Identification of an unexpected 2-oxonia[3,3]sigmatropic rearrangement/aldol pathway in the formation of oxacyclic rings. Total synthesis of (+)-aspergillin PZ

Article abstract of DOI:10.1016/j.tet.2011.09.079

This paper reports the first unambiguous evidence that the cascade synthesis of tetrahydrofuran-containing oxacyclic molecules depicted in Scheme 12 can take place by a 2-oxonia[3,3]sigmatropic/aldol mechanism rather than by a Prins cyclization/pinacol rearrangement sequence. The 8-oxabicyclo[3.2.1]octyl aldehyde products of this reaction, 20 and 29, were employed to complete the first total synthesis of the structurally remarkable isoindolone alkaloid (+)-aspergillin PZ (1). The lack of activity seen in two tumor cell lines for synthetic (+)-aspergillin PZ calls into question the suggestion that aspergillin PZ, like many aspochalasin diterpenes, might exhibit useful antitumor properties.

Full text of DOI:10.1016/j.tet.2011.09.079

Tetrahedron 67 (2011) 9837e9843
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Identification of an unexpected 2-oxonia[3,3]sigmatropic rearrangement/aldol
pathway in the formation of oxacyclic rings. Total synthesis of (þ)-aspergillin PZ
y
*
Stephen M. Canham, Larry E. Overman , Paul S. Tanis
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, CA 92697-2025, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 August 2011
Received in revised form 16 September 2011
Accepted 19 September 2011
Available online 24 September 2011
This paper reports the first unambiguous evidence that the cascade synthesis of tetrahydrofuran-
containing oxacyclic molecules depicted in Scheme 12 can take place by a 2-oxonia[3,3]sigmatropic/
aldol mechanism rather than by a Prins cyclization/pinacol rearrangement sequence. The 8-oxabicyclo
[3.2.1]octyl aldehyde products of this reaction, 20 and 29, were employed to complete the first total
synthesis of the structurally remarkable isoindolone alkaloid (þ)-aspergillin PZ (1). The lack of activity
seen in two tumor cell lines for synthetic (þ)-aspergillin PZ calls into question the suggestion that as-
pergillin PZ, like many aspochalasin diterpenes, might exhibit useful antitumor properties.
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated with admiration and friendship
to Professor Gilbert Stork in honor of his
90th birthday
Keywords:
Total synthesis
Prins-pinacol rearrangement
2-Oxonia[3,3]sigmatropic rearrangement
Mechanism
Cascade reaction
Natural products
1. Introduction
have additionally shown cytotoxicity in lymphoma (MH60) and
leukemia (ML60) cancer cell lines.4 In a phenotype assay,5 asper-
The isolation of aspergillin PZ (1, Fig. 1) from a sample of the soil
fungus Aspergillus awamori collected in Heibei province, China, was
reported in 2002 by Pei and co-workers.1 The constitution and
relative configuration of aspergillin PZ was elucidated by 2D NMR
studies and confirmed by single-crystal X-ray analysis. The penta-
cyclic structure of this isoindolone alkaloid contains ten contiguous
stereocenters and an unusual 12-oxatricyclo[6.3.1.02,7]dodecane
ring system (2). The isoindolone subunit found in aspergillin PZ is
common among compounds isolated from aspergillum molds.
Aspergillin PZ is closely related to the aspochalasin series of natural
products, particularly aspochalasin D (3),2 and members of the
cytochalasin family, such as the actin polymerization inhibitor cy-
tochalasin D (4).3 These previously reported natural products share
the same carbon framework, but lack the structurally unique 12-
oxatricyclo[6.3.1.02,7]dodecane core of aspergillin PZ.
gillin PZ (1) was reported to induce morphological deformation of
the conidia of P. oryzae at 0.089
m
M.1 Natural analogues 5 and 6 of
aspergillin PZ, whose three-dimensional structures have not been
disclosed, are reported to exhibit cytotoxicity against the HL-60
cancer cell line: 5¼29
m
g/mL, 6¼22
m
g/mL.6 The correlation be-
tween the conidia deformation phenotype and cytotoxicity, as well
as the cytotoxicity of related analogues, provided the implication
that aspergillin PZ might display anticancer activity, although no
such data have been reported to date.4,7
We were attracted to develop a synthesis of aspergillin PZ on the
basis of its novel structure, particularly the challenge in con-
structing its oxatricyclic ring system. In addition, synthetic access to
this rare natural product would allow a preliminary examination of
its therapeutic potential. We envisaged that the 12-oxatricyclo
[6.3.1.02,7]dodecane moiety of aspergillin PZ might be assembled
concisely by a Prins-pinacol cascade, a transformation that we have
employed to construct various oxapolycyclic ring systems.8,9 In our
earliest studies in this area, we utilized a Prins-pinacol cascade to
assemble several 12-oxatricyclo[6.3.1.02,7]dodecane structures.10
However, further elaboration of these products toward aspergillin
PZ appeared unattractive, leading us to redesign our synthetic
strategy. At the heart of the revised synthetic strategy depicted in
Several members of the aspochalasin family have been shown to
promote moderate deformation of Pyricularia oryzae conidia and
* Corresponding author. Tel.: þ1 949 824 7156; fax: þ1 949 824 3866; e-mail
address: leoverma@uci.edu (L.E. Overman).
y
Present address: Department of Chemistry, Columbia University, 3000 Broad-
way, New York, NY 10027, United States.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.079

9838
S.M. Canham et al. / Tetrahedron 67 (2011) 9837e9843
contrast, allylic epimer 10 would be expected to undergo Prins
cyclization in a boat geometry (C/D) to generate ultimately the
undesired oxabicyclic product 11.10b,15
H
H
H
H
H
The use of a late-stage intramolecular DielseAlder cycloaddition
in the synthesis of cytochalasin-type alkaloids was pioneered by
Stork16 and developed extensively by the Thomas group12 render-
ing its use in the total synthesis of aspergillin PZ appealing. As in
cases studied earlier, we anticipated that intramolecular cycload-
dition of a late-stage triene intermediate 7 (see Scheme 1) would
take place by an endo transition state to generate the aspergillin PZ
ring system.17
Herein we report that the cascade oxacyclic synthesis that typi-
cally proceeds by a Prins cyclization/pinacol rearrangement pathway
can in certain circumstances proceed competitively through a 2-
oxonia[3,3]sigmatropic rearrangement/aldol cyclization pathway.
We also describe the first total synthesis of (þ)-aspergillin PZ (1) and
preliminary evaluation of its antitumor activity.
H
NH
O
O
O
O
HO
12-oxatricyclo[6.3.1.02,7]dodecane
aspergillin PZ (1)
(2)
HO
H
H
Ph
H
NH
H
NH
O
O
O
AcO
HO
O
OH
OH
aspochalasin D (3)
cytochalasin D (4)
2. Results and discussion
2.1. A Prins-pinacol approach to the 8-oxabicyclo[3.2.1]octane
fragment
O
O
NH
O
NH
Our initial studies were carried out with racemic substrates and
began by elaboration of dihydropyran ester rac-1218 to aldehyde
rac-14 in three straightforward steps. Addition of the lithium ace-
tylide generated from alkyne 1519 to racemic aldehyde 14 provided
propargylic alcohols rac-16 and rac-17 in a 1.3:1 ratio and 95%
yield.20 Separation of these products on silica gel, followed by their
independent silylation and Lindlar reduction provided epimeric
cyclization precursors rac-18 and rac-19 in good yield (Scheme 3).
To evaluate experimentally our expectation that allylic precursors
rac-18 and rac-19 would generate different Prins-pinacol products,
these precursors were separately exposed to 0.5 equiv of SnCl4 at 0 ꢀC
(Scheme 4). Indeed these epimers did lead with high selectivity to
differentoxabicyclo[3.2.1]octyl aldehydeproducts, rac-20and rac-21;
however to our surprise, in each case 1H NMR analysis showed that
the siloxyethyl and formyl side chains of these products were trans,
not cis as we had expected. To confirm that the siloxyethyl side chain
was trans to the oxygen bridge in the product derived from precursor
rac-18, Prins-pinacolproductrac-20wastransformedinthreestepsto
crystalline p-bromobenzoaterac-22whoserelativeconfigurationwas
confirmed by single-crystal X-ray analysis.21
O
O
O
O
HO
5
6
Fig. 1. Aspergillin PZ, its 12-oxatricyclo[6.3.1.02,7]dodecane core, and related natural
products.
Scheme 1 are two multi-bond forming transformations: a Prins-
pinacol cascade to forge the 8-oxabicyclo[3.2.1]octane ring sys-
tem (9/8)11 and an intramolecular DielseAlder reaction to form
the isoindolone subunit.12
In an attempt to discern the origin of the unexpected trans al-
dehyde product, progress of the Prins-pinacol reaction of rac-18
was monitored by 1H NMR. From this experiment, it appeared that
two aldehyde products were formed initially, which slowly con-
verged to a single product as the reaction progressed. This finding
suggested that rac-20 was the result of epimerization that occurred
after the loss of the tert-butyldimethylsilyl group. Screening
a number of Lewis and Brønsted acids (BF3$OEt2, TiCl4, SnBr4,
TMSOTf, TfOH) for the Prins-pinacol reaction of rac-18, as well as
various quench conditions (Et3N, N,N-dimethylaniline, DMSO), did
not lead to the isolation of any of the formyl epimer of rac-20.
We reasoned that generation of the initial oxocarbenium ion
from a precursor having a better leaving group would allow the
cascade reaction to be carried out at a lower temperature, hopefully
facilitating isolation of the desired cis aldehyde epimer. Acetate was
chosen as the leaving group to facilitate ionization and in the hope
that its bidentate character might sequester the Lewis acid and
minimize epimerization. Glycosyl acetate rac-28 was synthesized
from dihydropyran ester rac-12 as summarized in Scheme 5. Epox-
idation of dihydropyran rac-12 with dimethyldioxirane (DMDO) at
ꢁ78 ꢀC, followed by opening of the epoxide with ethanethiol and
catalytic trifluoroacetic anhydride (TFAA) provided O,S-acetal rac-23
in 69% yield. This intermediatewas elaborated to propargylic alcohol
Scheme 1. Retrosynthetic analysis of aspergillin PZ.
Identification of (Z)-alkenyltetrahydropyranyl glycoside 9 as
a potential precursor of 8-oxabicyclo[3.2.1]octyl aldehyde 8 was
influenced by our previous demonstrations of the crucial role that
an allylic stereocenter can play in organizing the first step of
a Prins-pinacol cascade (Scheme 2).10b,13 As a 1,2-disubstituted
double bond is a relatively weak nucleophile, we anticipated that
the Prins cyclization step (A/B) would have a late transition state
that resembles the hydropyranyl cation intermediate.12,14 This
carbenium ion would be stabilized if the allylic hydrogen, rather
than the CeO
s-bond, were aligned for hyperconjugative in-
teraction with the vacant p-orbital. As a result, the oxocarbenium
generated from 9 was expected to cyclize preferentially in a chair
geometry to generate hydropyranyl cation B, which upon fast
pinacol rearrangement would form oxabicyclic product 8. In

S.M. Canham et al. / Tetrahedron 67 (2011) 9837e9843
9839
Scheme 2. Stereochemical analysis of the Prins-pinacol reaction.
Scheme 4. Unexpected formation of the trans aldehydes rac-20 and rac-21.
As we had hoped, the transformation of glycosyl acetate rac-28 to
an 8-oxabicyclo[3.2.1]octane product could be accomplished at low
temperature. For example, exposure of rac-28 to 0.5 equiv of SnCl4 in
CH2Cl2 at ꢁ78 ꢀC, followed by quenching with Et3N at ꢁ78 ꢀC, pro-
vided a 1.3:1 inseparable mixture of epimeric aldehyde products rac-
20 and rac-29 in 42% yield (Scheme 6). In situ monitoring of this re-
action by 1H NMR at ꢁ78 ꢀC indicated that these two aldehydes were
formed initially in a w1:1 ratio. Screening a variety of Lewis acids
(BF3$OEt2, TMSOTf, SnCl4, Sn(OTf)4, Sn(OTf)2, TiCl4, AlBr3), Brønsted
acids (TfOH, HN(Tf)2, TFA), solvents (CH2Cl2, pentane, EtCN), and lower
reactiontemperatures(ꢁ95ꢀC)wereunsuccessfulinimprovingeither
the diastereomeric ratio or the yield of the Prins-pinacol products.25
Scheme 3. Synthesis of the Prins-pinacol precursors rac-18 and rac-19.
rac-25 by silyl protection, reduction to the aldehyde, and addition of
the lithium salt of alkyne 15. The initially produced 1.3:1 mixture of
propargylic alcohol epimers could be increased to 10:1 by Swern
oxidation22 of the epimer mixture, followed by reduction of the
ketone product with diisobutylaluminum hydride (DIBALH) in
hexanes at ꢁ78 ꢀC.23 By this sequence, rac-25 (10:1 dr) was obtained
in 31% overall yield from rac-12. Semi-hydrogenation of rac-25 (Pd/
CaCO3, H2, quinoline) and silyl protection of the alcohol provided
rac-27 in 84% yield over 2 steps. The thio acetal was then selectively
hydrolyzed by reaction with MeI and Ag2CO3 in MeCN/H2O at 80 ꢀC,
and the resulting hemiacetal acetylated to provide acetate rac-28.24
2.2. Identification of a competitive 2-oxonia-[3,3]-
sigmatropic/aldol pathway
The apparent invariance of the ratio of 8-oxabicyclo[3.2.1]octyl
aldehydes rac-20 and rac-29 produced at low temperature from
glycosyl acetate precursor rac-28 suggested the possibility that
both were produced in kinetically controlled processes. Although
our earliest investigations of the Prins-pinacol reaction provided
compelling evidence that an alternative 2-oxonia[3,3]sigmatropic
rearrangement/aldol mechanism was not involved in the trans-
formations studied at the time,26 it appeared possible that such

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S.M. Canham et al. / Tetrahedron 67 (2011) 9837e9843
mechanism as long as intramolecular aldol cyclization of the ini-
tially produced sigmatropic isomer F is not more rapid than single-
bond rotation of this intermediate to generate intermediate G.28,29
To probe the possibility of the 2-oxonia[3,3]sigmatropic path-
way, d2-rac-28 was prepared by partial reduction of rac-25 with D2,
and subsequently elaborated to d2-rac-28 to evaluate if H/D ex-
change occurred over the course of the reaction. Subjecting d2-rac-
28 to 0.5 equiv of SnCl4 in CH2Cl2 at ꢁ78 ꢀC provided rac-20/rac-29
with no observed loss of deuterium by mass spectrometric analysis
(Scheme 8). Conversely, exposure of rac-28 to 2.1 equiv of SnCl4 in
the presence of 1.5 equiv of d4-CD3OD produced at ꢁ78 ꢀC the rac-
20/rac-29 mixture without incorporation of deuterium. The ab-
sence of H/D exchange in these experiments strongly suggests that
under the reaction conditions at ꢁ78 ꢀC the trans aldehyde product
rac-20 is directly produced in the cascade sequence and is not
formed by epimerization of its aldehyde epimer.
Scheme 5. Synthesis of glycosyl acetate rac-28.
Scheme 8. Deuterium labeling experiments.
More insight into the origin of trans 8-oxabicyclo[3.2.1]octyl
aldehyde rac-20 was obtained from studies of cis epimer rac-29.
Although this isomer could not be obtained in pure form from the
mixture of aldehyde epimers generated from glycosyl acetate rac-
28, it could be prepared from trans epimer rac-20 by a multi-step
sequence (vide infra). Exposure of cis aldehyde rac-29 to DBU at
room temperature for 12 h provided exclusively trans epimer rac-
20 (Table 1, entry 1). Subjecting the cis aldehyde rac-29 to SnCl4 or
HN(Tf)2 at ꢁ78 ꢀC in CH2Cl2 (entries 3 and 5) did not result in ob-
servable epimerization. Likewise, epimerization did not occur un-
der the conditions used to quench the reaction of acetate rac-28
(entry 2). However, when cis aldehyde rac-29 was subjected to
HN(Tf)2 or SnCl4 at 0 ꢀC, epimerization was quickly observed
Scheme 6. Initiation of the Prins-pinacol cascade at low temperature from glycosyl
acetate rac-28.
a process might be operative in the present case.27 As outlined in
Scheme 7, trans aldehyde rac-20 would be a potential direct prod-
uct of a 2-oxonia[3,3]sigmatropic rearrangement/aldol cyclization
Scheme 7. Potential Prins-pinacol and 2-oxonia[3,3]sigmatropic/aldol pathways.

S.M. Canham et al. / Tetrahedron 67 (2011) 9837e9843
9841
Table 1
Stability and epimerization of cis aldehyde epimer rac-29 under various reaction
conditions
Entry
Conditions
cis/transa
1
2
3
4
5
6
DBU, PhH, rt, 12 h
100% trans
100% cis
100% cis
1:1.9
100% cis
1:4
5 equiv Et3N, CD2Cl2, ꢁ78 ꢀC/rt, 12 h
0.5 equiv SnCl4, CH2Cl2, ꢁ78 ꢀC, 30 min
0.5 equiv SnCl4, CH2Cl2, 0 ꢀC, 15 min
15 mol % HN(Tf)2, CH2Cl2, ꢁ78/ꢁ40 ꢀC, 30 min
15 mol % HN(Tf)2, CH2Cl2, 0 ꢀC, 30 min
Scheme 9. Synthesis of enantioenriched 8-oxabicyclooctyl aldehyde 20.
a
Ratio of rac-29:rac-20 determined by integration of 1H NMR spectra.
(entries 4 and 6). Thus we conclude that the substantial formation
of the trans aldehyde product, rac-20, from glycosyl acetate pre-
cursor at ꢁ78 ꢀC is the result of a 2-oxonia[3,3]sigmatropic/aldol
pathway and not from epimerization of its cis stereoisomer rac-29.
Upon warming the reaction mixture to 0 ꢀC, rac-29 epimerizes such
that trans aldehyde rac-20 becomes the exclusive product. Whether
the substantial amount of the cis epimer rac-29 produced at ꢁ78 ꢀC
is the result of competitive reaction by Prins cyclization/pinacol
rearrangement and 2-oxonia[3,3]sigmatropic rearrangement/aldol
pathways, or exclusively the result of the latter pathway is
unknown.
2.3. Total synthesis of (D)-aspergillin PZ
The intervention of a 2-oxonia[3,3]sigmatropic/aldol pathway in
the critical assembly of the 8-oxabicyclo[3.2.1]octane unit of
aspergillin PZ showed that a concise synthesis of this structurally
unusual isoindolone alkaloid could not be realized by the synthetic
strategy outlined in Scheme 1. However, to establish whether de-
veloping a more concise approach was warranted, we decided to
use the chemistry established in this investigation to prepare
(þ)-aspergillin PZ in order to confirm or raise in question the
suggestion of its antitumor properties. This synthesis began with
enantioenriched dihydropyran 12 (92% ee), which was converted in
3 steps to aldehyde 14 (Scheme 9). By the use of Carreira’s
method,30 alkyne 1519 was added with high diastereoselectivity to
provide enantioenriched propargylic alcohol 16 in 92% yield. Pro-
tection of the alcohol, followed by Lindlar reduction gave cycliza-
tion precursor 18 in 80% yield. Exposure of alkenyl glycoside 18 to
0.5 equiv of SnCl4 at 0 ꢀC delivered 8-oxabicyclo[3.2.1]octyl alde-
hyde 20 in 49% yield.
After several potentially short sequences for inverting the C6
stereocenter of aldehyde 20 proved unworkable, a multi-step se-
quence was developed (Scheme 10). Cleavage of the silyl group of
20, followed by Pinnick oxidation31 and lactonization provided
trans lactone 31, which upon reaction with DBU in refluxing ben-
zene was converted in high yield to cis lactone 32. Reduction of this
intermediate with LiAlH4, followed by selective silylation with
TBDPSCl/DMAP and oxidation of the resulting alcohol 33 delivered
aldehyde 29 in 27% overall yield from its trans epimer 20.
Scheme 10. Preparation of cis aldehyde 29.
by a WittigeHorner approach,32 intermediate 36 was obtained in
41% yield by sequential Takai olefination33,34 and Suzuki cross-
coupling of vinyl iodide 34 with boronic acid 35.35 After elaborat-
ing diene 36 to dienyl aldehyde 37 in a conventional fashion, the
lithium enolate of lactam 38 was added to provide aldol adduct 39
in 77% yield for the 3 steps. Oxidation of this intermediate with
either DesseMartin periodinane36 or Swern conditions21 provided
the corresponding b-keto lactam in disappointingly low to mod-
erate, and variable yields (36e57%).37 Selenation of keto lactam 40
gave selenide 41, which upon oxidation with m-chloroperbenzoic
acid (m-CPBA) and heating at 100 ꢀC provided a single tetracyclic
product 42 in 56% overall yield.11 Removal of the benzoyl and silyl
groups from 42 unveiled synthetic (þ)-aspergillin PZ (1), [ D þ115,
a]
whose 1H and 13C NMR data matched closely those reported for the
natural product.1,38
With access to a synthetic sample of (þ)-aspergillin PZ (1), its
activity against two highly invasive tumor lines (A2058 melanoma
and DU145 prostate cancer) was determined. No useful activity
The elaboration of aldehyde 29 to (þ)-aspergillin PZ is sum-
marized in Scheme 11. After failing to elaborate the diene side chain
(IC50>10 m
M) was found in either cell line.39

9842
S.M. Canham et al. / Tetrahedron 67 (2011) 9837e9843
Scheme 11. Completion of the total synthesis of (þ)-aspergillin PZ.
[3,3]sigmatropic/aldol pathway, the first synthesis of (þ)-asper-
gillin PZ (1) reported here does not represent a satisfactory solution
to the synthetic challenges presented by this novel structure.
Nonetheless, this synthesis did allow a preliminary evaluation of
the biological properties of (þ)-aspergillin PZ to be carried out. The
lack of activity seen in two tumor cell lines for synthetic
(þ)-aspergillin PZ, calls into question the suggestion1,7 that asper-
gillin PZ, like many aspochalasin diterpenes, might exhibit useful
antitumor properties.
Acknowledgements
This research was supported by the NIH grants (NS-12389 and
GM-098601), a Lilly graduate fellowship for S.M.C., and a graduate
fellowship for P.S.T. from Allergan. The authors thank Dr. David
Horne and Dr. Sangkil Nam of City of Hope Developmental Cancer
Therapeutics Program (NIH P30CA 33572) for anticancer testing of
synthetic (þ)-aspergillin PZ; Professor Scott Rychnovsky (UC
Irvine) for insightful discussion; Dr. John Greaves (UC Irvine) for
assistance with mass spectrometric analyses; Dr. Joseph W. Ziller
(UC Irvine) for X-ray analyses; and Dr. Emile J. Velthuisen (Glax-
oSmithKline) for early synthetic investigations. Synthetic assis-
tance from Mr. Rico Petersen and Ms. Marita Lawler is gratefully
acknowledged. NMR and mass spectra were obtained at UC Irvine
using instrumentation acquired with the assistance of NSF and NIH
Shared Instrumentation grants.
Scheme 12. Prins-pinacol and [3,3]-sigmatropic rearrangement/aldol pathways.
3. Conclusion
The present study provides the first definitive evidence that the
cascade transformation depicted in Scheme 12 can take place by
a 2-oxonia[3,3]sigmatropic/aldol pathway as well as by the more
common Prins-pinacol mechanism. As the stereochemical outcome
of these two sequences can differ in some situations, as in the case
reported here, gaining additional insight into structural features
that favor a specific mechanistic pathway is important.29 In the
transformations reported here, the fact that the product of [3,3]-
sigmatropic rearrangement F (Scheme 7) is a highly stabilized, di-
Supplementary data
substituted
a-alkoxy carbenium ion, whereas the product E
(Scheme 7) of Prins cyclization is a secondary carbenium ion favors
the 2-oxonia-[3,3]-sigmatropic/aldol pathway.
Because the stereoselective construction of 8-oxabicyclo[3.2.1]
octyl aldehyde 29 was undermined by the intervention of 2-oxonia
Full experimental procedures and spectroscopic data for all new
compounds are available as supplementary data. Supplementary
data associated with this article can be found in the online version,
at doi:10.1016/j.tet.2011.09.079.

S.M. Canham et al. / Tetrahedron 67 (2011) 9837e9843
9843
22. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480e2482.
23. The diastereoselectivity in the reduction can be explained by dipole minimiza-
tion of the carbonyl and the adjacent tetrahydropyran CeO -bonds in the non-
polar solvent. This conformation forces the hydride nucleophile to approach the
side of the carbonyl group distal to the tetrahydropyran. See: Cornforth, J. W.;
Cornforth, R. H.; Matthew, K. K. J. Chem. Soc. 1959, 112e127 and Ref. 15.
24. Attempts to initiate the Prins-pinacol cascade by activation of the glycosyl
sulfide rac-27 (or the derived sulfoxide or sulfone) or by activation of the hemi-
acetal were unsuccessful.
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27. For select examples of 2-oxonia[3,3]sigmatropic rearrangements as a compet-
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9. For the use of Prins-pinacol reactions in the synthesis of oxabicyclic natural
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Chem. 2009, 74, 5458e5470; (b) Corminboeuf, O.; Overman, L. E.; Pennington,
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11. For alternative methods of forming 8-oxabicyclo[3.2.1]octane ring systems see:
(a) Ishida, K.; Kusama, H.; Iwasawa, N. J. Am. Chem. Soc. 2010, 132, 8842e8843;
(b) Kusama, H.; Ishida, K.; Funami, H.; Iwasawa, N. Angew. Chem., Int. Ed. 2008,
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28. In the parent system, the computed transition-state energy difference be-
tween Prins cyclization and [3,3]-sigmatropic rearrangement is small, see:
Alder, R. W.; Harvey, J. N.; Oakley, M. T. J. Am. Chem. Soc. 2002, 124,
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Swallow, S. J. Org. Chem. 1994, 59, 7148e7151; (f) Lopez, F.; Castedo, L.;
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29. Additional insight into this competition is provided by computational studies
recently carried out in the Furche group (UC Irvine); details to be published in
due course.
Zhang, L.-R.; Zhang, L.-H. Tetrahedron: Asymmetry 2007, 18, 2326e2331.
12. (a) Harkin, S. A.; Singh, O.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1984,
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1.02,7]dodecane Ring System by Prins-pinacol Reactions and A Total Synthesis
of (þ)-Aspergillin PZ. Ph.D. Dissertation, University of California, Irvine, 2010.
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18. (a) Smith, C. W.; Norton, D. G.; Ballard, S. A. J. Am. Chem. Soc. 1951, 73,
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3 steps as described in the Supplementary data.
19. Delorme, D.; Girard, Y.; Rokach, J. J. Org. Chem. 1989, 54, 3635e3640.
20. The relative configuration of propargylic alcohols rac-16 and rac-17 was de-
termined by treatment of the alcohols independently with p-TsOH and NOESY
analysis of the resulting cyclic acetals.
21. CCDC 833184 contains the supplementary crystallographic data for compound
rac-22, which can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
€
30. (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122,
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synthesis of related cytochalasins see Refs. 12b,d,e, but was not suitable for
base-sensitive, epimerizable substrates, such as 29.
33. Okazoe, T.; Takai, K.; Utimoto, K. J. Am. Chem. Soc. 1987, 109, 951e953.
34. The methyl ketone is the major byproduct produced from an
a-elimination and
carbene insertion, see: Hodgson, D. M.; Comina, P. J. Synlett 1994, 663e664.
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37. Alternative methods to couple lactam 38 with the 8-oxobicyclo[3.2.1]octane
fragment by addition of the lithium enolate of 38 to an acyl imidazole in-
termediate, or by a BayliseHillman reaction, were found to be low yielding, see
Ref. 15.
38. (a) Unfortunately, a sample of natural (þ)-aspergillin PZ was not available for
direct comparison. (b) The optical rotation of natural aspergillin PZ was not
reported.1
39. Data kindly provided by Dr. Sangkil Nam, Beckman Research Institute, City of
Hope, Duarte, California.