H),
4.29 (dd, 1H, J¼3, 6.5 Hz), 4.58 (dd, 1H, J¼4.5, 11.5 Hz),
4.92 (s, 1H), 6.32 (s, 1H), 6.90 (d, 1H, J¼8.5 Hz), 7.28 (d,
1H, J¼2 Hz), 7.39 (dd, 1H, J¼2, 8.5 Hz).
36: mp¼134–1368C; Rf¼0.55 (50% EtOAc in hexanes); 1H
NMR (500 MHz, CDCl3) d 1.03 (s, 3H), 1.04 (s, 3H), 1.09
(s, 3H), 1.12 (m, 1H), 1.70–1.82 (m, 3H), 1.74 (s, 3H),
1.98–2.07 (m, 2H), 2.08 (s, 3H), 2.32 (ddd, 1H, J¼9.5, 10.0,
19.0 Hz), 3.81 (d, 1H, J¼6.0 Hz), 3.97 (s, 1H), 3.99 (br,
1H), 4.63 (d, 1H, J¼12.5 Hz), 4.97 (d, 1H, J¼12.5 Hz); 13C
NMR (75 MHz, CDCl3) d 19.9, 21.3, 23.8, 25.0, 25.5, 26.0,
28.2, 29.8, 30.5, 38.4, 46.4, 61.3, 73.5, 84.0, 130.4, 139.1,

320
R. P. Hsung et al. / Tetrahedron 59 (2003) 311–324
170.8; IR (film) cm21 3381 br, 2992 s, 1731 vs; mass
spectrum (EI): m/e (%relative intensity) 236 (M2AcOH)þ
(43), 221 (59), 185 (51), 162 (76), 152 (77), 139 (100), 137
(79), 119 (75), 109 (85), 91 (47), 81 (97).
1H NMR (500 MHz, CDCl3) d 1.04 (s, 3H), 1.16 (s, 3H),
1.17 (s, 3H), 1.42 (s, 1H), 1.52 (ddd, 1H J¼5.0, 5.0,
14.0 Hz), 1.77 (ddd, 1H, J¼8.0, 9.5, 18.0 Hz), 1.95 (ddd,
1H, J¼4.0, 13.5, 13.5 Hz), 2.12 (ddd, 1H, J¼2.0, 8.0,
14.5 Hz), 2.18 (s, 3H), 2.34 (ddd, 1H, J¼4.0, 4.0, 12.0 Hz),
2.46–2.63 (m, 3H), 10.01 (s, 1H); 13C NMR (125 MHz,
CDCl3) d 18.5, 20.2, 24.7, 26.5, 27.8, 34.5, 37.8, 39.4, 39.8,
54.0, 81.3, 139.2, 158.4, 189.9, 212.7; IR (film) cm21 3488
brs, 2950 m, 1707 vs, 1665 vs; mass spectrum (EI): m/e
(%relative intensity) 250 Mþ· (37), 217 (24), 181 (36), 152
(100), 138 (40), 123 (49), 109 (34), 55 (44).
4.1.17. Ketone 38. Acetate 36 (1.45 g, 4.9 mmol) was
dissolved in CH2Cl2 (60 mL) along with NMO (860.0 mg,
˚
1.5 equiv.) and powdered 4 A molecular sieves (0.50 g).
TPAP (85.0 mg, 0.050 equiv.) was added, and the mixture
stirred overnight. The mixture was then transferred onto a
silica gel column loaded with CH2Cl2 and eluted until all of
the reaction mixture was on the column. The solvent was
then changed to CHCl3 and fractions were collected until
the product had eluted. Removal of solvent under vacuum
gave pure 38 (1.44 g, 4.9 mmol, 100%) as a white solid.
4.1.20. Ketone 39-AB-cis. Enal 37-a (100.0 mg,
0.40 mmol) was placed in a sealed tube along with
EtOAc (4 mL), Na2SO4 (100.0 mg), pyrone 8 (197.0 mg,
2.0 equiv.), and piperidinium HCl (42.0 mg, 1 equiv.). The
mixture was heated to 1508C for 5 d. Removal of solvent,
followed by filtration through silica gel (50% EtOAc in
hexanes), followed by flash silica gel chromatography (10%
acetone in CH2Cl2) afforded 39-cis (57.0 mg, 30%) as a
yellow solid.
38: mp¼153–1548C; Rf¼0.53 (50% EtOAc in hexanes); 1H
NMR (300 MHz, CDCl3) d 1.03 (s, 3H), 1.22 (s, 3H), 1.50
(s, 3H), 1.65 (ddd, 1H, J¼2.4, 6.6, 12.3 Hz), 1.69 (s, 3H),
1.72 (ddd, 1H, J¼1.1, 7.2, 13.5 Hz), 1.90 (ddd, 1H, J¼6.6,
11.4, 18 Hz), 2.02 (s, 3H), 2.08–2.28 (m, 4H), 2.90 (ddd,
1H, J¼6.6, 14.7, 15.0 Hz), 4.53 (d, 1H, J¼13.2 Hz), 4.92 (d,
1H, J¼12.9 Hz); 13C NMR (75 MHz, CDCl3) d 21.1, 21.2,
23.6, 23.7, 25.3, 27.0, 28.8, 35.9, 38.0, 38.7, 60.4, 63.5,
80.7, 129.8, 137.4, 171.2, 213.9; IR (film) cm21 3527 m,
3387 m, 2942 m, 1722 vs, 1703 s; mass spectrum m/e (%
relative intensity): 234 (100), 219 (41), 201 (34), 191 (26),
178 (36), 163 (48), 161 (46), 146 (48), 136 (89), 119 (49).
39-AB-cis: mp¼188–1908C; Rf¼0.39 (67% EtOAc in
hexanes); 1H NMR (500 MHz, CDCl3) d 0.91 (s, 3H),
1.10 (s, 3H), 1.31 (s, 3H), 1.45 (s, 3H), 1.49 (s, 1H), 1.61–
1.73 (m, 3H), 2.04 (ddd, 1H, J¼4.5, 8.5, 14.0 Hz), 2.13 (m,
1H), 2.23 (ddd, 1H, J¼4.5, 9.5, 18.5 Hz), 2.40 (ddd, 1H,
J¼7.0, 7.0, 17.0 Hz), 2.64 (ddd, 1H, J¼7.5, 7.5, 17.0 Hz),
3.87 (s, 3H), 3.88 (s, 3H), 6.01 (s, 1H), 6.33 (s, 1H), 6.84 (d,
1H, J¼8.5 Hz), 7.24 (d, 1H, J¼2.5 Hz), 7.34 (dd, 1H, J¼
2.5, 9.0 Hz); 13C NMR (125 MHz, CDCl3) d 23.0, 24.0,
26.1, 26.9, 30.2, 33.2, 33.4, 35.9, 38.9, 56.1, 56.2, 58.1,
78.9, 80.7, 96.1, 100.9, 108.3, 111.1, 114.3, 119.2, 124.0,
135.8, 149.3, 151.6, 160.6, 161.4, 163.0, 212.0; IR
(film) cm21 3484 brs, 2960 m, 1704 vs, 1625 m, 1515 vs.
mass spectrum (CI): m/e (%relative intensity) 480 (67), 465
(22), 446 (25), 437 (13), 327 (49), 261 (24), 165 (100), 137
(12); m/e calcd for C28H32O7 480.2148; found 480.2143.
4.1.18. Lactol. Ketone 38 (1.83 g, 6.27 mmol) was
dissolved in MeOH/H2O/THF (2:1:1, 50 mL) and powdered
K2CO3 (2.50 g, 3.0 equiv.) was added. The solution was
stirred overnight. Water (50 mL) was added and the solution
extracted (EtOAc, 5£25 mL). The combined organic
extracts were washed with brine and dried (Na2SO4).
Removal of solvents under vacuum yielded the lactol
(1.49 g, 94%) as a white solid which was determined to need
no further purification.
Lactol: mp¼147.5–148.5; Rf¼0.22 (50% EtOAc in hexanes);
1H NMR (500 MHz, CDCl3) d 1.01 (s, 6H), 1.13–1.18 (m,
1H), 1.16 (s, 3H), 1.45 (s, 3H), 1.56 (s, 1H), 1.64 (ddd, 1H,
J¼3.0, 4.5, 13.5 Hz), 1.68–1.86 (m, 3H), 1.98–2.02 (m,
1H), 2.06 (brdd, 1H, J¼6.0, 19.0 Hz), 2.22 (brdd, 1H, J¼
10.5, 18.0 Hz), 2.70 (s, 1H), 4.25 (brd, 1H, J¼13.0 Hz), 4.52
(brd, 1H, J¼13.5 Hz); 13C NMR (75 MHz, CDCl3) d 18.9,
23.4, 25.5, 26.9, 27.5, 28.4, 30.2, 31.6, 34.0, 38.3, 65.0,
75.8, 106.6, 122.8, 135.4; IR (film) cm21 3422br, 2949 s,
1648w; mass spectrum (EI): m/e (% relative intensity) 252
Mþ (2), 234 (M2H2O)þ (16), 149 (25), 138 (100), 123 (43),
109 (52).
4.1.21. Ketone 40-AB-trans. Pentacycle 42 (see below)
(100.0 mg, 0.21 mmol) was dissolved in CH2Cl2 (2 mL) and
NMO (36.0 mg, 1.50 equiv.) was added. TPAP (4.0 mg,
0.050 equiv.) was then added and the reaction was allowed
to stir at room temperature for two h. The solution was
loaded onto a short silica gel column and eluted with CHCl3.
Evaporation of solvent gave the ketone (96 mg, 95%) as a
yellow solid which formed needles when crystallized by
slow evaporation from CH2Cl2.
40-AB-trans: mp¼228–2308C (dec.); Rf¼0.14 (50%
1
EtOAc in hexanes); H NMR (500 MHz, CDCl3) d 1.09
(s, 3H), 1.20 (s, 3H), 1.55 (s, 3H), 1.66 (s, 3H), 1.71 (ddd,
1H, J¼6.0, 7.5, 14.0 Hz), 1.84 (ddd, 1H, J¼3.0, 5.0,
14.5 Hz), 1.98 (ddd, 1H, J¼4.0, 14.0, 14.0 Hz), 2.03 (m,
1H), 2.08 (ddd, 1H, J¼5.0, 10.0, 15.0 Hz), 2.33 (ddd, 1H,
J¼5.0, 14.0, 14.0 Hz), 2.63 (ddd, 1H, J¼5.5, 6.5, 14.0 Hz),
2.83 (ddd, 1H, J¼5.5, 10.0, 14.5 Hz), 3.95 (s, 3H), 3.96 (s,
3H), 6.38 (s, 1H), 6.92 (d, 1H, J¼8.5 Hz), 7.32 (d, 1H,
J¼2.0 Hz), 7.42 (dd, 1H, J¼2.0, 8.0 Hz), 7.47 (s, 1H); 13C
NMR (75 MHz, CDCl3) d 24.6, 26.0, 26.9, 27.6, 28.2, 33.9,
36.6, 37.3, 37.9, 56.2, 56.3, 57.3, 79.3, 79.7, 96.3, 101.0,
108.4, 111.2, 119.3, 119.6, 124.3, 134.1, 149.4, 151.6,
160.6, 161.9, 162.7, 211.3; IR (film) cm21 2926 m, 1711 vs,
4.1.19. Aldehyde 37-a. The lactol from the previous step
(300.0 mg, 1.19 mmol) was dissolved in CH2Cl2 (50 mL)
and PCC (1.03 g, 4 equiv.) was added. The solution turned
black, and was stirred overnight. The heterogeneous
mixture was filtered through silica gel, and eluted with
EtOAc/hexanes (1:1). Evaporation of all but 2 mL of
solvent followed by exposure of the remaining solution to
low vacuum (ca. 100 mmHg) gave 37-a (232.0 mg, 78%) as
clear prisms which were washed with hexanes.
37-a: mp¼162–1648C; Rf¼0.21 (50% EtOAc in hexanes);

R. P. Hsung et al. / Tetrahedron 59 (2003) 311–324
321
1602 m, 1514 vs; mass spectrum (CI): m/e (%relative
intensity) 481 (MþH)þ (100), 463 (MþHþ2H2O)þ (10),
87 (55), 84 (43), 74 (67), 73 (22); m/e calcd for C28H32O7
480.2143; found 480.2155.
extracts were washed successively with 0.5 M NaOH
(5 mL) and brine (5 mL). The solution was dried
(Na2SO4) and solvent removed to give crude 43 which
was filtered through silica to afford pure 43 (35.0 mg, 94%)
as a yellow solid.
4.1.22. Aldehyde 41. Triol 35 (1.55 g, 6.09 mmol)
˚
was dissolved in CH2Cl2 (40 mL) and 4 A molecular sieves
43: mp¼220–2218C (dec.); Rf¼0.29 (2:1 EtOAc in
hexanes); 1H NMR (500 MHz, CDCl3) d 0.96 (s, 3H),
1.02 (s, 3H), 1.19 (td, 1H, J¼3, 14 Hz), 1.34 (s, 3H), 1.58 (s,
3H), 1.65 (s, 1H), 1.71 (brs, 1H), 1.72–1.82 (m, 3H), 1.93–
2.00 (m, 2H), 2.08 (ddd, 1H, J¼2, 5, 13.5 Hz), 2.34 (dt, 1H,
J¼5.5, 13.5 Hz), 3.93 (s, 3H), 3.95 (s, 3H), 4.37 (dd, 1H,
J¼6, 9.5 Hz), 6.34 (s, 1H), 6.90 (d, 1H, J¼8.5 Hz), 7.02 (s,
1H), 7.29 (d, 1H, J¼2 Hz), 7.39 (dd, 1H, J¼2, 8.5 Hz); 13C
NMR (125 MHz, CDCl3) d 21.2, 23.6, 24.6, 27.1, 28.2,
28.9, 34.6, 35.6, 37.9, 49.9, 56.0, 56.2, 71.7, 80.9, 81.2,
96.2, 99.7, 108.2, 111.0, 114.8, 119.0, 124.2, 140.5, 149.2,
151.4, 160.0, 161.9, 162.5; IR (film) cm21 3496 brs, 2936
m, 1694 s, 1611 m, 1534 s, 1515 vs; mass spectrum (CI):
m/e (%relative intensity) 483 (MþH)þ (100), 465
(MþH2H2O)þ (18), 447 (MþH22H2O)þ (4), 181 (7), 65
(4); m/e calcd for C28H34O7 482.2299; found 482.2311.
(powdered, 200.0 mg) were added. TPAP (107.0 mg,
0.050 equiv.) was added. The reaction was stirred at room
temperature for 30 min at which time TLC (vanillin)
indicated consumption of starting material. The solution
was loaded onto a silica gel column and eluted with CHCl3.
Evaporation of solvent provided enal 41 (1.07 g, 70%) as an
unstable yellow syrup.
41: Rf¼0.49 (25% acetone in chloroform); 1H NMR d 1.03
(s, 6H), 1.18 (s, 3H), 1.70–1.82 (m, 4H), 2.00–2.18 (m,
2H), 2.13 (s, 3H), 2.25 (ddd, 1H, J¼2.5, 5.0, 14.0 Hz), 2.53
(ddd, 1H, J¼9.0, 9.0, 20.5 Hz), 3.16 (d, 1H, J¼5.0 Hz), 4.41
(s, 1H), 4.80 (m, 1H), 10.20 (s, 1H); 13C NMR d 19.3, 23.2,
24.5, 25.1, 26.2, 28.0, 30.2, 32.5, 35.1, 38.4, 72.0, 85.1,
138.8, 159.6, 194.6; IR (film) cm21 3380 brs, 2944 vs, 1754
s, 1666 vs, 1450 s; mass spectrum (EI): m/e (%relative
intensity) 234 (M2H2O)þ (100), 206 (7), 149 (54), 135
(52), 91 (48).
4.1.25. Tetraol 44. Diol 43 (42.0 mg, 87.0 mmol) was
dissolved in pyridine (0.25 mL) and solid OsO4 (33.0 mg,
1.50 equiv.) was added. The solution was stirred for 3 h at
which time TLC indicated consumption of starting material.
Saturated NaHSO3 (100 mL) was then added and the
solution was stirred for an additional 3 h. The mixture was
then filtered through celite to remove precipitate and the
celite was rinsed several times with EtOAc. The water
layer was then saturated with NaCl. Extraction (EtOAc,
10£5 mL) followed by drying (Na2SO4) and evaporation of
solvent afforded a brown tar which was purified by flash
chromatography (gradient, 60–90% EtOAc in hexanes) to
afford 44 (37.0 mg, 83%) as a white solid.
4.1.23. Diol 42. Enal 41 (155.0 mg, 0.62 mmol) was
dissolved in EtOAc (4 mL) and placed in a sealed tube
along with Na2SO4 (200.0 mg), piperidinium acetate
(89.0 mg, 1.0 equiv.), and pyrone 8 (154.0 mg, 1.0 equiv.).
The vessel was sealed under nitrogen and placed in a 708C
oil bath for 2 h. Solvent was removed in vacuo and the crude
1H NMR spectrum indicated a diastereomeric ratio in excess
of 15:1 favoring the desired isomer. The residue was filtered
through silica gel (50% EtOAc in hexanes) to afford impure
42 which was further purified by flash chromatography
(10% acetone in CH2Cl2) to afford the pure 42 (149.0 mg,
50%) as a yellow solid.
1
44: Rf¼0.10 (2:1 EtOAc in hexanes); H NMR (500 MHz,
CDCl3) d 0.94 (s, 3H), 1.03 (s, 3H), 1.13 (ddd, 1H, J¼3, 4.5,
13.5 Hz), 1.14 (s, 3H), 1.46 (s, 3H), 1.70–1.91 (m, 5H), 2.07
(ddd, 1H, J¼4.5, 13.5, 13.5 Hz), 2.55 (dt, 1H, J¼4.5,
14 Hz), 3.94 (s, 6H), 4.37 (dd, 1H, J¼5.5, 11 Hz), 4.82 (brs,
1H), 5.15 (s, 1H), 5.76 (brs, 1H), 6.39 (s, 1H), 6.92 (d, 1H,
J¼8.5 Hz), 7.28 (d, 1H, J¼2 Hz), 7.41 (dd, 1H, J¼2,
8.5 Hz); mass spectrum (CI): m/e (%relative intensity) 515
(M2H)2 (100), 497 (M2H2O2H)2 (10), 275 (9).
42: mp¼163–1658C; Rf¼0.24 (50% EtOAc in hexanes); 1H
NMR (500 MHz, CDCl3) d 1.02 (s, 3H), 1.04 (s, 3H), 1.31
(s, 3H), 1.53 (s, 3H), 1.76 (ddd, 1H, J¼2.5, 4.0, 12.0 Hz),
1.82–1.87 (m, 2H), 1.94 (ddd, 1H, J¼3.0, 4.5, 13.0 Hz),
2.07 (ddd, 1H, J¼3.5, 14.0, 14.0), 2.19 (m, 1H), 2.56 (dddd,
1H, J¼1.0, 5.5, 6.0, 6.0), 2.96 (brd, 1H, J¼14.5 Hz), 3.94 (s,
3H), 3.95 (s, 3H), 4.36 (d, 1H, J¼3.0 Hz), 4.55 (brd, 1H,
J¼6.5 Hz), 6.42 (s, 1H), 6.45 (s, 1H), 6.91 (d, 1H, J¼
8.5 Hz), 7.28 (d, 1H, J¼1.5 Hz), 7.41 (dd, 1H, J¼2.0,
9.0 Hz); 13C NMR (75 MHz, CDCl3) d 24.0, 24.3, 25.1,
27.8, 27.9, 28.1, 30.6, 31.1, 34.5, 38.5, 47.5, 56.2, 56.3,
72.1, 80.7, 96.7, 100.8, 108.2, 111.2, 111.3, 119.2, 124.2,
142.4, 149.3, 151.5, 160.0, 162.4, 162.8; IR (film) cm21
3378 brs, 3087 mw, 2930 s, 1693 s, 1682 s; mass spectrum
(CI): m/e (%relative intensity) 483 (MþH)þ (9), 466 (7),
465 (MþH2H2O)þ (43), 101 (17), 87 (100), 74 (20), 73
(35), 65 (40); m/e calcd for C28H34O7 482.2299; found
482.2306.
4.1.26. Product of triethylsilane/TFA and 44. Alcohol 44
(8.0 mg, 16.0 mmol) was dissolved in CH2Cl2 (50 mL) and
triethylsilane (50 mL). TFA (2 drops) was added, and the
solution stirred at room temperature for 2 h. Removal of
solvent under high vacuum afforded a tan solid which was
purified by PTLC (2:1 EtOAc in hexanes) to afford the
hexacycle as the only observed product.
Hexacycle: Rf¼0.18 (2:1 EtOAc in hexanes); 1H NMR
(500 MHz, CDCl3) d 0.88 (s, 3H), 0.95 (s, 3H), 1.24 (td, 1H,
J¼3, 13.5 Hz), 1.28 (s, 3H), 1.65 (s, 3H), 1.68 (m, 1H),
1.73–1.87 (m, 4H), 2.00–2.07 (m, 2H), 2.42 (br, 1H), 3.63
(br, 1H), 3.93 (s, 3H), 3.94 (s, 3H), 4.60 (dd, 1H, J¼5,
12 Hz), 4.90 (s, 1H), 6.30 (s, 1H), 6.89 (d, 1H, J¼8.5 Hz),
7.27 (d, 1H, J¼2 Hz), 7.38 (dd, 1H, J¼2, 8.5 Hz); 13C NMR
(125 MHz, CDCl3) d 14.7, 23.8, 24.4, 26.1, 26.5, 26.6, 30.7,
4.1.24. Diol 43. Pyrone 40-AB-trans (37.0 mg, 77.0 mmol)
was added to a solution of tetra-N-methyl ammonium
triacetoxyborohydride (10.0 equiv.) in AcOH (0.5 mL).
After 30 min, the reaction was poured into water (5 mL)
and extracted with CHCl3 (3£5 mL). The combined organic

322
R. P. Hsung et al. / Tetrahedron 59 (2003) 311–324
35.7, 36.5, 50.2, 56.2, 56.4, 71.2, 73.6, 80.1, 84.2, 88.7,
96.4, 98.5, 108.6, 111.2, 119.4, 124.2, 149.4, 151.7, 160.9,
163.8, 164.2; IR (film) cm21 3390 br, 2943 m, 1694 s, 1632
m, 1572 s, 1516 vs; mass spectrum (CI): m/e (%relative
intensity) 497 (M–H)2 (100), 291 (1); m/e calcd for
C28H34O8 498.2248; found 498.2252.
1737 vs, 1677 vs, 1574 m, 1516 vs; mass spectrum (CI): m/e
(%relative intensity) 543 (MþH)þ (24), 525 (MþH2
H2O)þ (100), 507 (MþH22H2O)þ (16), 483 (MþH2
AcOH)þ (66), 465 (MþH2H2O2AcOH)þ (37), 447 (Mþ
H22H2O2AcOH)þ (11), 289 (12), 261 (21); m/e calcd for
C30H39O9 543.2594; found 543.2610.
4.1.27. Acetate 45. Alcohol 44 (30.0 mg, 62.2 mmol) was
dissolved in Ac2O and 10% Pd on carbon (10.0 mg) was
added. The flask was evacuated and filled with hydrogen
from a balloon. The mixture was stirred for 3 h, at which
time TLC indicated consumption of starting material.
Filtration through celite to remove catalyst followed by
distillation of solvent afforded a crude mixture (10:1 by 1H
NMR) of 45 and triol 47. Flash chromatography (gradient,
50–80% EtOAc in hexanes) afforded 45 (32.0 mg, 93%) as
a white solid.
4.1.29. Triol 47. Acetate 46 (30.0 mg, 55.0 mmol) was
dissolved in THF (0.5 mL) and MeOH (0.5 mL). Powdered
K2CO3 (10.0 equiv.) was added, and the reaction stirred at
room temperature for 3 h at which time TLC indicated
consumption of starting material. Most of the solvent was
removed in vacuo and the resulting suspension was purified
via SiO2 chromatography (gradient, 50–100% EtOAc in
hexanes) to afford the triol 47 (25.0 mg, 90%) as a white
solid.
1
47: Rf¼0.12 (2:1 EtOAc in hexanes); H NMR (500 MHz,
Note that 45 was prepared quantitatively from 44 using
Ac2O and DMAP in pyridine/CH2Cl2 at rt via standard work
up and purification.
CDCl3) d 0.93 (s, 3H), 1.05 (s, 3H), 1.15 (m, 1H), 1.17 (s,
3H), 1.44 (s, 3H), 1.65–1.81 (m, 4H), 1.87 (dt, 1H, J¼3.5,
14.5 Hz), 2.03 (dt, 1H, J¼5.5, 14 Hz), 2.41 (dt, 1H, J¼5,
14 Hz), 2.89 (d, 1H, J¼18 Hz), 3.22 (d, 1H, J¼18 Hz), 3.92
(s, 3H), 3.93 (s, 3H), 4.56 (brs, 1H), 4.64 (dd, 1H, J¼5.5,
11 Hz), 4.70 (brs, 1H), 6.30 (s, 1H), 6.88 (d, 1H, J¼9 Hz),
7.24 (d, 1H, J¼1.5 Hz), 7.33 (dd, 1H, J¼2, 8.5 Hz); IR
(film) cm21 3349 brs, 2943 m, 1678 s, 1640 m, 1571 s, 1515
vs; mass spectrum (CI): m/e (%relative intensity) 501
(MþH)þ (100), 483 (MþH2H2O)þ (24), 465 (MþH2
2H2O)þ (9), 181 (6); m/e calcd for C28H36O8 500.2405;
found 500.2415.
1
45: Rf¼0.36 (2:1 EtOAc in hexanes); H NMR (500 MHz,
CDCl3) d 0.95 (s, 3H), 1.05 (s, 3H), 1.09 (td, 1H, J¼3,
14 Hz), 1.25 (s, 3H), 1.46 (s, 3H), 1.65 (m, 1H), 1.73 (td, 1H,
J¼3, 13.5 Hz), 1.81 (ddd, 1H, J¼3.5, 4, 15 Hz), 1.91 (dt,
1H, J¼4, 14 Hz), 2.04–2.14 (m, 2H, 2.06 (s, 3H), 2.56 (dt,
1H, J¼3.5, 13 Hz), 3.93 (s, 3H), 3.94 (s, 3H), 4.63 (s, 1H),
5.00 (s, 1H), 5.03 (brs, 1H), 5.39 (dd, 1H, J¼5.5, 10 Hz),
6.38 (s, 1H), 6.51 (s, 1H), 6.92 (d, 1H, J¼8.5 Hz), 7.26 (d,
1H, J¼2 Hz), 7.39 (dd, 1H, J¼2, 8.5 Hz); 13C NMR
(125 MHz, CDCl3) d 18.9, 22.1, 22.9, 24.5, 25.1, 25.9, 27.3,
30.2, 33.9, 39.1, 48.2, 56.2, 56.3, 62.0, 72.1, 78.5, 80.0,
83.7, 97.1, 100.2, 108.5, 111.3, 119.5, 123.6, 134.7, 149.5,
152.0, 164.5, 165.4, 170.9; IR (film) cm21 3389 brs, 2951
m, 1724 s, 1680 s, 1634 m, 1516 vs, 1463 s; mass spectrum
(CI): m/e (%relative intensity) 557 (M2H)2 (100), 539
(M2H2H2O)2 (3), 497 (M2H2AcOH)2 (24), 479
(M2H2H2O2AcOH)2 (22); m/e calcd for C30H38O10Na
581.2363; found 581.2381.
4.1.30. Ketone 48. Triol 47 (22.0 mg, 44.0 mmol) was
dissolved in CHCl3 (0.5 mL) along with NMO (8.0 mg,
1.50 equiv.) and TPAP (2.0 mg). The solution was stirred at
room temperature for 2 h at which time TLC indicated
complete conversion. The solution was loaded onto a SiO2
column packed in CH2Cl2. When all of the reaction solution
was loaded, the column was eluted with 5% acetone in
CHCl3 to afford 48 (20.0 mg, 90%) as a white solid.
1
48: Rf¼0.33 (2:1 EtOAc in hexanes); H NMR (300 MHz,
4.1.28. Acetate 46. Triol 45 (37.0 mg, 66.0 mmol) was
dissolved in CH2Cl2 (200 mL) and triethylsilane (200 mL).
Trifluoroacetic acid (6 drops) was added, and the reaction
stirred for 3 h. Removal of all solvent and acid was
accomplished by exposure to high vacuum for 30 min to
afford a tan solid. Purification by flash chromatography (1:1
EtOAc in hexanes) afforded 46 (32.0 mg, 89%) as a white
solid.
CDCl3) d 1.06 (s, 3H), 1.25 (s, 3H), 1.43 (s, 3H), 1.51 (s,
3H), 1.68–1.97 (m, 4H), 2.21 (ddd, 1H, J¼6, 10.2, 20 Hz),
2.35–2.48 (m, 2H), 2.84 (d, 1H, J¼17.7 Hz), 2.89 (ddd, 1H,
J¼6.9, 10.2, 15.9 Hz), 3.24 (d, 1H, J¼17.7 Hz), 3.93 (s,
3H), 3.94 (s, 3H), 4.12 (s, 1H), 6.05 (s, 1H), 6.36 (s, 1H),
6.91 (d, 1H, J¼8.4 Hz), 7.29 (d, 1H, J¼2.1 Hz), 7.39 (dd,
1H, J¼2.1, 8.4 Hz); 13C NMR (75 MHz, CDCl3) d 19.5,
24.0, 25.9, 26.4, 27.1, 27.9, 28.7, 35.4, 37.4, 38.7, 56.0,
56.1, 57.9, 74.1, 77.2, 79.8, 81.8, 83.2, 96.7, 108.2, 111.1,
118.8, 124.3, 149.2, 155.5, 158.8, 164.6, 216.0; IR
(film) cm21 3495 brs, 3377 brs, 2964 m, 1713 s, 1694 s,
1640 m, 1578 s, 1519 vs; mass spectrum (CI): m/e
(%relative intensity) 497 (M2H)2 (100), 479 (M2H2
H2O)2 (8); m/e calcd for C28H34O8 498.2248; found
498.2239.
1
46: Rf¼0.37 (2:1 EtOAc in hexanes); H NMR (500 MHz,
CDCl3) d 0.95 (s, 3H), 1.09 (s, 3H), 1.21 (m, 1H), 1.30 (s,
3H), 1.45 (s, 1H), 1.72–1.82 (m, 4H), 1.89 (dt, 1H, J¼4.5,
15 Hz), 1.96 (ddd, 1H, J¼5, 8, 12.5 Hz), 2.09 (dt, 1H, J¼5,
13.5 Hz), 2.18 (s, 3H), 2.41 (dt, 1H, J¼4, 13.5 Hz), 2.44 (d,
1H, J¼17.5 Hz), 2.91 (d, 1H, J¼18 Hz), 3.92 (s, 3H), 3.93
(s, 3H), 4.11 (s, 1H), 4.63 (s, 1H), 5.79 (dd, 1H, J¼5.5,
11.5 Hz), 6.33 (s, 1H), 6.91 (d, 1H, J¼8 Hz), 7.28 (d, 1H,
J¼2 Hz), 7.37 (dd, 1H, J¼2, 8 Hz); 13C NMR (1245 MHz,
CDCl3) d 17.0, 22.0, 24.2, 24.6, 24.7, 25.5, 27.2, 29.1, 29.4,
34.5, 39.0, 47.7, 56.0, 56.1, 73.0, 77.4, 81.0, 81.7, 96.5,
97.5, 108.2, 111.1, 118.8, 124.2, 149.2, 151.2, 158.8, 162.5,
164.4, 171.1; IR (film) cm21 3375 brs, 2952 m, 2927 m,
4.1.31. (6)-Arisugacin A (1). A 0.417 M solution of
Schlosser’s base was prepared by combining THF (5 mL),
potassium tert-butoxide (281.0 mg) and diisopropyl amine
(0.36 mL). The mixture was cooled to 2788C, and n-butyl
lithium (1.00 mL, 2.5 M in hexanes) was added. The
solution was stirred for 30 min, used for the deprotonation

R. P. Hsung et al. / Tetrahedron 59 (2003) 311–324
323
˜
We thank Professor S. Omura for a generous sample of
(þ)-arisugacin A.
immediately, and then discarded. Ketone 48 (4.0 mg,
8.0 mmol) was dissolved in THF (200 mL) with HMPA
(30 mL). The solution was cooled to 2788C and the
previously described solution of Schlosser’s base (290 mL,
15.0 equiv.) was added. The solution was stirred at 2788C
for 20 min and then allowed to warm to room temperature.
When room temperature was achieved, the solution was
again cooled to 2788C and solid phenylselenyl bromide
(9.0 mg, 5.0 equiv.) was added. The solution was main-
tained at 2788C for 20 min, and then allowed to warm while
stirring an additional 1 h. The reaction was quenched with
0.5 M HCl and extracted with EtOAc. Drying of extracts
and evaporation, followed by purification on a pipette
column (1:1 EtOAc in hexanes) afforded the selenide as a
white solid. The phenyl selenide was then dissolved in THF
(200 mL) and AcOH (40 mL). The solution was cooled to
08C and 30% hydrogen peroxide (5 mL) was added. The
solution was allowed to warm to room temperature and stir.
After 60 min, TLC indicated complete conversion. The
reaction was poured into saturated NaHCO3 (1 mL) and
extracted with CHCl3 (2£1 mL). The solvent was dried and
removed. The residue was purified by pipette column (1:1
EtOAc in hexanes) to afford (^)-arisugacin A (2.7 mg, 67%
for 2 steps) as a white solid.
References
˜
1. (a) Omura, S.; Kuno, F.; Otoguro, K.; Sunazuka, T.; Shiomi,
K.; Masuma, R.; Iwai, Y. J. Antibiotics 1995, 48, 745. For
biological activities of arisugacin see: (b) Kuno, F.; Otoguro,
˜
K.; Shiomi, K.; Iwai, Y.; Omura, S. J. Antibiotics 1996, 49,
˜
742. (c) Otoguro, K.; Kuno, F.; Omura, S. Pharmacol. Ther.
1997, 76, 45. (d) Otoguro, K.; Shiomi, K.; Yamaguchi, Y.;
˜
Arai, N.; Sunazuka, T.; Masuma, R.; Iwai, Y.; Omura, S.
J. Antibiotics 2000, 53, 50.
2. John, V.; Lieberburg, I.; Thorsett, E. D. Annual Report in
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3. (a) Ling, K. H.; Yang, C.-K.; Peng, F.-T. Appl. Environ.
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4. (a) Tomoda, H.; Tabata, N.; Yang, D. J.; Namatame, I.;
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292. (b) Smith, III., A. B.; Kinsho, T.; Sunazuka, T.; Omura, S.
The synthetic sample has an identical Rf value with the
natural sample in three different solvent systems: a. 2:1
EtOAc/hexanes: Rf¼0.27; b. 2:1 ether/hexanes Rf¼0.09; c.
Tetrahedron Lett. 1996, 37, 6461. (c) Nagamitsu, T.;
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˜
Y.; Omura, S.; Smith, III., A. B. J. Org. Chem. 1995, 60, 8126.
1
1:9 acetone/chloroform Rf¼0.24. In addition, the H NMR
(d) Parker, K. A.; Resnick, L. J. Org. Chem. 1995, 60, 5726.
5. For a 4-pyrone Diels–Alder approach to arisugacin A, see:
(a) Hsung, R. P. J. Org. Chem. 1997, 62, 7904. (b) Granum,
K. A.; Merkel, G.; Mulder, J. A.; Debbins, S. A.; Hsung, R. P.
Tetrahedron Lett. 1998, 39, 9597.
of the synthetic sample was unchanged by addition of
(þ)-arisugacin.
1
(^)-Arisugacin A: Rf¼0.27 (2:1 EtOAc in hexanes); H
NMR (500 MHz, pyridine-d5) d 1.19 (s, 3H), 1.30 (s, 3H),
1.46 (s, 3H), 1.50 (s, 3H), 1.86–1.98 (m, 3H), 2.90 (dt, 1H,
J¼4.5, 13.5 Hz), 3.17 (d, 1H, J¼17.5 Hz), 3.77 (s, 3H), 3.78
(s, 3H), 4.35 (d, 1H, J¼17.5 Hz), 5.95 (d, 1H, J¼10.5 Hz),
6.28 (d, 1H, J¼10 Hz), 6.79 (s, 1H), 7.00 (d, 1H, J¼9 Hz),
7.48 (d, 1H, J¼2 Hz), 7.59 (m, 1H), 7.69 (s, 1H), 8.95 (s,
1H); 13C NMR (75 MHz, pyridine-d5) d 22.4, 23.9, 24.2,
26.2, 26.5, 27.9, 29.9, 43.2, 56.3 (2C), 56.9, 76.6, 79.5, 81.8,
97.7, 98.3, 109.5, 112.6, 119.5, 124.6, 125.3, 150.0, 152.4,
153.5, 159.0, 163.6, 164.4, 202.6; IR (film) cm21 3357 brs,
2198 m, 1683 s, 1638 s, 1575 s, 1518 vs; mass spectrum
(CI): m/e (%relative intensity) 495 (M2H)2 (100), 477
(M2H2H2O)2 (7), 381 (95), 366 (4); m/e calcd for
C28H33O8 497.2170; found 497.2181.
6. For an acid condensation approach to arisugacin A, see:
Zehnder, L. R.; Dahl, J. W.; Hsung, R. P. Tetrahedron Lett.
2000, 41, 1901.
7. For our formal [3þ3] cycloaddition approach to arisugacin A,
see: Zehnder, L. R.; Hsung, R. P.; Wang, J.-S.; Golding, G. M.
Angew. Chem. Int. Ed. 2000, 39, 3876.
8. (a) For preliminary communications on the formal [3þ3]
cycloaddition approach, see: (a) Shen, H. C.; Degen, S. J.;
Mulder, J. A.; Hsung, R. P.; Douglas C. J.; Golding, G. M.;
Johnson, E. W.; Mathias, D. S.; Morgan, C. D.; Mueller, K. L.;
Shih, R. A., Abstract No. ORGN-664, 216th ACS National
Meeting, Boston, MA, Fall, 1998. (b) Hsung, R. P.; Shen,
H. C.; Douglas, C. J.; Morgan, C. D.; Degen, S. J.; Yao, L. J.
J. Org. Chem. 1999, 64, 690.
9. Hsung, R. P.; Wei, L.-L.; Sklenicka, H. M.; Shen, H. C.;
McLaughlin, M. J.; Zehnder, L. R. Trends in Heterocyclic
Chemistry; 2001; Vol. 7. p 1.
4.2. Supporting information
Experimental procedures as well as NMR spectral,
characterization data, and X-ray data are given for all new
compounds.
10. For two key accounts predated our studies: (a) Hua, D. H.;
Chen, Y.; Sin, H.-S.; Maroto, M. J.; Robinson, P. D.; Newell,
S. W.; Perchellet, E. M.; Ladesich, J. B.; Freeman, J. A.;
Perchellet, J.-P.; Chiang, P. K. J. Org. Chem. 1997, 62, 6888.
(b) Jonassohn, M.; Sterner, O.; Anke, H. Tetrahedron 1996,
52, 1473.
Acknowledgements
11. For related studies, see: (a) Cravotto, G.; Nano, G. M.;
Tagliapietra, S. Synthesis 2001, 49. (b) Hua, D. H.; Chen, Y.;
Sin, H.-S.; Robinson, P. D.; Meyers, C. Y.; Perchellet, E. M.;
Perchellet, J.-P.; Chiang, P. K.; Biellmann, J.-P. Acta
Crystallogr. 1999, C55, 1698. (c) Krasnaya, Z. A.; Bogdanov,
V. S.; Burova, S. A.; Smirnova, Y. V. Russ. Chem. 1995, 44,
2118. (d) Heber, D.; Berghaus, Th. J. Heterocycl. Chem. 1994,
R. P. H. thanks NIH [NS38049] and American Chemical
Society Petroleum Research Fund [Type-G] for financial
support, and the McKnight Foundation for a McKnight
Fellowship. We thank Drs Victor Young, Neil R. Brooks,
and Mr William W. Brennesel for solving X-ray structures.

324
R. P. Hsung et al. / Tetrahedron 59 (2003) 311–324
31, 1353. (e) Appendino, G.; Cravotto, G.; Tagliapietra, S.;
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also 1369.
12. For leading references on electrocyclic ring-closures involving
1-oxatrienes, see: (a) Shishido, K.; Ito, M.; Shimada, S.-I.;
Fukumoto, K.; Kametani, T. Chem. Lett. 1984, 1943.
(b) Shishido, K.; Hiroya, K.; Fukumoto, K.; Kametani, T.
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(c) Maynard, D. F.; Okamura, W. H. J. Org. Chem. 1995,
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21. These reactions are best carried out in toluene and/or EtOAc
using piperidine/Ac2O, or piperidinium salts as well as other
amine salts. Hydrochloride salts tend to be even more reactive.
L-Proline does not work well for this reaction contrary to other
literature accounts, especially in EtOAc.
22. (a) Overman, L. E.; Rabinowitz, M. H. J. Org. Chem. 1993, 58,
3235. (b) Overman, L. E.; Rabinowitz, M. H.; Renhowe, P. A.
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Mathias, D. S.; Degen, S. J.; Morgan, C. D.; Shih, R. A.;
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Tetrahedron 1999, 55, 13683.
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14. (a) McLaughlin, M. J.; Hsung, R. P. J. Org. Chem. 2001, 66,
1049. (b) McLaughlin, M. J.; Shen, H. C.; Hsung, R. P.
Tetrahedron Lett. 2001, 42, 609.
24. Zehnder, L. R.; Wei, L.-L.; Hsung, R. P.; Cole, K. P.;
McLaughlin, M. J.; Shen, H. C.; Sklenicka, H. M.; Wang, J.;
Zificsak, C. A. Org. Lett. 2001, 3, 2141.
15. For aza-variant of this formal [3þ3] cycloaddition reaction
using vinylogous amides, see: (a) Sklenicka, H. M.; Hsung,
R. P.; McLaughlin, M. J.; Wei, L.-L.; Gerasyuto, A. I.;
Brennessel, W. W. J. Am. Chem. Soc. 2002, 124, 10435.
(b) Wei, L.-L.; Sklenicka, H. M.; Gerasyuto, A. I.; Hsung, R. P.
Angew. Chem. Int. Ed. 2001, 40, 1516. (c) Sklenicka, H. M.;
Hsung, R. P.; Wei, L.-L.; McLaughlin, M. J.; Gerasyuto, A. I.;
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25. For a much earlier preliminary communication, see: Zehnder,
L. R.; Hsung, R. P.; Wang, J., Abstract No. ORGN-51, 220th
ACS National Meeting, Washington D.C., Spring, 2000.
26. For a preliminary communication on these results, see: Cole,
K. P.; Zehnder, L. T.; Wei, L.-L.; Wang, J.; Hsung, R. P.,
Abstract No. ORGN-178, 222nd ACS National Meeting,
Chicago, IL, Fall, 2001.
27. When using various peroxyacids, the best result gave the
tentatively assigned hexacycle (Ref. 28) as the major product
in 28% yield with the desired product in only 21% yield unlike
those reported (Ref. 16).
˜
16. For Omura’s approach, see: (a) Handa, M.; Sunazuka, T.;
Nagai, K.; Kimura, R.; Shirahata, T.; Tian, Z. M.; Otoguro, K.;
28. The hexacycle was likely a result of intramolecular trapping of
the incipient oxocarbenium intermediate by the C1–OH. Such
facile trapping by oxygen nucleophiles agrees well with our
previous experience in the model studies and with the
hexacycle that at this point is not useful for the arisugacin
synthesis
˜
Harigaya, Y.; Omura, S. J. Antibiotics 2001, 54, 382. For their
total synthesis of (^)-arisugacin A, see: (b) Sunazuka, T.;
Handa, M.; Nagai, K.; Shirahata, T.; Harigaya, Y. Org. Lett.
2002, 4, 367.
17. For our total synthesis, see: (a) Wang, J.; Cole, K. P.; Wei,
L. L.; Zehnder, L. R.; Hsung, R. P. Tetrahedron Lett. 2002, 43,
3337. (b) Cole, K. P.; Hsung, R. P.; Yang, X.-F. Tetrahedron
Lett. 2002, 43, 3341.
18. For a detailed account on formal [3þ3] cycloaddition reaction,
see: Shen, H. C.; Morgan, C. D.; Wang, J.; Cole, K. P.;
Douglas, C. J.; Hsung, R. P.; Coverdale, H. A.; Hahn, J. M.;
Liu, J.; McLaughlin, M. J.; Wei, L.-L.; Zehnder, L. R.;
Zificsak, C. A. J. Org. Chem. 2002, under review.
29. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc.
2000, 122, 7596.
19. (a) Corey, E. J.; Jardine, P. D. S.; Rohloff, J. C. J. Am. Chem.
Soc. 1988, 110, 3672. (b) Jenkins, P. R.; Menear, K. A.;