Studies culminating in the total synthesis and determination of the absolute configuration of (-)-saudin

Article abstract of DOI:10.1016/j.tet.2011.09.067

A full account of studies that culminated in the total synthesis of both antipodes and the assignment of its absolute configuration of Saudin, a hypoglycemic natural product. Two approaches are described, the first proceeding though bicyclic lactone intermediates and related second monocyclic esters. The former was obtained via asymmetric Diels-Alder cycloaddition and the latter by an asymmetric annulation protocol. Both approaches employ a Lewis acid promoted Claisen rearrangement, with the successful approach taking advantage of bidentate chelation to control the facial selectivity of the key Claisen rearrangement.

Full text of DOI:10.1016/j.tet.2011.09.067

Tetrahedron 67 (2011) 9787e9808
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studies culminating in the total synthesis and determination of the absolute
configuration of (ꢀ)-saudin
*
Robert K. Boeckman, Jr. , Maria Rico del Rosario Ferreira, Lorna H. Mitchell, Pengcheng Shao,
Michael J. Neeb, Yue Fang
Department of Chemistry, University of Rochester, Rochester, NY 14627-0216, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 August 2011
Received in revised form 12 September 2011
Accepted 15 September 2011
Available online 22 September 2011
A full account of studies that culminated in the total synthesis of both antipodes and the assignment of
its absolute configuration of Saudin, a hypoglycemic natural product. Two approaches are described, the
first proceeding though bicyclic lactone intermediates and related second monocyclic esters. The former
was obtained via asymmetric DielseAlder cycloaddition and the latter by an asymmetric annulation
protocol. Both approaches employ a Lewis acid promoted Claisen rearrangement, with the successful
approach taking advantage of bidentate chelation to control the facial selectivity of the key Claisen
rearrangement.
Keywords:
Total synthesis
Asymmetric DielseAlder
Claisen rearrangement
Lewis acid promotion
Stereoselectivity
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
presents five contiguous stereogenic centers, three of which (C13,
C9, and C16) are contiguous quaternary centers, two of which are all
carbon and 1,3-disposed on a six-membered ring. The natural
product was found to exhibit interesting biological activity. Treat-
ment of laboratory animals that had been rendered chemically
hyperglycemic resulted in lowering blood sugar levels although the
mechanism of action remains unknown. Based on these studies,
Saudin (1) was thought to have possible therapeutic value or serve
as a lead structure in the development of treatments for diabetes.1,2
Several groups have investigated the preparation of this in-
teresting and challenging natural product. Initial model studies
followed by a concise total synthesis of the racemate were reported
by Winkler in 1998e1999.3,4 In 2002, we reported the first enan-
tioselective total synthesis of both antipodes, firmly establishing
the absolute stereochemistry of natural (ꢀ)-saudin, as the structure
depicted in Fig. 1.5 Subsequent to that publication, several addi-
tional synthetic approaches have appeared including the studies of
Labadie6e8 and Stoltz.9,10 Herein we wish to report the details of our
studies that established a strategy and culminated in the total
synthesis of natural (ꢀ)-saudin (1) and its antipode.
Saudin (1) was isolated by Mossa et al. in 1985 from Clutya
Richardiana, and its structure and relative stereochemistry was
elucidated by X-ray crystallography.1 However, the absolute ste-
reochemistry remained unknown.1 Saudin (1) was presumed to be
a member of the Labdane class of diterpenes.1,2 Based upon bio-
genetic considerations, the configuration shown in Fig. 1 was ten-
tatively assumed, although Labdane terpenes of both enantiomeric
series have been found in nature.3 In Saudin (1), the Labdane
skeleton has been highly modified by late stage biogenetic oxida-
tion and rearrangement.1,2 The skeleton is highly oxygenated and
O
Fur
4
O
1
O
O
O
O
H
7
5
16
O
13
O
9
O
O
O
O
O
(-)-saudin (1)
2. Results and discussion
2.1. Retrosynthetic analysis
Fig. 1. (-)-Saudin.
Our retrosynthetic analysis, arbitrarily directed to what is now
* Corresponding author. E-mail address: rkb@rkbmac.chem.rochester.edu
(R.K. Boeckman Jr.).
recognized as the antipode of natural (ꢀ)-Saudin (1), began with
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.067

9788
R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
the sequential disconnection of the internal ketal unit and the furan
revealing lactol 2. Functional group modifications of 2 revealed g,d-
owing to the presence of the vinylic methyl group, which disrupted
orbital overlap (Fig. 2). To overcome these problems a different
camphor-derived dienophile 12 was designed. Chelated 12 should
exist in the conformation depicted in Fig. 3, avoiding steric in-
teractions between the vinylic methyl substituent and the angular
enone 3, the product of a putative Claisen rearrangement of bicyclic
allyl vinyl ether 4. Enol ether 4 was expected to be available by O-
alkylation of the enolate dianion derived from enantiomerically
pure epoxylactone 5 and an enantiomerically pure allyl electrophile
(halide, sulfonate, or triflate) as shown in Scheme 1. The Claisen
rearrangement was identified as the key transformation in this
sequence owing to the expected large driving force for rearrange-
ment permitting the stereoselective creation of the required 1,3-
disposed quaternary carbon centers at C13 and C16 of Saudin (1).
proton. The
b face of the complex appears congested by the gem-
dimethyl bridge and by interaction with the bridgehead proton.
Thus attack of the diene should occur primarily from the bottom
a
face of the dienophile complex. This assumption was confirmed
by NOE experiments in the presence of TiCl4.
Ln
M
O
O
OR
HOOC
O
O
O
O
O
4
O
H
O
O
M
H
7
H
MLn
5
1
N
O
N
OH
+
H
16
O
N
O
13
O
O
9
O
O
OH
Ph
O
O
O
O
Ph
O
O
(+)-saudin (1)
O
O
O
12
11
2
OR
Fig. 2. Destabilizing allylic strain.
O
OR
O
O
H
O
OH
X
OR
+
OH
O
O
O
O
O
O
O
TiCl4
O
N
TiCl4
N
13
14
4
5
3
6
TIPSO
TIPSO
O
Scheme 1.
OTIPS
OTIPS
2.2. Assembly of epoxy ketone 5
Fig. 3. Transition states for enantioselective Diels Alder reaction.
A route to epoxy ketone 5 employing an asymmetric Diel-
seAlder reaction was first investigated.11,12 A chiral auxiliary was
employed to afford control over the absolute configuration of the
quaternary center eventually residing at C13. Three dienes of gen-
eral structure 9, bearing both silicon and ester protecting groups
(TBS acetate 9a, bis-acetate 9b, and bis-OTIPS 9c) were prepared
from common intermediate 8, itself derived from commercially
available alkyne 7 by mercury catalyzed hydration (Scheme 2).
Formation of bis-acetate 9b was incomplete affording a small
amount (10%) of 10.
The reaction was carried out in the presence of TiCl4. Bis trii-
sopropyl ether derivative 9c gave best results and adducts 13 and 14
(Scheme 3) were isolated in 92% yield (ratio 13/14¼88:12). The
temperature proved to be critical since no reaction took place at
ꢀ40 ꢁC while hydrolysis of the diene occurred at ꢀ10 to 0 ꢁC.
OTIPS
OTIPS
OTIPS
O
O
°
TiCl4, -20 C
N
+
+
OTIPS
H
92%
9c
OTIPS
OTIPS
Xc
14
OTIPS
O
O
OTIPS
Xc
13
9c
12
13/14= 88:12
TIPSOTf
94%
Scheme 3.
TEA
1) Ac2O, TEA
100%
HgO, H2O
H2SO4
The stereochemistry of major isomer 13 was elucidated by X-ray
O
OTBS
analysis after cleavage of the silyl enol ether to afford crystalline
ketone 15 (Scheme 4).11 The observed stereochemistry is in
agreement with the expected transition state wherein the diene
approaches the imide in an endo orientation from the less hindered
OH
OH
OAc
2) TBSOTf, TEA
CH2Cl2
63%
72%
8
7
9a
KHMDS
18-crown-6
then Ac2O
a
face (Fig. 3).
O
OTIPS
OTIPS
O
O
HF
HF
OAc
O
TBAF
(1 eq)
+
OTIPS
OTIPS
OTIPS
Xc
14
9b/10 ~9:1
O
OAc
OAc
O
O
O
O
O
O
Xc
15
Xc
13
16
17
9b
Scheme 2.
10
Scheme 4.
Both silyl groups of adduct 13 could be cleaved with HF affording
Attempted cycloaddition of dienophile 11 with 9aec in the
presence of a variety of Lewis acids and also under thermal con-
ditions failed repeatedly, probably resulting from steric hindrance
directly keto lactone 16 (Scheme 4). Similar deprotection of the
minor adduct 14 afforded lactone 12, spectroscopically identical to
16 but exhibiting equal and opposite optical rotation, confirming

R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
9789
that 16 and 17 were enantiomeric and that both 16 and 17 were
endo adducts derived from approach of the diene from the and
face of the dienophile-LA complex, respectively (Fig. 3).
Major isomer 13 was transformed into the desired enone 19
using a two-step sequence. Although attempted Saegusa reaction
on the silyl enol ether failed, treatment with 2 equiv of phenyl
selenyl bromide afforded the unsaturated derivative 18 (a second
2.3. Preparation of the enantiomerically pure sidechain
triflate 6 (X[OTf)
a
b
The alkenyl sidechain was prepared using the conventional se-
quence depicted in Scheme 8, starting from commercially available
Roche ester 24.15 Protection of the primary alcohol as TBDPS ether
followed by reduction of the carboxylic ester with DIBAl-H, gave
alcohol 25. Oxidation of 25 to the unstable aldehyde and direct re-
action with isopropyl diethylphosphonoacetate afforded un-
saturated ester 26 in 69% yield from 24. Reduction of 26 with DIBAl-
H afforded the allylic alcohol 27 in 90% overall yield. The corre-
sponding triflate 6 (X¼OTf) was prepared in situ by deprotonation
with n-BuLi and reactionwith triflic anhydride in an estimated >90%
yield by NMR.12,13 The allylic triflate proved to be too reactive to be
isolated, thus it was generated and used in situ at low temperature.
To assure that the optical purity was maintained during prepa-
ration of 6 (X¼OTf), the Mosher ester of 27 was prepared, but the
resolution of the signals for the two isomers was insufficient for NMR
analysis. Thus, ester 26 was degraded (ozonolysis followed by re-
duction) to alcohol 25 and esterification gave a single isomer of the
corresponding Mosher ester (similar derivatization of racemic 25
gave a mixture of two isomers that showed different spectroscopic
properties).12
molecule of PhSeBr probably reacts with the corresponding
a-
seleno derivative with elimination of diphenyldiselenide, making
the oxidation step unnecessary). Subsequent deprotection of the
primary silyl ether with TBAF, with concomitant lactonization, gave
19 in optically pure form (Scheme 5).12b,13
PhSe Br
SePh
OTIPS
NaHCO3
PhSeBr
(2 eq)
O
O
O
TBAF
92%
68%
OTIPS
OTIPS
H
O
O
O
OTIPS
B-
Xc
13
O
Xc
18
O
Xc
19
Scheme 5.
Alternatively, lactone 19 could be obtained by Michael addition
An analogous, simpler alkenyl sidechain, lacking the secondary
methyl group, was also prepared starting with 28 using the se-
quence depicted in Scheme 9. The alkynol 28, after protection of the
primary alcohol, was alkylated with para-formaldehyde to afford
29 in 85% overall yield. The triple bond was then reduced with LAH
and EtOH in THF to give exclusively the E allylic alcohol 30 in 96%
yield that was similarly activated in situ as the triflate 31 (>90%).12
of chiral vinylogous carbamates 20 derived from methyl tetronic
acid to ethyl vinyl ketone affording Michael adduct 21 after hy-
drolytic workup. The enantiomeric excesses were modest (60% ee
as illustrated for a-methyl naphthyl amine) but employing S-pro-
line in the cyclization of diketone 21 to hydroxy ketones 22 allowed
us to enhance the ee to an acceptable 89% (Scheme 6).12b Several
chiral imines and Lewis acids were examined in an attempt to
improve the selectivity in the Michael addition but all efforts were
unsuccessful.
2.4. Reductive coupling of epoxy ketone 5 and triflate 6
Preliminary studies of the reduction and concomitant trapping of
epoxy ketone 5 with electrophiles established that the usual one
electronreductants, suchasLi/NH3,16 Linapthalenide,17 andLidi-tert-
butylbiphenylide18 were too basic and/or nucleophilic, resulting in
eitherdegradationof5orreduction/eliminationbacktotheenone 19.
Examination of the literature revealed a little used one electron
reductant, Li or Na trimesitylborylide (Liþ or Naþ TMB), originally
developed byDarling, based on early work of Brown andothers, as an
alternative to Li/NH3 for reduction of enones and related unsaturated
compounds.19,20 Although Darling envisioned trimesitylborane
(TMB) more as a medium supporting such reductions, we found that
Naþ TMB can be generated stoichiometrically by stirring of Na metal
(5 equiv)withTMB (2.0 equiv)inanhydTHFat rtfor8 hproducingan
intensely blue colored solution. Addition of epoxy ketone 5 (1 equiv)
to this solution at ꢀ78 ꢁC and stirring at ꢀ78 ꢁC for 24 h followed by
quenching with aq NH4Cl afforded the hydroxy ketone 22. Alterna-
tively, quenching with TBDMSCl (5 equiv) afforded hydroxysilyl enol
ether 32 upon workup in 71% yield (Scheme 10).12b
Scheme 6.
With enone 19 in hand we explored epoxidation of 19 to epoxy
ketone 5 (Scheme 7). The lability of the g-lactone ring under basic
conditions precluded the use of the usual methods for nucleophilic
epoxidation of 19. Alternatively, reduction of 19 with NaBH4
afforded a mixture of allylic alcohols 23 in 75% yield. Epoxidation of
the mixture 23 with m-CPBA afforded the expected intermediate
epoxy alcohols, which were directly reoxidized with PDC to afford
epoxy ketone 5 as a single diastereomer in 92% overall yield.12,13
Apparently, the concave surface of 23 is sufficiently congested
that approach of m-CPBA is precluded in spite of the well-known
directing effects of allylic hydroxyl groups on the stereochemistry
of epoxidation.14
O-Allylation of hydroxyenol dianion could also be effected by
quenching with allyl bromide/HMPA then pH¼7 phosphate buffer
affording the corresponding O-allyl hydroxyenol ether in 64% yield.
Analogously, in situ mono trapping of the presumed enolate alk-
oxide dianion with triflate 6 in the presence of HMPA proceeded to
afford allyl hydroxyenol ether 33 in 52% yield (unoptimized), as
depicted in Scheme 10.12b
O
OH
O
1) mCPBA
2.5. Introduction of the C16 quaternary carbon via Claisen
rearrangement
NaBH4
75%
O
2) PDC, 3Å sieves
92% (overall)
O
O
Regrettably, no reliable conditions were found to effect the de-
sired thermal or Lewis acid promoted Claisen rearrangement of 33.
The principal products resulted from degradation back to enone 19
and allylic alcohol 27. This outcome likely results from autocatalytic
O
O
O
O
5
19
23
Scheme 7.

9790
R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
1) Swern
MeO2C
i-PrO2C
1) TBDPSiCl, TEA
2) Dibal, Et2O
HO
OTBDPS
OH
OTBDPS
2) t-BuOK
O
P
OEt
OEt
i-PrO2C
26
24
25
82% yield for 2 steps
69% overall from 24
n-BuLi, Tf2O
>90%
Dibal
Et2O
HO
OTBDPS
TfO
OTBDPS
6 X=OTf
93%
27
Scheme 8.
1) TBDPSiCl, Im
OH
LAH
HO
29 R=TBDPS
X
OTBDPS
30 X=OH
31 X=OTf
OR
THF, EtOH
96%
2) n-BuLi, (CH2O)n
85%
n-BuLi
Tf2O
>90%
28
Scheme 9.
O
aq NH4Cl
94%
OH
O
O
O
22
1) Na+TMB.-
THF -78oC
Na+TMB.-
THF -78oC
O
OTBDPS
O
2)
6
OH
O
OTBDMS
HMPA/Et2O
O
O
O
52%
33
TBDMSCl
71%
5
OH
O
O
32
Scheme 10.
O
O
O
decomposition of 33 initiated by elimination of a catalytic amount
of water from 33 and hydrolysis of the remaining 33 to 22 and al-
cohol 27 and subsequent elimination of water from 22 to afford 19
and regenerate the catalytic amount of water.
As a result, the sequence was modified by use of an allyl dienol
ether lacking the labile C9 hydroxyl group. The linearly conjugated
enolate was smoothly generated by slow addition of NaHMDS in
THF to enone 19 in THF at ꢀ78 ꢁC, as demonstrated by trapping
with TBSOTf affording 34, exclusively, in good yield (Scheme
11).12a,13
H
H
OTBDPS
125°C
76%
OTBDPS
+
OTBDPS
O
O
O
35
O
O
O
36
37
3:1
Scheme 12.
ClaiseneCope rearrangement of 35.21 Indeed, when Claisen rear-
rangement was conducted at temperatures exceeding 125 ꢁC vari-
able amounts of the product(s) of tandem ClaiseneCope
rearrangement wereisolated. At temperaturesexceeding 150 ꢁC, the
product(s) of tandem ClaiseneCope rearrangement became pre-
dominant or exclusive as the temperature was increased. After
chromatographic separation of 36 and 37, the structure and relative
stereochemistry of 36 was confirmed by single crystal X-ray analysis
of crystalline ketol 38, obtained by desilylation of 36 with HF in
acetonitrile in 77% yield (Scheme 13). Unfortunately, the Claisen
rearrangement of 35 had afforded as the major diastereomer 36, the
undesired diastereomer for conversion to Saudin (1). We reasoned
OTBS
O
O
a) NaHMDS
THF -78°C
1) NaHMDS
-78°C THF
OTBDPS
b) TBSOTf
>80%
2) HMPA
3)
6
O
O
O
77%
O
O
O
35
34
19
Scheme 11.
Having confirmed the exclusive formation of the linearly conju-
gated dienolate from 19, treatment of that linear Na enolate derived
from 19 with HMPA followed by allylic triflate 6 at ꢀ78 ꢁC afforded
the O-allylated dienol ether 35 in 77% yield. We were pleased to see
that the desired thermal Claisen rearrangement of 35 now pro-
ceeded smoothly upon heating 35 for 2 h at 125 ꢁC providing a 3:1
mixture of diastereomeric Claisen rearrangement products 36 and
37 in 76% yield (Scheme 12). Since the ketones 36 and 37 are sub-
strates for a Cope rearrangement, prolonged heating or higher
temperatures had to be avoided to prevent the undesired tandem
Scheme 13.

R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
9791
that steric interactions involving the methyl substituent of the allylic
chain could be held responsible for this preference (Fig. 4).12a,13
deficiency of the Lewis acidic center. Under optimal conditions,
using Et2AlCl$PPh3, the selectivity rises to 1:5 (40/41). In the case of
35 the synergism of the two asymmetric centers combine to
overwhelm the magnitude of the effects owing to the nature of the
Lewis acid affording a remarkable enhancement from 3:1 to 24:1
(36/37) in all cases. However, in all cases the effect of the Lewis acid
promotion is to increase the selectivity toward the undesired di-
astereomers rather than reverse the diastereoselectivity as hoped.A
plausible mechanistic rationale is shown in Fig. 5. As illustrated,
these results do not invalidate the previous mechanistic hypothe-
ses, however they do indicate that kinetic and irreversible com-
plexation of the Lewis acid is unlikely. These results further
demonstrate that the interaction of the allylic sidechain with the
C13 methyl group dominates the diastereoselectivity in the rear-
rangements of 35 and 39, regardless of the presence or absence of
the secondary methyl group or the use of Lewis acid promoters.13
O
O
O
36
37
O
OTBDPS
OTBDPS
O
O
Fig. 4. Transition states for thermal Claisen rearrangement of 35.
Assuming that introduction of the methyl group by alkylation at
C4 would not be problematic at a later stage, we reasoned that this
steric interaction should be minimized when 31 was utilized as
electrophile. The O-alkylation of 19 was done under the same
conditions specified above. Subsequent thermal rearrangement of
39, unfortunately, did not markedly improve the observed dia-
stereoselectivity for the desired diastereomer 40 affording a 1:1
mixture of 40 and 41 (Scheme 14). Again, high temperatures had to
be avoided to prevent formation of the products of the competing
tandem ClaiseneCope process.21 Adducts 40 and 41 were depro-
tected as before with HF in acetonitrile and readily separated
chromatographically to provide free hydroxy ketone 42 and an
uncharacterized desmethyl analog of 42 whose configurations
were assigned by analogy to 36 and 37. The direction in the change
in the observed facial selectivity (from 1:3 to 1:1) was in agreement
with our reasoning, but the magnitude was less than anticipated,
revealing the primary controller of the stereoselectivity was the C13
quaternary center with a lesser contribution from the sidechain
stereocenter.13
2.6. Elaboration of Claisen adduct 40 toward saudin (1)
Based on the idea that increasing the diastereoselectivity of the
Claisen rearrangement could be deferred until evidence was accrued
that the synthetic approach was likely to afford Saudin (1), further
elaboration of ketone 40 was then undertaken. Ketone 42 was ob-
tained in 43% yield by deprotection of the 40/41 mixture with HF in
CH3CN. After Jones oxidation of 42 to the corresponding acid and
iodolactonization, iodolactone 43 was rearranged in two steps to af-
fordtricyclicintermediate44in35%overallyield. Epoxidationwithm-
CPBA unexpectedly gave the undesired
b isomer 45, whose structure
was corroborated by X-ray crystallographic analysis (Scheme 15).12a
O
O
OTBDPS
O
O
H
H
NaHMDS
THF-HMPA
OTBDPS
OTBDPS
Δ
°
-78 Cto rt
+
then 31
O
19
O
O
40
O
°
at -78 C
O
O
39
O
O
41
1:1
Scheme 14.
We then investigated Lewis acid promoted rearrangements of
both substrates (35 and 39) with the hope that coordination with
a Lewis acid would favorably alter the stereochemical outcome of
the Claisen rearrangements of these substrates. The results of these
studies are summarized in Table 1.13
O
O
O
L.A.
TBDPSO
R = H, CH3
R
L.A.
R
Table 1
L.A.
O
R
L.A.
Evaluation of Lewis Acid promoters of the Claisen rearrangement of 35.
TBDPSO
Entry Substrate Lewis acid (equiv) Time (h) Temp (ꢁC) 36/41:37/40a (yield)
O
TBDPSO
O
O
1
2
3
4
5
6
7
8
9
39
39
39
39
39
39
35
35
35
35
None
i-Bu3Al (2)
Me3Al (2)
2
18
0.9
2
1.5
0.5
2
0.2
2
105
25
25
1:1 (81%)
2:1 (33%)b
3:1 (90%)
O
O
MAD* (4)
25
2.5:1 (88%)
4:1 (57%)c
5:1 (94%)
Et2AlCl$Ph3P (2)
Et2AlCl$Ph3P (2)
None
Me3Al (2)
MAD* (4)
ꢀ50
R
25
TBDPSO
faster
R
125
45
25
3:1 (76%)
O
O
24:1 (60%)d
24:1 (43%)d
24:1 (39%)d
L.A.
TBDPSO
L.A.
slower
37
O
O
10
Et2AlCl$Ph3P (2)
0.5
25
O
O
a
/
40
36/41
Total yield of isolated chromatographically pure materials.
Yield adjusted for conversion of 67%.
Yield adjusted for conversion of 30%.
b
c
Fig. 5. Transition states for Lewis acid promoted Claisen rearrangement of 35.
d
Yields unoptimized for these cases.
A less direct route was then devised to install the oxygen
function at C9, a fully substituted position, with the correct ste-
reochemistry in a substrate suitable for the incorporation of the
furan ring (Scheme 16). The sequence begins with conversion of
enol lactone 44 to Weinreb amide 46 in 95% yield.22 Oxidation of 46
with DesseMartin periodinane23 provided aldehyde 47 in 90%
The optimal Lewis acid for rearrangement of 35 and 39 was
found to be the 1:1 complex of Et2AlCl and Ph3P, which provided
high yields and clean products at rt. The stereoselectivity in the
rearrangement of 39 appears to increase both with increasing steric
bulk of the ligands on the Lewis acid, and with increasing electron

9792
R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
To implement this approach, we required the monocyclic enone
51 rather than 19. To assess the viability of the new route, early
intermediates were initially prepared in racemic form (Scheme
17).26 Michael addition of ethyl 2-methylacetoacetate to ethyl vi-
nyl ketone, catalyzed by NaOMe, afforded diketone 52, that was
converted without purification to the desired 53 along with its
regiosiomer 54 (53/54 w4:1) by treatment with pyrrolidinium
acetate. Since keto esters 53 and 54 were inseparable, basic hy-
drolysis and neutralization during which the undesired beta-keto
acid derived from 54 underwent decarboxylation, afforded only
the pure acid 55, which was then re-esterified under basic condi-
tions to afford enone 51 in 50% overall yield from ethyl 2-
methylacetoacetate (Scheme 17).26c
Highly enantiomerically enriched (ꢀ)-51 was obtained using
Scheme 15.
chiral vinylogous carbamate (þ)-56 as starting material.27 Michael
O
O
O
OMe
OMe
OH
N
N
O
O
O
O
Dess-Martin
periodinane
H
O
H
O
H
CHO
MeClAlN(OMe)Me
H
H
H
CH2Cl2
95%
90%
O
COOMe
44
COOMe
47
COOMe
46
O
O
O
OMe
OMe
OMe
Li
N
N
N
1)
O
O
O
O
H
O
AgBF4
H
O
CHO
NEt3/CH3CN
THF
NBA
THF / H2O
61%
O
OH
H
H
2) Dess-Martin
O
(1:5 v/v)
75%
O
O
periodinane
48%
O
O
Br
MeOOC
Scheme 16.
MeOOC
MeOOC
48
49
50
yield. Exposure of aldehyde 47 to N-bromoacetamide in aq THF
affords a mixture of bromo hemiacetals 48 (6:1
a
:
b
) in 61% yield via
O
O
O
O
O
addition of the electrophilic bromine from the
b face as expected
Pyrrolidine
AcOH
toluene, Δ
based upon the observed stereochemistry of epoxidation of 44.24
Exposure of 48 to AgBF4 in the presence of Et3N then provided
NaOMe
MeOH
OEt
+
COOEt
52
the desired
a
-epoxy aldehyde 49 by silver induced ionization and
O
O
O
concomitant epoxide formation with inversion at C9. Addition of 3-
lithio furan25 to aldehyde 49 affords, again after oxidation of the
intermediate mixture of alcohols with DesseMartin periodinane,23
the desired 3-furyl ketone 50 in 48% overall yield (unoptimized)
from 49.
K2CO3
Me2SO4
aq KOH
MeOH, Δ
+
acetone, Δ
O
50%
COOEt
COOH
55
COOMe
51
overall
COOEt
53
54
Unfortunately efforts to further elaborate furyl ketone 50 by
initial reductive deoxygenation of the a-keto ether linkage were
Scheme 17.
unsuccessful. Although cleavage of the desired CeO bond could be
successfully accomplished, the resulting ketone enolate underwent
undesired intramolecular aldol processes more rapidly than
quenching of the enolate by protonation occurred leading to indane
derivatives. Attempts to effect reductive scission of the CeO bond
under acidic conditions were also unsuccessful.
addition of (þ)-56 to ethyl vinyl ketone in toluene at 0 ꢁC in the
presence of ZnCl2 afforded diketone (ꢀ)-51 in 61% yield. Diketone
(ꢀ)-51 (>90% ee) was purified prior to cyclization. As a result,
treatment of (ꢀ)-51 with pyrrolidinium acetate under reflux
afforded principally (ꢀ)-53 (95% ee) with improved regioselectivity
(53/54 w18:1) in 87% yield.26c Although the sap-
onificationereesterification steps were unnecessary, the methyl
ester (ꢀ)-51 was prepared for ease in NMR analysis (Scheme 18).26c
The absolute configuration of (ꢀ)-51 was deduced from the
mechanism of the Michael addition, since the sense of the chiral
induction is well known. Furthermore, it was confirmed by trans-
formation of lactone (þ)-19 (Scheme 5) into ethyl ester (ꢀ)-53. Also
2.7. A revised synthetic approach utilizing precursors lacking
the g-lactone
In order to better control the diastereoselectivity of the key
Claisen rearrangement, a modified retrosynthetic analysis was then
devised that retained a Claisen rearrangement as the key step but
employed substrates with more conformational freedom by re-
by derivatization of carboxylic acid R-(þ)-52 with R-(þ)-
a-methyl
moval of the fused
g-lactone ring. It was hoped that the increased
benzyl amine, which afforded a crystalline amide whose structure
was corroborated by single crystal X-ray analysis.
By analogy to the enolization of enone 19, the thermodynamic
enolate derived from (ꢀ)-51 was O-alkylated with allylic triflate 6
to afford Claisen precursor 57 (40% isolated yield) along with C-
conformational freedom would permit alteration of the reactive
conformation of the enol ring by use of a Lewis acid capable of
chelation between the enol oxygen and the carbonyl of the ester
group at C13
.

R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
9793
51 and 22, while the use of THF inhibited both processes, leading to
recovery of starting ether 58. To our delight, our studies led to op-
timized conditions involving the use of 2.5 equiv of TiCl4 and
2.5 equivof Me3Al in CH2Cl2 at ꢀ65 ꢁC that permitted rearrangement
of (ꢀ)-58 cleanly affording a 75% isolated yield of the desired isomer
(ꢀ)-59, having the correct relative stereochemistry between the two
quaternary centers C13 and C16, and a sidechain sufficiently func-
tionalized for further elaboration.
H
O
O
O
NH
O
ZnCl2
+
OEt
°
toluene, 0 C
61%
COOEt
(-)-52
(+)-56
O
O
Pyrrolidine
AcOH
toluene, Δ
1) aq KOH, MeOH, Δ
The observed facial selectivity can be rationalized by invoking
bidentate coordination of Ti(IV) to the oxygen atoms of the starting
material, stabilizing a boat conformation in which the reaction
leading to the major isomer takes place axially, as preferred stereo-
2) K2CO3, MeSO4
acetone, Δ
87%
COOEt
(-)-53
(95% ee)
COOMe
95%
(-)-51
face(TS I vs TS II, Fig. 6).28
(95% ee)
electronically, and from the lesshindered
a
Scheme 18.
O
R
O
LnTi
R
LnTi
O
alkylated by-products. When 31 was used as electrophile the cor-
responding enol ether 58 was obtained in 65% yield (Scheme 19).
O
60
59
MeO
MeO
TS II
TS I
O
KHMDS
OTBDPS
O
THF-HMPA
R
Fig. 6. Transition states for TiCl4 promoted Claisen rearrangement of 57 and 58.
°
-78 Cto rt
then 6 (R=Me) or 31 (R=H)
TfO
OTBDPS
COOMe
(-)-51
COOMe
57 (R=CH3)
58 (R=H)
2.9. Elaboration of ketone (L)-59
R
°
-78 C
Deprotection of silyl ether (ꢀ)-59 with 2.5 equiv of TBAF in the
presence of 1 equiv of HOAc spontaneously led to a mixture of
hemiketals(w1:1)thatweredirectlyconvertedtosinglemethylketal
(þ)-61 in 99% yield upon treatment with excess CH3OH/CH(OCH3)3
(1:1 v/v) in the presence of pTsOH hydrate (Scheme 21). Hydro-
boration of the less hindered, monosubstituted olefin with 9-BBN
selectively afforded the expected primary alcohol (þ)-62 in 87%
yield. Alcohol (þ)-62 was then oxidized in two steps to the corre-
sponding carboxylic acid by sequential Swern and Pinnick oxidations
(Scheme 21).29,30 Direct oxidation of (þ)-62 using PDC31 also pro-
ceeded efficiently(75%yield)butpurification of the resulting product
more problematic. Thus, the two-step sequence was employed since
it proved to be higher yielding and does not require purification as
well as avoiding the use of heavy metals. Direct epoxidation of the
aforementioned carboxylic acid with m-CPBA followed by acid
treatment afforded lactone (þ)-63 as a single diastereomer in 73%
overall yield from (þ)-62. Steric congestion around the ketone car-
bonyl in (þ)-63 resulted in complete chemoselectivity during the
Scheme 19.
2.8. Claisen rearrangement of monocyclic substrates
We envisioned that use of a bidentate Lewis acid to promote the
Claisen rearrangement of 57 and 58 would allow coordination of
both oxygens (those of the vinyl ether and the ester) forcing the six-
membered ring into a boat conformation, favoring the axial ap-
proach from the bottom face as required.28
Initial experiments were conducted using both substrates (57
and 58) to identify the best conditions for the [3,3]-sigmatropic
rearrangement. TiCl4 was employed as the Lewis acid. The results
in terms of reactivity and diastereoselectivity were in agreement
with those obtained previously (see Table 1).13 Methylated analog
57 afforded mixtures of isomers along with several by-products
including large amounts of enone (þ)-51. This decomposition
pathway could not be avoided by introducing additives such as
bases, Ph3X (X¼P, As, Sb), R3Al, etc. or by use of less reactive Ti(IV)
Lewis acids.
In contrast, the desmethyl analog, allyl enol ether 58, upon
treatment with 2.5 equiv of TiCl4, was cleanly converted into Claisen
adducts 59 and 60 with very good facial selectivity (59/60 w10:1 at
ꢀ78 ꢁC) along with (þ)-51 (Scheme 20). We then attempted opti-
mization of this transformation. We noted that addition of Me3Al as
proton scavenger minimized decomposition to the enone without
interfering with the stereochemical outcome as did increasing the
reaction temperature, but, in the latter case, the diastereoselectivity
exhibited in formation of 59 and 60 was adversely affected (59/60
w5:1 at ꢀ30 ꢁC). The influence of the solvent was also examined
resulting in the finding that less polar solvents (such as hexanes or
toluene) retarded the Claisen reaction, promoting the formation of
addition of 3-lithiofuran25 affording a
d-lactol 64. No products of
addition to the other potentially electrophilic centers were observed.
The crude lactol 64 was directly oxidized to acid (þ)-65 in 70% overall
yield over three steps, via the corresponding primary alcohol tauto-
mer of 64, using successive Swern29 and Pinnick30 oxidations thus
avoiding undesired internal ketalization (Scheme 21).
Opening of the epoxide group of (þ)-65 was promoted by
BF3$Et2O. The intermediate carbenium ion underwent immediate
intramolecular trapping by the free carboxylic acid, and the newly
formed primary alcohol underwent concomitant lactonization
affording as the final result of this reaction cascade bis-lactone 66
that was isolated in an unoptimized 38% yield (Scheme 22).32 In
order to introduce the methyl group at the
a C4 position of the d-
lactone (Saudin numbering), both ketone functions had to be pro-
tected. This protection operation, which required high tempera-
tures and prolonged reaction times, was accomplished by
treatment of 66 with TsOH in CH3OH/(CH3O)3CH affording ketal
enol ether 67 in a mediocre 45% yield. The reaction is likely sluggish
as a result of steric hindrance at the neopentyl carbonyl carbon of
the cyclohexanone ring. Alkylation of 67 by treatment with LDA at
ꢀ78 ꢁC and quenching with CH3I under kinetic conditions afforded
O
O
O
OP
+
O
OP
+
H
H
OP
COOMe
51
COOMe
58
COOMe
59
COOMe
60
an isomeric mixture of alkylation products 68 (68
b/68a w6:1) in
Scheme 20.
71% yield (92% bsrm) resulting from mainly axial methylation in

9794
R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
O
O
CH3O
O
OTBDPS
CH3O
H
H
9-BBN / THF
65°C 1h
H
1) TBAF
HOAc
then
2) CH3OH/CH(OCH3)3
(xs 1:1 v/v)
OH
NaBO3
COOCH3
(+)-61
COOCH3
(+)-62
COOCH3
pTsOH (cat)
87%
(-)-59
COOH
H
1) (COCl)2 DMSO
Et3N CH2Cl2
1) (COCl)2
DMSO Et3N
CH2Cl2
O
O
O
O
H
Li
O
H
2) NaClO2 NaH2PO4
O
THF
O
O
O
HO
O
O
2) NaClO2
NaH2PO4
O
-78°C
3) mCPBA NaHCO3
CH2Cl2
4) 10% HCl / THF
COOCH3
(+)-63
COOCH3
64
COOCH3
(+)-65
O
70% overall
from (+)-63
73%
Scheme 21.
CH3OH/CH(OCH3)3
BF3-Et2O
(xs 1:1 v/v)
CH3CN rt
38%
pTsOH (cat)
45%
LDA / THF
-78°C
1N HCl
then
°
CH3I -78°C
71% (92% brsm)
(6:1
> 95%
Scheme 22.
which the major isomer was confirmed to possess the desired
stereochemistry at C4 (Saudin numbering) by NOE measurements.
Small amounts of saudin (1) were obtained from 68b via sequential
deprotection with concomitant lactone hydrolysis and cyclization.
We later observed that Saudin formed directly during the depro-
tection step as shown in Scheme 22. However, after attempts at
optimization, the yield could be improved only modestly to 25%.
Epimerization at the newly formed 2ꢁ methyl chiral center at C4
eventual C4 position (Saudin numbering) in lactones 68 and 69, the
order of ring formation had to be modified. To accomplish this
change, the lactol 64, in equilibrium with the ring opened primary
alcohol 70, was protected as the acetate (ꢀ)-71 in >90% yield (81%
overall directly from (þ)-63 by in situ trapping with Ac2O), to avoid
its participation in the opening of the epoxide. Subsequent treat-
ment of (ꢀ)-71 with BF3-Et2O as before afforded the internal ketal
(þ)-72 in 90% yield.32 The acetate group present in (þ)-72 was
saponified in near quantitative yield and the corresponding alcohol
73 was oxidized by successive Swern28 and Pinnick29 oxidations to
carboxylic acid 74 in 96% yield over two steps. Direct trans-
formation of 73 into 74 was successful in 65% yield using catalytic
TEMPO/NaOCl and NaClO2 as co-oxidant,33 although the yield was
lower owing to competing oxidation of the furan ring (Scheme 23).
during deprotection is most likely responsible since lactone 69
was obtained as a major by-product when starting with near ho-
mogenous 68
a
b.
2.10. Final elaboration of (L)-saudin (1) from lactone (D)-63
Formation of the key d-lactone ring was then effected by con-
During the final conversion to Saudin, in order to avoid the
version of acid 74 into the crystalline enol lactone (ꢀ)-75 upon
evident thermodynamic preference for the wrong epimer at the
OH
OAc
O
O
O
O
O
O
H
H
H
Ac2O, DMAP
O
HO
O
O
py-CH2Cl2
rt 1h
>90%
O
O
O
O
O
COOCH3
COOCH3
70
COOCH3
(-)-71
64
COOH
H
1) (COCl)2
DMSO Et3N
CH2Cl2
O
O
OAc
OH
H
H
O
BF3-Et2O
K2CO3
O
O
O
CH3CN
90%
O
CH3OH-H2O
>98%
O
2) NaClO2
NaH2PO4
O
O
COOCH3
COOCH3
(+)-72
COOCH3
96%
74
73
Scheme 23.

R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
9795
treatment of 74 with TFAA in the presence of NaOAc, in 67% overall
yield from 73 over three steps. The structure and stereochemistry of
(ꢀ)-75 were confirmed by single crystal X-ray analysis (Scheme 24).
The creation of the enol lactone ring overcame the difficulties en-
countered during protection of the hindered carbonyl group.
Attempted alkylation of (ꢀ)-75 with LDA followed by addition of
excess MeI, under a variety of reaction conditions, led to mixtures of
76
of LDA was used. Reasoning that diisopropyl amine could enhance
the proton exchange between the starting lactone enolate and 76
leading to epimerization and polyalkylation,34 we decided to use
a
and 76
b
and 74 along with unreacted (ꢀ)-75, even when excess
a
/
b
the more hindered and stronger base Li-TMP, which is known to
reduce the formation of aggregates.35 Our hypothesis was con-
firmed when complete conversion of 75 was observed and a ki-
netically controlled mixture of 76 (76
75% yield accompanied by only traces of 77. In contrast to 68
and 69 , the desired isomer was now thermodynamically
preferred. Thus, after chromatographic separation of 76 and 76
the undesired isomer 76 was epimerized to 76 by treatment with
a/76b w1:1.5) was isolated in
a
/
b
a/b
a
b,
b
a
a substoichiometric amount of LDA in 88% yield providing 76a in
Scheme 25.
70% total yield.36
With the successful assembly of 76a, having the correct ste-
reochemistry and oxidation state at all positions, it only remained
to assemble the bis ketal structure of Saudin. Our first attempts
involved mild selective hydrolysis of the enol lactone and treat-
ment of the intermediate methyl ester with TMSOTf. Under these
enantioselective synthesis of (ꢀ)-Saudin (1). The synthetic
(ꢀ)-Saudin (1) had identical spectroscopic properties and melting
point (204e206 ꢁC) to both natural (ꢀ)-Saudin (1), and synthetic
(þ) Saudin (1) except for optical rotation (½a D22
ꢀ14; c 0.460, CHCl3),
ꢂ
conditions, saudin was isolated in 50% overall yield from 76a.
which was equal and opposite in sign.1,2
However, a by-product, containing two methoxy groups, was also
obtained when the reaction was quenched before completion.
Thus, in order to avoid the presence of methanol in the reaction
mixture, harsher hydrolysis conditions were employed to afford the
intermediate bis carboxylic acid 78. Direct treatment of the crude
diacid 78 with TMSOTf afforded saudin (1) in 70% isolated yield
(Scheme 24).
3. Conclusion
The studies described herein resulted in the successful total
synthesis of both natural (ꢀ)-Saudin (1) and its antipode (þ)-Sau-
din (79), thus enabling the assignment of the absolute configura-
Scheme 24.
The spectroscopic properties of the synthetic saudin were
identical to those reported for the natural product, and as was the
melting point (mp 204e206 ꢁC).1,2 However, the optical rotation,
tion of natural (ꢀ)-Saudin as that depicted in Fig. 1 and Scheme 25.
During the course of this work, novel asymmetric DielseAlder
methodology developed in our laboratory was employed. Basic
studies of the effect of Lewis acid promoters on the stereochemistry
of the Claisen rearrangement were undertaken resulting in the
novel application of TiCl4, a bidentate chelating promoter, to con-
trol the facial selectivity in the key Claisen rearrangement step that
established the relative stereochemistry of the 1,3-disposed qua-
ternary centers present in Saudin.
had opposite sign (½a D22
þ14; c 0.460, CHCl3) to that of natural
ꢂ
(ꢀ)-Saudin (1) confirming that the synthetic material was
(þ)-Saudin (1). The absolute configuration of natural (ꢀ)-saudin (1)
can then be assigned as shown in Fig. 1 and Scheme 25.
We then applied the above described sequence, beginning with
R-(þ)-a-methyl benzyl amine as chiral auxiliary, to achieve the first

9796
R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
4. Experimental section
Buffalo or the nation mass spectrometry facility at the Department
of Chemistry University of California, Riverside. Ionization tech-
niques consisted of electron impact (EI) and chemical ionization
(CI). Optical rotation values were measured on a PerkineElmer-241
polarimeter. Samples were inserted into a cell with a path length of
1 dm. Melting points were determined using a ThomaseHoover
capillary melting point apparatus and are uncorrected. Elemental
analyses were obtained from Galbraith Laboratories. X-ray struc-
tural determinations were performed using an EnrafeNonius CAD4
diffractometer with calculations performed with the Molecular
Structures Corporation TEXAN crystallographic software package.
4.1. General methods
All non-aqueous reactions were conducted in flame or oven-
dried glassware under an argon atmosphere and were stirred
magnetically unless otherwise noted. Air-sensitive reagents and
solutions were transferred via syringe (unless noted otherwise) and
were introduced to the apparatus through rubber septa. Solids
were introduced under a positive pressure of argon. Temperatures,
other than rt, refer to bath temperatures unless otherwise in-
dicated. All distillations were performed under an argon atmo-
sphere or at reduced pressure attained by either a water aspirator
(15e30 mmHg) or an oil pump (<1 mmHg).
4.2. Synthesis and characterization
The phrase ‘concentrated in vacuo’ refers to removal of solvents
4.2.1. 4-Keto-3-methyl-2-penten-1-ol (8)37. To
a suspension of
€
by means of a Buchi rotary-evaporator attached to a water aspirator
mercuric oxide (red) (2.5 g, 12 mmol) in water (250 mL) was added
sulfuric acid (w2 mL). The mixture was heated to 60 ꢁC and then
commercially available trans-3-methyl-2-pentene-4-yn-1-ol (7)
(22 g, 0.23 mol) was added dropwise over 20 min. The resulting
mixture was stirred at 60 ꢁC for 1 h, then cooled to ambient tem-
perature. The mixture was vacuum filtered through a pad of Celite,
which was washed thoroughly with methylene chloride, and then
the organic layer was separated from the biphasic filtrate. The
aqueous layer was then extracted with methylene chloride
(2ꢃ150 mL). The organic layers were combined, washed with brine
(200 mL), dried over sodium sulfate, and concentrated in vacuo.
Chromatography (1:1 ether/hexane) gave 16.5 g (63%) of keto al-
(15e30 mmHg) followed by pumping to constant weight
(<1 mmHg).
Liquid chromatography was performed using forced flow (flash
chromatography) of the indicated solvent system on EM Reagents
silica gel 60 (230e400) mesh. Acid sensitive compounds were
chromatographed on EM Reagents silica gel 60 (230e400) mesh,
which had been deactivated by stirring with 5% triethylamine/hex-
anes then equilibrated in the flash columnwith the indicated solvent
system. The Waters Prep 500 system equipped with a refractive
index detector was employed for preparative scale separations.
Analytical thin layer chromatography (TLC) was performed us-
ing EM silica gel 60 F-254 pre-coated glass plates (0.25 mm). Vi-
sualization was effected by either short-wave UV illumination, or
by dipping into a solution of ceric ammonium molybdate (0.2 g
Ce(SO4)2, 4.8 g (NH4)6Mo7O24,10 mL concd H2SO4, 90 mL H2O) or p-
anisaldehyde (0.5 mL p-anisaldehyde, 0.5 mL concd H2SO4, 9 mL
95% EtOH, 2 drops HOAc) followed by heating on a hot plate.
Reagent grade solvents were used without purification for all
extractions and workup procedures. Deionized water was used for
all aqueous reactions and for the preparation of all aqueous solu-
tions. Reaction solvents and reagents were dried and purified
according to published literature procedures by distillation under
argon or vacuum from the appropriate drying agent: Distilled from
sodium/benzophenone ketyl: tetrahydrofuran, diethyl ether. Dis-
tilled from calcium hydride: hexamethylphosphoramide, methy-
lene chloride, toluene, triethylamine. Distilled from phosphorous
pentoxide/trifluoromethanesulfonic anhydride. Recrystallized from
ethanol: triphenylphosphine, 2,6-di-tert-butyl-4-methylphenol
(BHT). Other reagents and solvents were used as received.
Proton and carbon nuclear magnetic resonance (NMR) spectra
were obtained on a General Electric/Nicolet QE-300 (300 MHz),
Bruker Avance 400 MHz or Bruker Avance 500 MHz spectrometers.
In some cases, quaternary carbons could not be observed in the 13C
spectra or peaks were insufficiently resolved resulting in fewer
carbon resonances than expected. Chemical shifts are reported in
cohol 8 as an amber liquid having 1H NMR (300 MHz, CDCl3):
(t, 1H, J¼4.7 Hz), 4.43 (d, 2H, J¼4.7 Hz), 2.56 (s (br), 1H), 2.33 (s, 3H),
d 6.70
1.74 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 200.3, 142.8, 136.7, 59.7,
25.3, 11.2; IR (film): 3600e3100 (br), 2928, 1662, 1432 cmꢀ1; EIMS:
114 (Mþ).
4.2.2. 3-Methyl-2,5-triisopropylsiloxy-1,3-butadiene (9c)38. To a so-
lution of hydroxy ketone 8 (19 g, 0.17 mol) in CH2Cl2 (1 L) was
added triethylamine (98 mL, 0.71 mol) followed by triisopropylsilyl
triflate (108 g, 0.35 mol). The reaction mixture was stirred at 25 ꢁC
for 16 h, poured into satd aq NaHCO3 (500 mL), and extracted with
CH2Cl2 (2ꢃ500 mL). The organic layer was dried over sodium sul-
fate and concentrated in vacuo. Chromatography (100% hexanes)
on silica gel deactivated with 5% triethylamine/hexanes provided
68 g (94%) of diene 16 as an oil: 1H NMR (300 MHz, CDCl3):
d 6.24 (t,
1H, J¼5.8 Hz), 4.44 (s, 1H), 4.42 (s, 2H), 4.29 (s, 1H), 1.76 (s, 3H),
1.34e1.22 (m, 3H), 1.16e1.09 (m, 39H); 13C NMR (75 MHz, CDCl3):
d
157.2, 130.5, 128.6, 90.5, 61.0, 18.1, 17.9, 13.5, 12.8, 12.0; IR (film):
2943, 2892, 2866, 1593, 1463 cmꢀ1; EIMS: 269 (MþꢀTIPS), 253
(MþꢀOTIPS).
4.2.3. (1R,4S)-2-((30R,40S)-2040-Dimethyl-10-triisopropylsiloxy-30-trii-
sopropylsiloxymethyl-cyclohexene-40-carbonyl)-4,7,7-trimethyl-2-
azabicyclo[2.2.1]heptan-3-one (13). To a solution of imide 12 (29 g,
0.13 mol) and diene 9c (68 g, 0.16 mol) in methylene chloride
(800 mL) cooled to ꢀ25 ꢁC was added titanium tetrachloride (1.0 M
in methylene chloride, 180 mL, 0.13 mol) dropwise (w17 h) via
syringe pump. Upon completion of the addition, the mixture was
stirred an additional 1 h at ꢀ20 ꢁC. Pyridine (25 mL) was added, the
mixture warmed to 25 ꢁC, and filtered through a silica gel pad
(200 g) with elution by ether, and then the filtrate was concen-
trated in vacuo. The crude mixture was first purified by flash
chromatography (1% ether/hexanes) on silica gel deactivated with
5% triethylamine/hexanes and then further purified by MPLC (1%
ether/hexane) to provide 67 g (80%) of major cycloadduct 13 as
a colorless oil and 9.3 g (11%) of minor cycloadduct 14 as an oil.
parts per million (d) downfield from tetramethylsilane and are in-
ternally referenced to the deuterated solvent. 1H NMR data are
reported as follows: chemical shift (multiplicity, coupling constant
(Hz), number of hydrogens). Multiplicities are denoted accordingly:
s (singlet), br s (broad signal), d (doublet), dd (doublet of doublets),
ddd (doublet of doublet of doublets), dt (doublet of triplets), tt
(triplet of triplets), dq (doublet of quartets), t (triplet), q (quartet), p
(pentuplet), m (multiplet). Infrared spectra (IR) were acquired on
a Shimadzu FT-IR taken neat and are reported in wavenumbers
(cmꢀ1) with polystyrene as a standard. Low resolution mass spectra
(LRMS) were obtained using either a VG-7035 spectrometer,
a HewletePackard 5970 Mass selective detector coupled to an HP
5890 gas chromatograph, or a Shimadzu LCMS-2010 mass spec-
trometer. High resolution mass spectra were obtained at the De-
partment of Chemistry at the State University of New York at
Major cycloadduct 13 had: ½a D22
ꢂ
ꢀ112 (c 1.9, CHCl3); 1H NMR
(300 MHz, CDCl3):
d
4.23 (s, 1H), 3.69 (dd, J¼10, 4.1 Hz, 1H), 3.46
(dd, J¼10, 5.1 Hz, 1H), 3.31 (s (br), 1H), 2.51 (m, 1H), 2.13 (m, 2H),

R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
9797
2.03 (m, 1H), 1.82e1.43 (m, 4H), 1.71 (s, 3H), 1.29 (s, 3H), 1.07 (m,
9.3 Hz, 1H), 2.81 (m, 2H), 2.60e1.80 (m, 10H), 1.49 (s, 3H), 1.33 (s,
3H), 1.11 (d, J¼6.5 Hz, 3H), 1.05 (d, J¼6.4 Hz, 3H); 13C NMR (75 MHz,
21H), 1.03 (s, 3H), 0.99 (m, 21H), 0.93 (s, 3H) 0.89 (s, 3H); 13C NMR
(75 MHz, CDCl3):
d
178.0, 176.7, 143.0, 109.3, 66.5, 56.8, 47.2, 44.8,
CDCl3): d 210.3, 210.0, 180.6, 179.9, 69.4, 67.2, 50.3, 47.7, 43.9, 41.2,
30.8, 29.1, 27.0, 26.5, 18.8, 18.5, 18.1, 18.0, 17.8, 16.8, 13.2, 11.9, 9.9; IR
(film): 2943, 2866, 1746, 1681, 1463 cmꢀ1; FAB MS: 648 (Mþ). Anal.
Calcd for C37H69NO4Si2: C, 68.56; H, 10.73. Found: C, 68.18; H, 10.96.
36.4, 36.1, 31.1, 31.0, 22.7, 22.6,12.6,10.9; IR (film): 2971, 2934, 2875,
1769, 1715, 1486, 1453 cmꢀ1; EIMS: 182 (Mþ).
Minor cycloadduct 14 had: ½a D22
ꢂ
þ3.4 (c 16, CHCl3); 1H NMR
4.2.7. (1R,4S)-2-((30R,40S)-2040-Dimethyl-30-triisopropylsilox-
ymethylcyclohex-20-ene-10-one-40-carbonyl)-4,7,7-trimethyl-2-
azabicyclo[2.2.1]heptan-3-one (18). To a solution of enol ether 13
(63 g, 0.097 mol) in methylene chloride (60 mL) and methanol
(600 mL) was added NaHCO3 (82 g, 0.97 mol), followed by phe-
nylselenenyl bromide (48 g, 0.20 mol). The resulting mixture was
stirred at 25 ꢁC for 3 h. The reaction mixture was concentrated to
remove methanol, diluted with methylene chloride (700 mL) and
poured into H2O (900 mL). The layers were separated and the
aqueous layer was extracted with methylene chloride (2ꢃ500 mL).
The organic layers were combined, dried over sodium sulfate, and
concentrated in vacuo. Chromatography (elution by 8:1 hexane/
(300 MHz, CDCl3):
d
4.46 (s, 1H), 3.83 (dd, J¼10.2, 3.5 Hz, 1H), 3.62
(dd, J¼10.2, 4.2 Hz, 1H), 3.29 (s (br), 1H), 2.50 (m, 1H), 2.11 (m, 2H),
1.98 (m, 2H), 1.83e1.50 (m, 3H), 1.71 (s, 3H), 1.17 (s, 3H), 1.07 (m,
21H), 1.03 (s, 3H), 0.99 (m, 21H), 0.91 (s, 3H), 0.88 (s, 3H). 13C NMR
(75 MHz, CDCl3):
d
¼177.0, 176.8, 143.2, 108.3, 65.7, 64.6, 56.6, 46.4,
46.3, 45.7, 30.1, 29.4, 27.0, 26.9, 18.9, 18.1, 17.9, 16.3, 13.3, 11.9, 9.8; IR
(film): 2943, 2892, 2866, 2724, 1746, 1678, 1463 cmꢀ1; EIMS: 495
(Mþꢀchiral auxiliary), 460 (MþꢀCH2OTIPS).
4.2.4. (1S,5R,6R) and (1S,5S,6R)-2,5-Dimethyl-4,9-dioxo-8-
oxabicyclo[4.3.0]nonane (16). To
a solution of enol ether 13
(0.29 g, 0.45 mmol) in acetonitrile (5 mL) at rt was added hydro-
fluoric acid (48%, w0.5 mL). The reaction mixture was capped and
stirred for 3 h. At this time, 10% sodium bicarbonate (10 mL) was
added, and extracted with methylene chloride (3ꢃ10 mL). The
combined organic layers were dried over sodium sulfate and con-
centrated in vacuo. Chromatography (1:1 ether/hexanes) afforded
70 mg (85%) of keto lactones (5R)-16 and (5S)-16 in w1:1 mixture
ether) provided 32 g (68%) of enone 18 as an oil having: ½a D22
ꢀ66.0
ꢂ
(c 15.7, CHCl3); 1H NMR (300 MHz, CDCl3):
d
¼4.16 (dd, J¼10, 8.7 Hz,
1H), 4.06 (d, J¼1 Hz, 1H), 3.92 (dd, J¼10, 2.8 Hz, 1H), 3.16 (m, 2H),
2.42 (m, 2H), 2.04 (m, 1H), 1.96 (s, 3H), 1.91e1.52 (m, 3H), 1.36 (s,
3H), 1.07 (s, 24H), 0.96 (s, 3H), 0.93 (s, 3H); 13C NMR (75 MHz,
CDCl3):
d
¼203.7, 177.4, 176.2, 67.6, 64.8, 57.0, 56.2, 47.2, 47.0, 33.6,
31.1, 29.7, 29.1, 26.4, 21.5, 18.7, 18.1, 17.9, 17.7, 11.8, 9.7; IR (film) 2943,
of epimers as a colorless oil having ½a D22
ꢂ
þ90 (c 5.2, CHCl3); 1H NMR
2866, 1739, 1717, 1676, 1462 cmꢀ1; EIMS: 489 (Mþ), 446 (Mþꢀ Pr).
i
(300 MHz, CDCl3):
d
4.50 (dd, J¼10, 5.5 Hz, 1H), 4.36 (t, J¼9.3 Hz,
This material was used as obtained in the next transformation.
1H), 4.15 (dd, J¼10, 1.9 Hz, 1H), 3.74 (t, J¼9.3 Hz, 1H), 2.81 (m, 2H),
2.60e1.80 (m, 10H), 1.49 (s, 3H), 1.33 (s, 3H), 1.11 (d, J¼6.5 Hz, 3H),
4.2.8. (1S)-1,5-Dimethyl-4,9-dioxo-8-oxabicyclo[4.3.0]non-5-ene
(19). To a solution of enone 18 (32 g, 66 mmol) in tetrahydrofuran
(300 mL) was added tetra-n-butylammonium fluoride (1.0 M in
THF, 69 mL, 69 mmol) The resulting solution was stirred at 25 ꢁC for
16 h. The reaction mixture was poured into 1 M hydrochloric acid
(500 mL) and extracted with methylene chloride (3ꢃ400 mL). The
organic layers were combined, dried over sodium sulfate, and
concentrated in vacuo. Chromatography (elution by 2:1 hexane/
ethyl acetate) provided 11 g (92%) of enone lactone 19 as a solid.
Enone 19 was further purified by recrystallization from toluene
1.05 (d, J¼6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 210.2, 210.0,
180.6, 180.0, 69.4, 67.1, 50.2, 47.6, 43.9, 42.0, 41.4, 41.2, 36.3, 36.1,
31.1, 30.9, 22.7, 22.6, 12.6, 10.8; IR (film): 2971, 2934, 2875, 1770,
1716, 1486, 1455 cmꢀ1; EIMS: 182 (Mþ).
4.2.5. (1R,4S)-2-((20R,30R,40S)-2040-Dimethyl-30-triisopropylsilox-
ymethyl cyclohexanone-40-carbonyl)-4,7,7-trimethyl-2-azabicyclo
[2.2.1]heptan-3-one (15). To a solution of enol ether 13 (0.24 g,
0.37 mmol) in tetrahydrofuran (4 mL) at rt was added tetrabuty-
lammonium fluoride (1 M in THF, 0.37 mL, 0.37 mmol). The re-
action mixture was stirred for 15 min before being quenched with
satd NH4Cl solution and extracted with CH2Cl2 (3ꢃ10 mL). The
combined organic layers were dried over sodium sulfate and con-
centrated in vacuo. Chromatography (4:1 hexanes/ether) afforded
0.14 g (80%) of ketone 15 as a crystalline solid. Ketone 15 could be
further purified by recrystallization from heptane and had: mp
affording 19 as a white solid with mp 97e98 ꢁC and having ½a D22
ꢂ
þ186 (c 1.61, CHCl3); 1H NMR (300 MHz, CDCl3):
d 5.01 (s, 2H), 2.60
(m, 2H), 2.24 (ddd, J¼13.2, 5, 2.2 Hz, 1H), 2.1 (m, 1H), 1.76 (s, 3H),
1.50 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 196.5, 178.3, 154.5, 128.8,
67.2, 41.3, 32.4, 29.5, 21.2, 10.7; IR (film): 2975, 2936, 1780, 1712,
1672, 1450 cmꢀ1; EIMS: 180 (Mþ); Anal. Calcd for C10H12O3: C,
66.65; H, 6.71. Found: C, 66.93; H, 6.94.
79e81 ꢁC; ½a 2D2
ꢂ
ꢀ45 (c 5.8, CHCl3); 1H NMR (300 MHz, CDCl3):
d
4.35 (s, 1H), 3.81 (dd, J¼11, 4 Hz, 1H), 3.41 (d J¼11 Hz, 1H,), 3.21 (s
4.2.9. (R)-(ꢀ)-4-Hydroxy-2-methyl-3-[10(100-naphthyl)ethylamino]-
(br), 1H), 2.94 (td, J¼13, 8 Hz, 1H), 2.66 (m, 1H), 2.38 (m, 2H), 2.00
butenoic acid
with R-(þ)-
g-lactone (20). A 250-mL pressure bottle, charged
-naphthyl ethyl amine (27.1 g, 0.158 mol), a-methyl-
(m, 1H), 1.81 (m, 2H), 1.58 (m, 5H), 1.20e1.00 (m, 27H), 0.95 (s, 3H),
a
0.92 (s, 3H); 13C NMR (75 MHz, CDCl3):
d
209.6, 176.2, 175.7, 65.8,
tetronic acid (18.0 g, 0.158 mol), and toluene (50 mL), was sealed
and heated to 150 ꢁC. After 40 h, the reaction mixture was cooled,
unsealed and diluted with CH2Cl2 (2 L) and filtered through
Buchner funnel to remove some undissolved solid. The filtrate was
washed with satd. aq NaHCO3 (2ꢃ200 mL), H2O (100 mL) and brine
(100 mL), dried over Na2SO4, and concentrated in vacuo to afford
the crude yellowish solid. The crude solid was suspended in Et2O
(100 mL), filtered through a Buchner funnel, rinsed with Et2O
(3ꢃ50 mL), and concentrated in vacuo to afford 34.0 g (90%) of
product 20 as a white crystalline solid. An analytical sample had:
61.3, 56.2, 47.4, 46.3, 44.8, 39.9, 36.2, 31.5, 30.0, 26.0, 18.2, 17.7, 17.3,
17.1, 11.4, 11.2, 9.1; IR (film): 2963, 2943, 2867, 1743, 1716, 1674,
i
1458 cmꢀ1; EIMS: 448 (Mþꢀ Pr).
4.2.6. (1R,5R,6S) and (1R,5S,6S)-2,5-Dimethyl-4,9-dioxo-8-
oxabicyclo[4.3.0]nonane (17). To
a solution of enol ether 14
(97 mg, 0.15 mmol) in acetonitrile (3 mL) at rt was added hydro-
fluoric acid (48%, w0.3 mL). The reaction mixture was capped and
stirred for 24 h. At this time the mixture was quenched with 10%
sodium bicarbonate (15 mL), and extracted with methylene chlo-
ride (3ꢃ8 mL). The combined organic layers were dried over so-
dium sulfate and concentrated in vacuo. Chromatography (1:1
ether/hexanes) afforded 22 mg (81%) of w1:1 mixture of keto lac-
½
a 2D2
ꢂ
ꢀ196 (c 1.18, 1:1 CH3OH/CHCl3); 1H NMR (1:1 CD3OD/CDCl3):
d
7.78 (d, J¼8.4 Hz, 1H), 7.67 (d, J¼7.9 Hz, 1H), 7.56 (d, J¼7.3 Hz, 1H),
7.36e7.20 (m, 4H), 5.10 (q, J¼7.8 Hz, 1H), 4.42 (d, J¼15.3 Hz, 1H),
4.29 (s, 1H), 3.96 (d, J¼15.3 Hz, 1H), 1.45 (d, J¼7.8 Hz, 6H); 13C NMR
tone epimers (5S)-17 and (5R)-17 as a colorless oil that had: ½a D22
ꢂ
(1:1 CD3OD/CDCl3): d 178.2, 163.5, 139.0, 133.8, 129.6, 128.8, 127.8,
ꢀ96.9 (c 1.96, CHCl3); 1H NMR (300 MHz, CDCl3):
d
4.50 (dd, J¼10,
126.2, 125.5, 125.3, 121.7, 121.6, 88.6, 65.9, 49.8, 22.5, 6.0; IR (CHCl3):
5.5 Hz 1H), 4.36 (t, J¼9.3 Hz, 1H), 4.15 (dd, J¼10, 1.9 Hz, 1H), 3.74 (t,
3374, 3017, 2944, 2833, 1635, 1448 cmꢀ1; EIMS: 267 (Mþ); HRMS

9798
R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
calcd for C17H17NO2: m/z 267.1259. Found: 267.1237. Crude 20 was
used without further purification.
suspension of allylic alcohols 23 (0.700 g, 3.85 mmol) and finely
ground NaH2PO4 (1.60 g, 11.0 mmol) in CH2Cl2 (20 mL) was added
solid 80% m-CPBA (1.24 g, 5.77 mmol) portionwise in small por-
tions. The mixture was stirred at 0 ꢁC for 10 h before quenched with
satd aq Na2S2O5 (5 mL). The aqueous layer was extracted with
CH2Cl2 (3ꢃ10 mL), and the combined organic layer was washed
with satd aq NaHCO3 (2ꢃ5 mL), H2O (5 mL) and brine (10 mL),
dried over Na2SO4, concentrated in vacuo to afford 0.543 g (71%) of
epoxy alcohols pure enough to be used for subsequent reaction
without further purification. For spectroscopic analysis, a sample of
the epoxy alcohols was purified by silica gel chromatography
(elution by 4:1 then 1:1 hexanes/EtOAc) to afford the epoxy alco-
4.2.10. (4RS,8S)-Dimethyl-1,5-dioxo-(9S)-hydroxy-2-oxabicyclo
[4.3.0]nonane (22). To a solution of ZnCl2 (4.24 g, 31.1 mmol) in THF
(50 mL) were added TMSCl (20.0 mL, 156 mmol) and lactone 20
(8.30 g, 31.1 mmol). The mixture was cooled to ꢀ78 ꢁC, and a solu-
tion of ethyl vinyl ketone (5.59 g, 66.5 mmol) in THF (10 mL) was
added dropwise. The reaction mixture was stirred at ꢀ78 ꢁC for
20 h, then the reaction was quenched by addition of 2 N HCl (5 mL)
at ꢀ78 ꢁC. The reaction mixture was allowed to warm to rt and
continue to stir for 2 h. The aqueous layer was extracted with Et2O
(3ꢃ10 mL), and the combined organic layer was washed with satd
aq NaHCO3 (10 mL), H2O (10 mL) and brine (10 mL), dried over
Na2SO4, concentrated in vacuo, and purified by chromatography by
silica gel column (elution by 9:1 then 4:1 hexanes/EtOAc) to afford
4.52 g (73%, 60% ee) of pure Michael adduct 21 having 1H NMR:
hols having 1H NMR:
d
4.26 (s, 2H), 3.80 (dd, J¼10.0 Hz, 5.6 Hz, 1H),
1.84e1.67 (m, 2H), 1.52e1.18 (m, 2H), 1.47 (s, 3H), 1.34 (s, 3H); 13C
NMR:
d 179.3, 97.3, 76.2, 71.2, 64.7, 37.3, 28.7, 24.6, 18.0, 16.1; IR
(CHCl3): 2940, 1777, 1379 cmꢀ1; EIMS: 198 (Mþ). To a stirring sus-
ꢀ
pension of freshly activated molecular sieves 3 A (2.2 g) and the
d
4.69 (d, J¼16.9 Hz, 1H), 4.58 (d, J¼16.9 Hz, 1H), 2.48 (t, J¼7.2 Hz,
epoxy alcohols (0.512 g, 2.59 mmol) in CH2Cl2 (20 mL), was added
finely ground PDC31 (1.54 g, 4.09 mmol). The reaction mixture was
stirred at rt for 2 h when TLC analysis (silica gel, 1:1 hexanes/EtOAc)
showed the absence of the starting material. Celite (1.3 g) was
added and the reaction mixture was stirred for another 20 min,
then filtered through a column of silica gel, eluted with Et2O and
concentrated in vacuo to afford 0.468 g (92%) of pure epoxy ketone
2H), 2.35 (q, J¼7.3 Hz, 2H), 1.95 (q, J¼7.2 Hz, 2H), 1.25 (s, 3H), 0.95 (t,
J¼7.3 Hz, 3H); IR (CHCl3): 2978, 2938, 1803, 1757, 1713, 1454 cmꢀ1
;
EIMS: 198 (Mþ). Diketo lactone 21 (3.30 g, 16.7 mmol) and (S)-
proline (0.115 g, 1.00 mmol) were stirred in DMF (20 mL) at rt for
48 h. The brown-colored reaction mixture was filtered and the fil-
trate was diluted with H2O (50 mL) and EtOAc (100 mL). The
aqueous layer was extracted with EtOAc (3ꢃ50 mL), and the com-
bined organic layer was washed with H2O (2ꢃ20 mL) and brine
(10 mL), dried over Na2SO4, concentrated in vacuo, and chromato-
graphed by silica gel column (4:1 then 1:1 hexanes/EtOAc) to afford
5 as white crystals ½a D22
ꢂ
þ26.3 (c 6.85, CHCl3) 1H NMR:
d 4.33 (d,
J¼10.8 Hz, 1H), 4.28 (d, J¼10.8 Hz, 1H), 2.72 (dt, J¼14.5, 5.8 Hz, 1H),
2.25 (dt, J¼14.5, 3.2 Hz, 1H), 2.05e1.99 (m, 2H), 1.52 (s, 3H), 1.42 (s,
3H); 13C NMR:
d 204.3, 177.7, 74.6, 64.0, 62.5, 37.5, 31.9, 31.1, 18.0,
1.50 g (55%, 89% ee) of
b-hydroxy keto lactone 22 and 1.50 g (45%)
12.1; IR (CHCl3): 2937, 2834, 1782, 1720, 1464 cmꢀ1; EIMS (Mþ):
of unreacted starting diketo lactone 21. Lactone 22 had 1H NMR:
196; HRMS calcd for C10H12O4: m/z 196.0736. Found: 196.0748.
d
4.10 (d, J¼10.5 Hz, 1H), 4.00 (d, J¼10.5 Hz, 1H), 2.70 (q, J¼6.7 Hz,
1H), 2.59e2.52 (m, 1H), 2.44e2.32 (m, 1H), 2.18 (s, 1H), 2.05e2.02
(m, 1H), 1.88e1.82 (m, 1H), 1.49 (s, 3H), 1.16 (d, J¼6.7 Hz, 3H); 13C
4.2.13. (R)-(þ)-3-(tert-Butyldiphenylsilyloxy)-2-methylpropanol
(25)15. To a solution of 5.00 g (42.3 mmol) of (S)-(þ)-Methyl-3-
hydroxy-2-methylpropanoate (24) in dry DMF (40 mL) was added
imidazole (6.34 g, 93.1 mmol), tert-butyldiphenylchlorosilane
(12.8 g, 46.5 mmol) and a catalytic amount of DMAP (0.129 g,
1.06 mmol). The reaction mixture was stirred for 2 h when TLC
(silica gel, 1:1 hexanes/EtOAc) showed the absence of the starting
material. The reaction mixture was diluted with EtOAc (300 mL),
the organic layer was washed with water (3ꢃ50 mL) and brine
(20 mL), dried over Na2SO4, and concentrated in vacuo to afford
15.1 g (100%) of practically pure silyloxy ester as a colorless oil. For
spectroscopic analysis, a sample of the silyloxy ester was prepared
NMR:
d 207.8, 179.9, 82.7, 73.4, 49.4, 47.1, 35.9, 30.9, 13.8, 7.0; IR
(CHCl3): 3413, 2977, 2941, 1779, 1720 cmꢀ1; EIMS: 198 (Mþ); HRMS
calcd for C10H14O4: m/z 198.0892. Found: 198.0889.
4.2.11. (4S,8S)-Dimethyl-1,5-dioxo-2-oxabicyclo[4.3.0]non-4(9)-ene
(19)26b. A solution of
b-hydroxy keto lactone 22 (0.430 g,
2.17 mmol) in toluene (50 mL) was refluxed for 2 h with azeotropic
water removal via a DeaneStark trap. Et2O (100 mL) was added to
the cooled solution which was washed with satd aq NaHCO3
(2ꢃ20 mL), and brine (10 mL), dried over Na2SO4, and concentrated
in vacuo to afford 0.391 g (100%, 89% ee) of enone lactone 19 as
a white solid after recrystallization from toluene having mp
by silica gel column chromatography (9:1 hexanes/EtOAc): ½a D22
ꢂ
þ13.1 (c 4.58, CHCl3); 1H NMR:
d 7.78e7.69 (m, 4H), 7.47e7.41 (m,
95e96 ꢁC and ½a 2D2
ꢂ
þ181 (c 6.1, CHCl3) or 94% ee; 1H NMR:
d
5.00 (s,
6H), 3.91e3.68 (m, 2H), 3.72 (s, 3H), 2.80e2.73 (m, 1H), 1.20 (d,
2H), 2.70e2.53 (m, 2H), 2.27e2.05 (m, 2H), 1.75 (s, 3H), 1.52 (s, 3H);
J¼6.9 Hz, 3H), 1.08 (s, 9H); 13C NMR:
d 175.4, 135.6, 133.5, 129.7,
IR (CHCl3): 2975, 2936,1780,1712,1672,1450 cmꢀ1; EIMS: 180 (Mþ).
127.7, 65.9, 51.5, 42.4, 26.7, 19.2, 13.5; IR (neat): 3071, 3049, 2931,
2857,1960,1891,1742,1428 cmꢀ1; EIMS: 325 (MꢀOCH3), 299 (Mꢀt-
Bu). To a cold (ꢀ78 ꢁC) solution of silyloxy ester (15.0 g, 42.1 mmol)
in Et2O (160 mL) was added dropwise 1 M DIBAl-H in hexanes
(84 mL, 84 mmol). The reaction mixture was warmed to rt and
stirred for 10 h when no starting material was left by TLC (silica gel,
4:1 hexanes/EtOAc). The clear solution was cooled to 0 ꢁC and
quenched by dropwise addition of MeOH (25 mL) followed by ad-
dition of a saturated aqueous solution of Rochelle0s salt (sodium
potassium tartrate) (80 mL). The reaction mixture was allowed to
warm to rt and stirred vigorously until two homogeneous layers
resulted. The separated aqueous layer was extracted with Et2O
(2ꢃ50 mL), the combined organic layer was washed with brine
(30 mL), dried over Na2SO4, concentrated in vacuo and chromato-
graphed (silica gel, 9:1 hexanes/EtOAc) to afford 13.8 g (100%) of
4.2.12. (4R,8S)-Dimethyl-4(9)-epoxy-1,5-oxo-2-oxabicyclo[4.3.0]
nonane (5). To a cold (0 ꢁC) solution of enone lactone 19 (1.50 g,
8.33 mmol) in EtOH (100 mL) was added NaBH4 (0.315 g,
8.33 mmol) with stirring. The resulting suspension was allowed to
warm to rt and stirred for 20 h when TLC showed almost complete
consumption of starting material 19. The reaction was quenched by
addition of 1 N HCl (15 mL) dropwise at 0 ꢁC. The reaction mixture
was concentrated to remove EtOH as much as possible and the
residue was diluted with CH2Cl2 (50 mL), washed with satd aq
NaHCO3 (10 mL), H2O (10 mL) and brine (10 mL), dried over Na2SO4,
concentrated in vacuo, and purified by silica gel chromatography
(elution by 4:1 then 1:1 hexanes/EtOAc) to afford 1.13 g (75%) of
allylic alcohols 23 having 1H NMR:
d
4.77 (d, J¼13.4 Hz, 1H), 4.72 (d,
J¼13.4 Hz, 1H), 4.07 (t, J¼7.5 Hz, 1H), 2.75 (s, br, 1H), 2.17e2.10 (m,
pure alcohol 25 as a colorless oil: ½a D22
ꢂ
þ7.1 (c 3.49, CHCl3); 1H NMR
1H), 1.85e1.80(m, 1H), 1.80e1.52 (m, 2H), 1.66 (s, 3H), 1.31 (s, 3H);
(400 MHz):
d 7.75e7.73 m, 4H), 7.50e7.42 (m, 6H), 3.80e3.63 (m,
13C NMR:
d
180.6, 132.4, 131.5, 70.3, 68.1, 41.0, 29þ.0, 28.8, 21.9, 14.7;
4H), 2.76 ((t, J¼5.0 Hz 1H), 2.07e2.01 (m, 1H), 1.12 (s, 9H), 0.89 (d,
IR (CHCl3): 3468, 2974, 1771 cmꢀ1; EIMS: 182 (M ). To a cold (0 ꢁC)
J¼6.9 Hz, 3H); 13C NMR:
d 135.6, 133.3, 129.8, 127.8, 68.5, 67.4, 37.4,

R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
9799
26.9, 19.2, 13.2; IR (neat): 3358 (br), 3071, 3049, 2998, 2930, 2858,
7.51e7.43 (m, 6H), 5.71e5.69 (m, 2H), 4.12 (d, J¼4.9 Hz, 2H),
3.69e3.57 (m, 2H), 2.54e2.46 (m, 1H), 1.16 (s, 9H), 1.13 (d, J¼6.8 Hz,
1958, 1888, 1824, 1772 cmꢀ1
;
EIMS: 271 (Mꢀt-Bu), 269
(MꢀCH3CHCH2OH).
3H); 13C NMR:
d 135.7, 135.3, 134.0, 129.7, 128.9, 127.7, 68.6, 63.7,
39.0, 27.0, 19.4, 16.5; IR (neat): 3351 (br), 3071, 3049, 2959, 2930,
2857, 1958, 1888, 1824, 1427 cmꢀ1; EIMS: 355 (Mþþ1), 297 (Mþꢀt-
Bu). HRMS calcd for C18H21O2Si: m/z 297.1311. Found: 297.1283.
4.2.14. (R)-(E)-(þ)-Ethyl-5-(tert-butyldiphenylsilyloxy)-4-methyl-2-
pentenoate (26). To a cold (ꢀ78 ꢁC) solution of oxalyl chloride
(7.0 mL, 10.3, 81.5 mmol) in CH2Cl2 (200 mL) was added dropwise
a solution of DMSO (11.6 mL, 163 mmol) in CH2Cl2 (50 mL). The
reaction mixture was stirred for another 15 min at ꢀ78 ꢁC after
addition and then a solution of alcohol 26 (13.8 g, 38.7 mmol) in
CH2Cl2 (100 mL) was added dropwise with stirring. After stirring
for 1 h at ꢀ78 ꢁC, Et3N (27.3 mL, 195.6 mmol) was added dropwise
and stirring was continued for 15 min at this temperature. The
reaction mixture was allowed to warm to 0 ꢁC for ca. 30 min with
stirring and diluted with satd aq NH4Cl (50 mL). The aqueous layer
was extracted with CH2Cl2 (3ꢃ50 mL), the combined organic layer
was washed with satd aq NH4Cl (2ꢃ100 mL), H2O (50 mL) and brine
(50 mL), dried over Na2SO4, and concentrated in vacuo to afford
13.6 g (100%) of practically pure aldehyde (S)-3-(tert-butyldiphe-
4.2.16. (R)-(E)-5-(tert-Butyldiphenylsilyloxy)-4-methyl-2-pentenyl
trifluoromethane sulfonate (6). To a solution of allylic alcohol 27
(500 mg, 1.41 mmol) in Et2O (1.0 mL) was added 1.43 M solution of
t-BuLi in hexanes (0.986 mL, 1.41 mmol) at ꢀ78 ꢁC. After stirring for
10 min, the reaction mixture was transferred by cannula to a solu-
tion of Tf2O (0.237 mL, 1.41 mmol) in Et2O (0.5 mL). The reaction
mixture was stirred at ꢀ78 ꢁC for 30 min, and used immediately for
the alkylation reaction.
4.2.17. 4-tert-Butyldiphenylsiloxy-1-butyne39. To a solution of 8.4 g
(0.12 mol) of 3-butyn-1-ol (28) in 200 mL of anhyd THF was added
16 g (0.24 mol) of imidazole and 33 g (0.12 mol) tert-butyldiphe-
nylsilyl chloride. The reaction mixture was stirred at rt for 18 h, and
then concentrated in vacuo. The crude residue was partitioned
between ether and water and the phases were separated. The
aqueous phase was then further extracted twice with 200 mL
portions of ether. The combined organic phases were dried over
Na2SO4 and the solvent removed in vacuo to provide 38 g (>99%) of
alkynol silyl ether as an oil which was used without further puri-
nylsilyloxy)-2-methylpropanal15 having 1H NMR:
d 9.80 (d,
J¼1.3 Hz, 1H), 7.77e7.67 (m, 4H), 7.47e7.39 (m, 6H), 3.95e3.85 (m,
2H), 2.66e2.58 (m, 1H), 1.13 (d, J¼6.9 Hz, 3H), 1.08 (s, 9H). 13C NMR:
d
204.5, 135.6, 133.2, 129.8, 127.8, 64.1, 48.8, 26.8, 19.2, 10.3. IR
(neat): 2958, 2931, 2858, 2712, 1961, 1890, 1824, 1737, 1427 cmꢀ1
.
EIMS: 269 (Mꢀt-Bu), 239 (MꢀOCH2CH(CH3)CHO). The aldehyde
was immediately used in the next step without further purification.
To a cold (0 ꢁC) solution of ethyl diisopropylphosphonoacetate
(14.7 g, 54.1 mmol) in THF (100 mL) under argon was added a fil-
tered solution of t-BuOK (5.62 g, 50.1 mmol) in THF (300 mL). After
stirring for 1 h at rt, the reaction mixture was cooled to ꢀ78 ꢁC. To
the stirred solution, crude (S)-3-(tert-butyldiphenylsilyloxy)-2-
methylpropanal (27.9 g, 134 mmol) in THF (100 mL) was added
dropwise. The reaction mixture was slowly warmed to rt, stirred for
7 h at rt, and quenched with satd aq NH4Cl (80 mL) and H2O
(50 mL). The separated aqueous layer was extracted with Et2O
(2ꢃ100 mL) and the combined organic layer was washed with H2O
(100 mL) and brine (100 mL), dried over Na2SO4, and concentrated
in vacuo. The residue was purified by chromatography (silica gel,
fication: 1H NMR (300 MHz, CDCl3):
d 7.71 (m, 4H), 7.44 (m, 6H),
3.81 (t, J¼7.0 Hz, 2H), 2.48 (dt, J1¼7.0, J2¼2.5 Hz, 2H), 1.97 (t,
J¼2.6 Hz, 1H), 1.09 (s, 9H); 13C NMR (75 MHz, CDCl3):
d 135.3, 133.5,
129.3, 127.3, 81.1, 68.9, 62.2, 26.6, 22.3, 18.9; IR (film): 3307, 3071,
3050, 2958, 2931, 2880, 2857, 2121, 1960, 1892, 1822, 1589, 1472,
1427 cmꢀ1; EIMS: 251 (Mþꢀt-Bu), 221 (MþꢀPh).
4.2.18. 5-tert-Butyldiphenylsilyloxy-2-pentyn-1-ol (29)40. A solution
of 38 g (0.12 mol) of 4-tert-butyldiphenylsiloxy-1-butyne in 800 mL
of anhyd THF was cooled toꢀ78 ꢁC and 110 mL of a 1.48 M solution of
n-butyllithium in hexane (0.16 mol) was added dropwise. The
resulting solution was stirred at ꢀ78 ꢁC for 1 h, warmed to ambient
temperature over 2.5 h, and then recooled to ꢀ78 ꢁC. A 9.3 g
(0.31 mol) sample of solid dry para-formaldehyde was added in one
portion and the resulting suspensionwas allowed to warm to rt over
16 h. The mixture was concentrated in vacuo and then partitioned
between 400 mL of ether and 400 mL of water. The phases were
separated and the aqueous phase was further extracted twice with
300 mL portions of ether. The combined organic phases were dried
over Na2SO4 and concentrated in vacuo. Chromatography (with
elution by 4:1 hexane/ether) provided 36 g (85%) of 5-tert-Butyldi-
phenylsiloxy-2-pentyn-1-ol (29) as an oil: 1H NMR (300 MHz,
9:1 then 4:1 hexanes/EtOAc) to afford 30.6 g (82%) of trans-a,b-
unsaturated ester 26 (trans/cis >95:5) as a pale yellow oil having:
½
a 2D2
ꢂ
þ13.5 (c 2.44, CHCl3); 1H NMR:
d 7.77e7.68 (m, 4H), 7.46e7.39
(m, 6H), 7.01 (dd, J¼15.8, 7.2 Hz,1H), 5.88 (d, J¼15.8 Hz, 1H), 4.23 (q,
J¼7.0 Hz, 2H), 3.62 (d, J¼6.4 Hz, 2H), 2.61e2.55 (m, 1H), 1.32 (t,
J¼7.0 Hz, 3H), 1.09 (s, 12H); 13C NMR:
d 166.6, 151.3, 135.6, 133.6,
129.7, 127.7, 121.2, 67.6, 60.1, 39.1, 26.9, 19.3, 15.6, 14.3; IR (neat):
3071, 3049, 2959, 2930, 2857, 1960, 1888, 1825, 1721, 1651,
1427 cmꢀ1; EIMS: 351 (MþꢀOEt), 339 (Mþꢀt-Bu). HRMS calcd for
C20H23O3Si: m/z 339.1416. Found: 339.1387.
CDCl3):
2.52 (m, 2H), 1.92 (s (br),1H), 1.10 (s, 9H); 13C NMR (75 MHz, CDCl3):
d 135.6, 133.6, 129.7, 127.7, 83.3, 79.6, 62.4, 51.2, 26.8, 22.9, 19.2; IR
(film): 3583e3389 (br), 3072, 3048, 2931, 1590, 1963, 1894, 1830,
1471,1428 cmꢀ1; EIMS: 281 (Mþꢀt-Bu), 251 (MþꢀPh). This material
was used as obtained for further transformations.
d
7.72 (m, 4H), 7.44 (m, 6H), 4.22 (m, 2H), 3.82 (t, J¼7 Hz, 2H),
4.2.15. (R)-(E)-(þ)-5-(tert-Butyldiphenylsilyloxy)-4-methyl-2-
penten-1-ol (27). A solution of trans-
a,
b-unsaturated ester 26
(7.6 g, 19.2 mmol) in Et2O (400 mL) was cooled to ꢀ78 ꢁC. To the
solution, 1 M DIBAL in hexanes (48 mL, 48 mmol) was added
dropwise. The reaction mixture was stirred at ꢀ78 ꢁC for 5 h until
no starting material remained by TLC (silica gel, 1:1 hexanes/
EtOAc). The clear solution was quenched by dropwise addition of
MeOH (60 mL) at ꢀ78 ꢁC followed by addition of a saturated
aqueous solution of Rochelle0s salt (sodium potassium tartrate)
(200 mL). The reaction mixture was allowed to warm to rt and stir
vigorously until two homogeneous layers resulted (ca. 2 h). The
separated aqueous layer was extracted with Et2O (2ꢃ100 mL), and
the combined organic layer was washed with brine (50 mL), dried
over Na2SO4, and concentrated in vacuo. The residue was purified
by chromatography (silica gel, elution by 4:1 then 1:1 hexanes/
EtOAc) to afford 22.0 g (93%) of allylic alcohol 27 as a colorless oil
4.2.19. 5-tert-Butyldiphenylsiloxy-2-penten-1-ol
(30)41. Ethanol
(2.4 g, 53 mmol) was added dropwise to a suspension of 1.1 g of 95%
LAH (27 mmol) in 80 mL of anhyd THF at 0 ꢁC under Ar. A solution of
8.46 g 5-tert-butyldiphenylsiloxy-2-pentyn-1-ol (25 mmol) in
50 mL of anhyd THF was then added dropwise. Upon completion of
the addition, the 0 ꢁC bath was removed and the reaction mixture
was warmed to rt then heated to reflux for 1 h. The mixture was
quenched carefully with water and NaOH, and the resulting white
aluminum salts were vacuum filtered through a sinter glass funnel.
The salts were washed repeatedly with hot ether, and the combined
filtrates were dried over Na2SO4 and concentrated in vacuo.
exhibiting ½a 2D2
ꢂ
þ4.6 (c 1.00, CHCl3); 1H NMR:
d 7.77e7.75 (m, 4H),

9800
R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
Chromatography (with elution by 3:1 hexanes/ether) provided
resulting blue colored solution was stirred at rt for 8 h and cooled to
ꢀ78 ꢁC. To it was added a solution of epoxy ketone 5 (33.0 mg,
0.168 mmol) in THF (0.5 mL) dropwise. Stirring was continued at
ꢀ78 ꢁC for 24 h followed by addition of HMPA (0.2 mL) and a solu-
tion of allylic triflate 6 (236 mg, 0.485 mmol, prepared in situ, see
31 above) in Et2O (1 mL) via cannula. The reaction mixture was
stirred at ꢀ78 ꢁC for 45 min and quenched with phosphate buffer
(KH2PO4/Na2HPO4, pH¼7.5) (3 mL) at ꢀ78 ꢁC. After warming to rt,
the aqueous layer was extracted with EtOAc (3ꢃ10 mL), and the
combined organic layer was washed with H2O (2ꢃ5 mL) and brine
(5 mL), dried over Na2SO4, concentrated in vacuo, and chromato-
graphed on silica gel (elution with 9:1 then 4:1 hexanes/EtOAc) to
afford 46.7 mg (52%) of O-alkylation product 33 as a colorless oil
8.2 g (96%) of 5-tetr-Butyldiphenylsiloxy-2-penten-1-ol as a color-
less oil having: 1H NMR (300 MHz, CDCl3):
d
7.68 (m, 4H), 7.40 (m,
6H), 5.68 (m, 2H), 4.08 (s(br), 2H), 3.72 (t, J¼8 Hz, 2H), 2.32 (m, 2H),
1.50 (s (br), 1H), 1.06 (s, 9H); 13C NMR (75 MHz, CDCl3):
135.6,
d
133.9, 131.1, 129.7, 129.3, 127.7, 63.6, 63.5, 35.6, 26.9, 19.3; IR (film):
3331, 3070, 3048, 2930, 2857, 1963, 1894, 1830, 1472, 1428 cmꢀ1
;
EIMS: 283 (Mþꢀt-Bu), 253 (MþꢀPh).
4.2.20. 5-tert-Butyldiphenylsiloxy-1-trifluoromethanesulfonyl-2-
pentene (31). To a solution of alcohol 30 (9.9 g, 29 mmol) in Et2O
(25 mL) cooled to ꢀ78 ꢁC was added n-BuLi (1.5 M in hexane,19 mL,
29 mmol) dropwise. The resulting solutionwas stirredfor 0.5 h, then
slowly added dropwise via cannula to neat, freshly distilled triflic
anhydride (8.2 g, 29 mmol) at ꢀ78 ꢁC. The solution was stirred at
ꢀ78 ꢁC for 0.5 h, then used immediately in subsequent reactions.
having: ½a 2D2
ꢂ
þ66.0 (c 0.90, CHCl3); 1H NMR:
7.66 (d, J¼7.6 Hz, 4H),
d
7.46e7.36 (m, 6H), 5.72e5.52 (m, 2H), 4.23e4.14 (m, 4H), 3.58e3.47
(m, 2H), 2.47e2.38 (m, 2H), 2.23e2.19 (m, 2H), 2.00e1.92 (m, 1H),
1.71 (s, 3H), 1.66e1.57 (m, 1H), 1.23 (s, 3H), 1.06 (s, 9H), 1.05 (d,
4.2.21. (4R,8S)-Dimethyl-1,5-dioxo-(9S)-hydroxy-2-oxabicyclo[4.3.0]
nonane and (4S,8S)-dimethyl-1,5-dioxo-(9S)-hydroxy-2-oxabicyclo
J¼6.8 Hz, 3H); 13C NMR:
d 179.6, 151.8, 137.0, 135.6, 133.8, 129.6,
127.6, 125.2, 111.4, 78.2, 73.6, 68.4, 68.2, 45.4, 39.0, 27.4, 26.8, 21.8,
19.3, 17.3, 16.4, 9.7; IR (neat): 3453 (br), 3071, 3048, 2931, 2858,
1769, 1673, 1589, 1471 cmꢀ1; EIMS: 534 (Mþ), 477 (Mꢀt-Bu); HRMS
(CI) calcd for C32H42O5Si: m/z 534.2796. Found: 534.2798.
[4.3.0]nonane (22). To
a solution of trimesitylborane (TMB)
(130 mg, 0.353 mmol) in THF (1 mL) was added freshly cut sodium
chips (35 mg, 1.52 mmol). The resulting blue colored solution was
stirred at rt for 8 h and cooled to ꢀ78 ꢁC. To it was added a solution
of epoxy ketone 5 (33.0 mg, 0.168 mmol) in THF (0.5 mL) dropwise.
Stirring was continued at ꢀ78 ꢁC for 3 h quenched with 1 mL of
satd aq NH4Cl at ꢀ78 ꢁC. After warming to rt, the mixture was
extracted with EtOAc (3ꢃ10 mL), and the combined organic layers
were washed with H2O (2ꢃ5 mL) and brine (5 mL), dried over
Na2SO4, concentrated in vacuo and chromatographed on silica gel
(elution by 9:1 then 4:1 hexanes/EtOAc) to afford 31.4 mg (94%) of
4.2.24. (ꢀ)-(1S)-4-((E)(40R)-50-tert-butylydiphenylsiloxy-40-methyl-
20-pentenyloxy)-2,5-dimethyl-9-oxo-8-oxabicyclo[4.3.0]nona-4,6-
diene (35). To a solution of enone 19 (0.10 g, 0.57 mmol) in tet-
rahydrofuran (2 mL) cooled to ꢀ78 ꢁC was added sodium bis-
trimethylsilylamide (1.0 M in THF, 0.57 mL, 0.57 mmol) dropwise
via syringe pump over 0.5 h. Upon completion of the addition,
hexamethylphosphoramide (HMPA) (0.50 mL) was added and the
resulting dark yellow solution was stirred at ꢀ78 ꢁC for 0.5 h. Al-
lylic triflate 6 (0.49 g, 1.0 mmol) was added via cannula as a solu-
tion in ether (1.5 mL) and the resulting solution was stirred for 1 h
at ꢀ78 ꢁC. The mixture was poured into aqueous sodium bi-
carbonate (15 mL) and extracted with ether (2ꢃ25 mL). The
combined organic layers were dried over sodium sulfate and
concentrated in vacuo. Chromatography (7:1 hexane/ether) pro-
lactone 22 as a colorless oil having: 1H NMR:
d
4.10 (d, J¼10.5 Hz,
1H), 4.00 (d, J¼10.5 Hz, 1H), 2.70 (q, J¼6.7 Hz, 1H), 2.59e2.52 (m,
1H), 2.44e2.32 (m, 1H), 2.18 (s, 1H), 2.05e2.02 (m, 1H), 1.88e1.82
(m, 1H), 1.49 (s, 3H), 1.16 (d, J¼6.7 Hz, 3H); 13C NMR:
d 207.8, 179.9,
82.7, 73.4, 49.4, 47.1, 35.9, 30.9, 13.8, 7.0; IR (CHCl3): 3413, 2977,
2941, 1779, 1720 cmꢀ1; EIMS: 198 (Mþ); HRMS calcd for C10H14O4:
m/z 198.0892. Found: 198.0889.
vided 0.23 g (77%) of allyl dienol ether 35 as an oil having: ½a D22
ꢂ
4.2.22. (4,8S)-Dimethyl-5-(dimethyl-tert-butylsilyloxy)-(9S)-hy-
droxy-1-oxo-2-oxa bicyclo[4.3.0]non-4(5)-ene (32). To a solution of
trimesitylborane (TMB) (190 mg, 0.515 mmol) in THF (2 mL) was
added freshly cut sodium chips (30 mg, 1.30 mmol). The resulting
blue colored solution was stirred at rt for 8 h and cooled to ꢀ78 ꢁC.
To it was added a solution of epoxy ketone 5 (50.0 mg, 0.255 mmol)
in THF (0.5 mL) dropwise. Stirring was continued at ꢀ78 ꢁC for 24 h
followed by addition of a solution of TBDMSCl (192 mg, 1.28 mmol)
in THF (0.5 mL). The reaction mixture was slowly warmed to
ꢀ40 ꢁC, stirred at that temperature for 3 h and quenched with
phosphate buffer (KH2PO4/Na2HPO4, pH¼7.5) (3 mL) at ꢀ40 ꢁC.
After warming to rt, the aqueous layer was extracted with EtOAc
(3ꢃ10 mL), and the combined organic layer was washed with H2O
(5 mL) and brine (5 mL), dried over Na2SO4, concentrated in vacuo,
and chromatographed by silica gel column (9:1 then 4:1 hexanes/
EtOAc) to afford 56.2 mg (71%) of pure silyl enol ether 32 as a col-
ꢀ66.5 (c¼5.6, CHCl3); 1H NMR (300 MHz, CDCl3):
d 7.67 (m, 4H),
7.42 (m, 6H), 6.50 (s, 1H), 5.74 (dd, J¼16, 6.7 Hz, 1H), 5.62 (dt, J¼16,
5.5 Hz, 1H), 4.30 (d, J¼5.5 Hz, 2H), 3.56 (m, 2H), 2.42 (m, 3H), 2.01
(m, 2H), 1.75 (s, 3H), 1.30 (s, 3H), 1.08 (s, 9H), 1.07 (d, J¼9 Hz, 3H);
13C NMR (75 MHz, CDCl3):
d 181.5, 149.8, 137.2, 135.6, 133.8, 130.1,
129.6, 129.4, 127.6, 125.5, 107.0, 69.1, 68.3, 42.6, 39.0, 28.2, 26.8,
22.6, 21.5, 19.3, 16.4, 10.5; IR (film): 3071, 3048, 2957, 2931, 2858,
1793, 1650, 1620, 1472, 1461, 1428 cmꢀ1. This material was used as
obtained in the next transformation.
4.2.25. (þ)-(1S,5R)-5-((30R,40R)-50-tert-butyldiphenylsiloxy-40-
methyl-10-penten-30-yl)-1,5-dimethyl-4,9-dioxo-8-oxabicyclo[4.3.0]
non-6-ene (36) and (þ)-(1S,5S)-5-((30S,40R)-50-tert-butyldiphenylsi-
loxy-40-methyl-10-penten-30-yl)-1,5-dimethyl-4,9-dioxo-8-oxabicyclo
[4.3.0]non-6-ene (37). A solution of dienol ether 35 (0.32 g,
0.62 mmol) in toluene (5 mL) was placed in a dry, base washed
sealed tube and heated at 125 ꢁC for 2 h. The reaction mixture
allowed to cool to ambient temperature and then concentrated in
vacuo. Chromatography on silica gel (elution with 3:1 hexane/
ether) provided 240 mg (76%) of ketones 36 and 37 as a 3:1 mixture
of diastereomeric Claisen products. The mixture could be further
purified by HPLC (85:15 hexane/ether), which provided pure
orless oil having: 1H NMR:
d
4.23 (d, J¼9.3 Hz, 1H), 4.17 (d, J¼9.3 Hz,
1H), 2.11e2.09 (m, 2H), 1.98e1.91 (m, 1H), 1.82 (s, 1H), 1.69 (s, 3H),
1.65e1.60 (m, 1H), 1.24 (s, 3H), 0.94 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H);
13C NMR:
d 179.8, 149.2, 110.9, 78.3, 73.6, 45.5, 27.4, 26.8, 25.7, 18.1,
17.4, 10.3, ꢀ3.7, ꢀ3.9; IR (CHCl3): 3596 (br), 2956, 2931, 2858, 1771,
1667, 1472 cmꢀ1; EIMS: 312 (Mþ). HRMS calcd for C16H28O4Si: m/z
312.1757. Found: 312.1742.
samples of each diastereomer. Major diastereomer (36): ½a D22
þ39.0
ꢂ
(c 2.64, CHCl3); 1H NMR (300 MHz, CDCl3):
d 7.64 (m, 4H), 7.41 (m,
4.2.23. (þ)-5-[(E)-50-tert-Butyldiphenylsilyloxy-40-methyl-20-pente-
nyloxy]-(4,8S)-dimethyl-(9S)-hydroxy-1-oxo-2-oxabicyclo[4.3.0]non-
4(5)-ene (33). To a solution of TMB (130 mg, 0.353 mmol) in THF
(1 mL) was added freshly cut sodium chips (35 mg, 1.52 mmol). The
6H), 6.74 (s, 1H), 5.56 (dt J¼16.8, 10.4 Hz, 1H,), 5.17 (dd, J¼10.6,
1.6 Hz, 1H), 4.93 (dd, J¼16.8, 1.6 Hz, 1H), 3.28 (dd, J¼10, 8 Hz, 1H),
3.16 (dd, 1H, J¼10, 8 Hz), 2.72 (dd, J¼9.7, 7.1 Hz, 1H), 2.56 (m, 1H),
2.27 (ddd, J¼18.6, 7.8, 2.3 Hz, 1H), 2.11 (m, 1H), 1.90 (m, 1H), 1.65 (m,

R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
9801
1H), 1.36 (s, 3H), 1.28 (s, 3H), 1.06 (s, 9H), 0.84 (d, J¼9 Hz, 3H); 13C
129.6, 129.4127.8, 127.6, 106.8, 69.0, 63.3, 42.6, 35.6, 28.2, 26.8, 22.6,
21.5, 19.2, 10.5; IR (film): 3117, 3070, 3048, 2931, 2858, 1793, 1649,
1620, 1472, 1460, 1445, 1428 cmꢀ1; EIMS: 445 (Mþꢀt-Bu).
This material was used as obtained in the next transformation.
NMR (75 MHz, CDCl3): d 211.2,180.5,135.6,135.5,134.7,133.5,133.4,
130.0, 129.8, 129.7, 127.7, 120.0, 67.6, 52.4, 51.2, 43.9, 35.6, 34.7, 28.0,
26.8, 26.3, 21.8, 19.2, 14.0; IR (film): 2927, 2855, 1798, 1709, 1461,
1428 cmꢀ1; EIMS: 516 (Mþ), 459 (Mþꢀt-Bu). HRMS (CI) calcd for
C32H40O4Si: m/z 516.7549. Found: 516.7555.
4.2.28. (þ)-(1S,5R)-5-((30R)-50-tert-Butyldiphenylsiloxy-10-penten-
30-yl)-1,5-dimethyl-4,9-dioxo-8-oxabicyclo[4.3.0]non-6-ene (40) and
Minor diastereomer (37): ½a D22
ꢂ
þ46.6 (c 2.36, CHCl3); 1H NMR
(300 MHz, CDCl3):
d
7.62 (m, 4H), 7.41 (m, 6H), 6.45 (s, 1H), 5.44 (dt,
(þ)-(1S,5S)-5-((30S)-50-tert-butyl
diphenylsiloxy-10-penten-30-yl)-
J¼17.2, 10.1 Hz, 1H), 5.04 (d, J¼17.2 Hz, 1H), 5.03 (d, J¼10 Hz, 1H),
3.62 (dd, J¼10, 3 Hz, 1H), 3.45 (dd, J¼10, 2.5 Hz, 1H), 2.66 (m, 2H),
2.31 (m, 1H), 2.17 (m, 1H), 1.75 (s, 3H), 1.72 (m, 2H), 1.13 (d, J¼9 Hz,
1,5-dimethyl-4,9-dioxo-8-oxabicyclo[4.3.0]non-6-ene (41). A solu-
tion of dienol ether 39 (8.9 g, 18 mmol) in toluene (15 mL) was
placed in a dry, base washed sealed tube and heated to 105 ꢁC for
2 h. The reaction mixture was allowed to cool to ambient temper-
ature, transferred to a round bottomed flask and concentrated in
vacuo. Chromatography on silica gel (elution with 4:1 hexane/
ether) provided 7.2 g (81%) of ketones 40 and 41 as approximately
a 1:1 mixture. The mixture could be further purified by HPLC (85:15
hexane/ether) to provide the pure diastereomers: (1) 40 having:
3H), 1.07 (s, 9H), 1.02 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 208.5,
181.1, 138.0, 135.7, 135.6, 134.2, 133.6, 133.5, 130.6, 129.8, 129.7,
127.8, 127.6, 118.5, 66.7, 55.7, 51.1, 44.3, 36.2, 34.3, 33.2, 26.9, 22.8,
19.2, 17.8, 14.6; IR (film):3071, 2931, 2857, 1798, 1716, 1634, 1462,
1428 cmꢀ1; EIMS: 516 (Mþ), 459 (Mþꢀt-Bu), 429 (MþꢀPh).
Lewis acid promoted Claisen rearrangements of were also
conducted using the above procedure at various temperatures
from ꢀ50 ꢁC to 125 ꢁC by addition of 35 in toluene to a solution of
the Lewis acid promoter (2e4 equiv) at the requisite temperature
or at rt followed by heating. The results are described in Table 1
above.
½
a 2D2
ꢂ
þ14.3 (c 0.7, CHCl3); 1H NMR (300 MHz, CDCl3):
d 7.64(m, 4H),
7.40 (m, 6H), 6.62 (s, 1H), 5.43 (dt, 1H, J¼16.9, 9.8 Hz), 5.07 (d, 1H,
J¼10.1 Hz), 4.98 (d, 1H, J¼16.9 Hz), 3.72 (m, 1H), 3.54 (m, 1H), 2.81
(m, 2H), 2.36 (m, 1H), 2.16 (m, 1H), 1.79 (m, 2H), 1.62 (m, 1H), 1.55 (s,
3H), 1.12 (s, 3H), 1.04 (s, 9H); 13C NMR (75 MHz, CDCl3):
d 208.7,
181.2, 137.9, 135.7, 135.6, 135.5, 133.4, 130.1, 129.8, 129.7, 129.6, 127.7,
127.6, 118.6, 61.5, 55.6, 44.6, 44.1, 34.0, 32.8, 31.1, 26.8, 22.2, 19.1,
13.5; IR (film): 3071, 2930, 2856, 1798, 1716, 1471, 1462, 1456,
1428 cmꢀ1; FDMS: 445 (Mþꢀt-Bu). HRMS calcd for C31H38O4Si: m/z
502.7280. Found: 502.7280.
4.2.26. (þ)-(1S,5S)-5-((30S,40R)-50-Hydroxy-40-methyl-10-penten-
30yl)-1,5-dimethyl-4,9-dioxo-8-oxabicyclo[4.3.0]non-6-ene hemiketal
(38). To a solution of ketone 36 (16 mg, 0.030 mmol) in 3:1 ace-
tonitrile/tetrahydrofuran (0.30 mL) at rt was added 48% hydro-
fluoric acid (w100
mL). The reaction mixture was stirred for 36 h
(2) Compound 41 having: ½a D22
ꢂ
þ30.8 (c 7.26, CHCl3); 1H NMR
before being diluted with methylene chloride (3 mL) and poured
into 10% sodium bicarbonate solution. The aqueous layer was
extracted with methylene chloride (2ꢃ5 mL) and the combined
organic extracts were dried over sodium sulfate and concentrated
in vacuo. Chromatography on silica gel (elution with 3:2 hexanes/
ether) provided 6.4 mg (77%) of hemiketal 38 as a white crystalline
solid. Hemiketal 38 could be further purified by recrystallization
(300 MHz, CDCl3): d 7.65 (m, 4H), 7.40 (m, 6H), 6.68 (s, 1H), 5.48 (dt,
J¼17, 10 Hz, 1H), 5.12 (dd, J¼10, 1 Hz, 1H), 4.97 (d, J¼17 Hz, 1H), 3.62
(m, 2H), 2.64 (m, 2H), 2.41 (ddd, J¼18.4, 6.7, 2.1 Hz, 1H), 2.05 (ddd,
J¼13.2, 7.1, 2.1 Hz, 1H), 1.91 (m, 1H), 1.58 (m, 2H), 1.44 (s, 3H), 1.27 (s,
3H), 1.06 (s, 9H); 13C NMR (75 MHz, CDCl3):
d 211.2, 180.8, 136.5,
135.7, 135.6, 133.8, 133.7, 129.7, 129.6, 129.4, 127.6, 119.4, 61.7, 52.2,
47.8, 44.1, 34.8, 33.0, 28.4, 26.9, 25.7, 21.7, 19.1; IR (film): 3133, 3071,
2931, 1790, 1714, 1471, 1462, 1455, 1428 cmꢀ1; FDMS: 445 (Mþꢀt-
Bu). HRMS calcd for C31H38O4Si: m/z 502.7280. Found: 502.7269.
Lewis acid promoted Claisen rearrangements of were also
conducted using the above procedure at various temperatures
from ꢀ50 ꢁC to 125 ꢁC by addition of 35 in toluene to a solution of
the Lewis acid promoter (2e4 equiv) at the requisite temperature
or at rt followed by heating. The results are described in Table 1
above.
from toluene to mp 195e196 ꢁC and having: ½a D22
þ81 (c 1.1,
ꢂ
CHCl3). 1H NMR (300 MHz, CDCl3):
d
6.69 (s, 1H), 5.57 (ddd, J¼17,
10, 10 Hz, 1H), 5.23 (dd, J¼10, 2 Hz, 1H), 5.15 (dd, J¼17, 2 Hz, 1H),
3.60 (d, J¼8 Hz, 2H), 3.32 (t, J¼12 Hz, 1H), 2.23 (td, J¼14, 4 Hz, 1H),
2.13 (m, 1H), 2.04 (s, 1H), 1.85 (td, J¼13, 4 Hz, 1H), 1.72 (m, 1H), 1.60
(m, 1H), 1.47 (s, 3H), 1.23 (s, 3H), 0.74 (d, J¼6 Hz, 3H); 13C NMR
(75 MHz, CDCl3):
d 187.4, 135.9, 135.2, 127.7, 119.7, 98.2, 66.3, 53.5,
44.6, 42.2, 32.6, 29.2, 28.7, 23.8, 23.7, 15.2; IR (film): 3426, 2953,
2873, 1786, 1639, 1463 cmꢀ1; EIMS: 278 (Mþ). The structure and
stereochemistry of 38 was confirmed by single crystal X-ray
analysis.
4.2.29. (þ)-(1S,5R)-5-((30R)-50-Hydroxy-10-penten-30-yl)-1,5-
dimethyl-4,9-dioxo-8-oxabicyclo
[4.3.0]non-6-ene
(42)
and
(þ)-(1S,5S)-5-((30S)-50-hydroxy-10-penten-30yl)-1,5-dimethyl-4,9-
dioxo-8-oxabicyclo[4.3.0]non-6-ene hemiketal. To a mixture of ke-
tones 40 and 41 (6.2 g, 12 mmol) in acetonitrile (50 mL) was added
hydrofluoric acid (48e52% aqueous solution, ca. 1 mL). The mixture
was stirred at rt for 2 h at which time it was poured into aqueous
sodium bicarbonate (100 mL) and extracted with methylene chlo-
ride (3ꢃ80 mL). The combined organic layers were dried over so-
dium sulfate and concentrated in vacuo. Chromatography on silica
gel (2:1 hexanes/ethyl acetate) provided 1.4 g (43%) of keto alcohol
42 and 1.2 g (37%) of the title hemiketal as a solids. Keto alcohol 42
could be further purified by recrystallization from methylene
chloride/heptane and the hemiketal could be recrystallized from
4.2.27. (ꢀ)-(1S)-4-((E)-50-tert-Butylydiphenylsiloxy-20-penteny-
loxy)-1,5-dimethyl-9-oxo-8-oxabicyclo[4.3.0]nona-4,6-diene (39). To
a solution of enone 19 (4.0 g, 22 mmol) in THF (50 mL) cooled to
ꢀ78 ꢁC was added sodium bistrimethylsilylamide (1.0 M in THF,
22 mL, 22 mmol) dropwise via syringe pump over 0.5 h. Upon
completion of the addition, HMPA (19 g, 0.11 mol) was added and
the resulting dark yellow solution was stirred at ꢀ78 ꢁC for 0.5 h.
Allylic triflate 31 (14 g, 29 mmol) was added quickly via cannula as
a solution in ether and the resulting solution was stirred for 1 h at
ꢀ78 ꢁC. The mixture was poured into aqueous sodium bicarbonate
(120 mL) and extracted with ether (3ꢃ100 mL). The combined or-
ganic layers were dried over sodium sulfate and concentrated in
vacuo. Chromatography on silica gel (elution with 8:1 hexane/
ether) provided 8.9 g (81%) of allyl dienol ether 39 as an oil having:
toluene. Keto alcohol 42 had mp 127e128 ꢁC, ½a D22
þ77 (c 6.7,
ꢂ
CHCl3) and 1H NMR (300 MHz, CDCl3):
d
6.63 (s, 1H), 5.54 (dt, J¼19,
10 Hz, 1H), 5.12 (d, J¼10 Hz, 1H), 5.10 (d, J¼17 Hz, 1H), 3.70 (m, 1H),
3.55 (m, 1H), 2.85 (t (br), J¼11 Hz, 1H), 2.81 (td, J¼15, 6 Hz, 1H), 2.39
(dm, J¼11 Hz, 1H), 2.15 (dm, J¼13 Hz, 1H), 1.77 (m, 2H), 1.72 (s, 3H),
½
a 2D2
ꢂ
ꢀ70.8 (c 8.19, CHCl3); 1H NMR (300 MHz, CDCl3):
d 7.69 (m,
4H), 7.42 (m, 6H), 6.51 (s, 1H), 5.79 (dt, J¼15, 7 Hz, 1H), 5.64 (dt,
J¼15, 6 Hz, 1H), 4.29 (d, J¼6 Hz, 2H), 3.73 (t, J¼7 Hz, 2H), 2.41 (m,
4H), 2.02 (m, 1H), 1.76 (s, 3H), 1.74 (m, 1H), 1.30 (s, 3H), 1.08 (s, 9H);
1.42 (m, 2H), 1.15 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 208.8, 181.2,
138.1, 135.9, 130.1, 118.7, 60.1, 55.5, 44.7, 44.2, 34.0, 32.7, 31.1, 22.1,
13.9; IR (film): 3750, 3123, 3074, 2944, 2879, 1793, 1717, 1636, 1458,
13C NMR (75 MHz, CDCl3):
d
181.5, 149.8, 135.5, 133.8, 131.2, 130.1,

9802
R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
1421 cmꢀ1; EIMS: 264 (Mþ). Anal. Calcd for C15H20O4: C, 68.15; H,
7.63. Found: C, 67.74; H, 7.81.
of N-nitroso-N-methylurea to a biphasic mixture of ether (20 mL)
and 20% potassium hydroxide solution (20 mL). The resulting yellow
diazomethane solution was added directly to the above residue, and
the mixture was stirred vigorously overnight to ensure complete
evaporation of excess diazomethane. The reaction mixture was
concentrated in vacuo and then chromatographed (2:1, hexanes/
ethyl acetate) to provide 0.49 g (53%) of vinyl ether 44 as a thick oil
Title hemiketal had mp 154e155 ꢁC, ½a D22
þ19.6 (c 8.4, CHCl3),
ꢂ
and 1H NMR (300 MHz, CDCl3):
d
¼6.72 (s, 1H), 6.15 (ddd, J¼17, 11,
5 Hz, 1H), 5.19 (d, J¼2 Hz, 1H), 5.14 (d (broad, J¼7 Hz), 1H), 4.07
(ddd, J¼12, 11, 3 Hz, 1H), 3.70 (dd, J¼11, 5 Hz, 1H), 2.78 (d(br),
J¼13 Hz, 1H), 2.26 (s(br), 1H), 2.24 (td, J¼14, 4 Hz, 1H), 2.03 (qd,
J¼13, 6 Hz, 1H), 1.82 (td, J¼14, 4 Hz, 1H), 1.67 (dt, J¼13, 3 Hz, 1H),
1.55 (m, 2H), 1.45 (s, 3H), 1.34 (s, 3H); 13C NMR (75 MHz, CDCl3):
having ½a 2D2
ꢂ
ꢀ87 (c 1.9, CHCl3); 1H NMR (300 MHz, CDCl3):
d 6.42 (s,
1H), 4.57 (dd, J¼13, 1.3 Hz, 1H), 4.37 (dd, J¼13, 1.3 Hz, 1H), 4.28 (m,
1H), 3.68 (s, 3H), 2.83 (ddd, J¼15,12, 5.3 Hz,1H), 2.72 (dd, J¼19, 7 Hz,
1H), 2.50 (m, 2H), 2.24 (dt, J¼17, 5 Hz,1H), 2.00 (dd, J¼18,12 Hz,1H),
1.50 (td, J¼13, 4 Hz, 1H), 1.36 (s, 3H), 1.25 (s, 3H); 13C NMR (75 MHz,
d
¼182.2, 138.6, 136.4, 127.6, 115.9, 98.4, 60.2, 44.6, 43.6, 42.2, 32.5,
29.1, 25.5, 24.2, 23.8; IR (film): 3486, 3000, 2983, 2965, 2926, 2874,
1777, 1646, 1395 cmꢀ1; EIMS: 264 (Mþ).
CDCl3):
d 210.6, 176.3, 169.0, 141.3, 114.0, 71.0, 65.8, 52.4, 48.9, 43.2,
4.2.30. (1S,5R)-5-((30R)-50-Carboxy-10-penten-30-yl)-1,5-dimethyl-
4,9-dioxo-8-oxa bicyclo[4.3.0]non-6-ene. To an aqueous solution of
1.5 M sulfuric acid (32.7 mL, 49.0 mmol) at 0 ꢁC was added chro-
mium trioxide (2.04 g, 20.4 mmol). To the resulting orange solution
was added a solution of keto alcohol 42 (1.30 g, 5.54 mmol) in ac-
etone (10 mL). The mixture was stirred for 2 h before the excess
chromic acid was quenched by the addition of solid tartaric acid
(w2 g). When a deep blue solution resulted, the mixture was
extracted with methylene chloride (3ꢃ40 mL). The combined or-
ganic extracts were washed with brine, dried over sodium sulfate
and concentrated in vacuo to provide 1.36 g (98%) of the derived
35.9, 35.8, 33.1, 29.0, 28.6, 25.0; IR (film): 2971, 2921, 1735, 1725,
1644, 1460, 1435, 1407 cmꢀ1; EIMS: 308 (Mþ). HRMS calcd for
C16H21O6 (MþþH): m/z 309.1334. Found: 309.1324.
4.2.33. (ꢀ)-(1S,4aR,4bS,8aR,10S,10aR)-Tetradecahydro-1-carbometh-
oxy-1,4a-dimethyl-4,6-dioxo-10(10a)-epoxy-7,9-dioxaphenanthrene
(45). To a solution of vinyl ether 44 (87 mg, 0.28 mmol) in meth-
ylene chloride were added monobasic sodium phosphate hydrate
(0.23 g, 1.7 mmol) and m-chloroperoxybenzoic acid (0.15 g,
0.85 mmol). The mixture was stirred at ambient temperature for
12 h before being diluted with aqueous sodium bicarbonate (5 mL)
and extracted with methylene chloride (3ꢃ5 mL). The organic
layers were combined, dried over sodium sulfate and concentrated
in vacuo. Chromatography on silica gel (elution by 2:1 ethyl acetate/
hexanes) provided 77 mg (84%) of epoxide 45 as a crystalline solid
that could be further purified by recrystallization from methylene
chloride/heptane to afford 45 as a white solid having mp 170 ꢁC
carboxylic acid as an oil: ½a D22
ꢂ
þ79.6 (c 12, CHCl3); 1H NMR
(300 MHz, CDCl3):
d 11.4 (s (broad), 1H), 6.66 (s, 1H), 5.55 (m, 1H),
5.13 (s, 1H), 5.08 (d, J¼5 Hz, 1H), 3.23 (t, J¼9 Hz, 1H), 2.84 (td, J¼15,
6 Hz, 1H), 2.53 (dd, J¼14, 2 Hz, 1H), 2.41 (dt, J¼13, 1 Hz, 1H), 2.29
(dd, J¼15, 1 Hz, 1H), 2.17 (dm, J¼11 Hz, 1H), 1.79 (td, J¼14, 4 Hz, 1H),
1.71 (s, 3H), 1.11 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 208.1, 180.8,
177.6, 138.7, 134.0, 129.6, 119.0, 54.8, 44.1, 44.0, 34.2, 33.9, 32.8, 22.0,
13.6; IR (film): 3260(b), 3124, 2982, 1794, 1713, 1637, 1560, 1508,
1458, 1420 cmꢀ1; EIMS: 278 (Mþ).
(dec), ½a 2D2
ꢂ
ꢀ95.2 (c 1.35, CHCl3), and 1H NMR (300 MHz, CDCl3):
d
5.11 (s, 1H), 4.46 (d, J¼13 Hz, 1H), 4.32 (d, J¼12 Hz,1H), 3.98 (s,1H),
3.69 (s, 3H), 2.75 (m, 3H), 2.39 (m,1H), 2.11 (dd, J¼12, 5 Hz,1H), 2.01
This material was used directly in the next transformation.
(dd, J¼17, 12 Hz, 1H), 1.82 (m, 1H), 1.41 (s, 3H), 1.19 (s, 3H); 13C NMR
(75 MHz, CDCl3):
d 209.7, 172.4, 169.3, 79.6, 71.1, 62.0, 59.4, 52.4,
4.2.31. (1S,5R)-5-((30R,40R)-40-Iodomethyl-g-lacton-30-yl)-1,5-dime-
thyl-4,9-dioxo-8-oxabicyclo[4.3.0]non-6-ene (43). To a solution of
potassium iodide (4.7 g, 28 mmol) and sodium bicarbonate (1.2 g,
14 mmol) in water (25 mL) was added the preceding carboxylic acid
(1.3 g, 4.7 mmol) as a solution in methylene chloride (5 mL). The
mixture was stirred vigorously and then iodine (1.2 g, 4.9 mmol)
was added. The mixture was stirred for 16 h before being extracted
with methylene chloride (3ꢃ20 mL). The organic layers were
combined, washed with 10% sodium thiosulfate solution until col-
orless, dried over sodium sulfate and concentrated in vacuo to
49.4, 45.5, 33.5, 33.4, 28.5, 26.5, 22.3, 19.7; IR (film): 2951, 1731,
1712, 1460, 1407 cmꢀ1; EIMS: 308 (Mþꢀ16 (O)). HRMS calcd for
C16H21O7: m/z 325.3392. Found: 325.3399.
4.2.34. (ꢀ)-(1S,2R,5S,8aR)-1,2,3,5,6,7,8,8a-Octahydro-5-carbometh-
oxy-5,8a-dimethyl-1-methyl-ene carbo-N-methoxy-N-methylamido-
3-oxa-8-oxo-2-naphthyl alcohol (46). To a suspension of methox-
ymethylamine hydrochloride (61 mg, 0.63 mmol) in methylene
chloride (1 mL) at 0 ꢁC was added dropwise trimethylaluminum
(2.0 M in hexane, 0.32 mL, 0.63 mmol). When complete dissolution
was observed, the solution was transferred via cannula to a solution
of vinyl ether 44 (88 mg, 0.29 mmol) in methylene chloride (2 mL)
at 0 ꢁC. The reaction mixture was stirred at 0 ꢁC for 30 min before
being quenched with satd Rochelle’s salts (10 mL) and extracted
with methylene chloride (3ꢃ10 mL). The combined organic layers
were dried over sodium sulfate and concentrated in vacuo to pro-
provide 1.3 g (68%) of iodolactone 43 as an oil having ½a D22
þ65
ꢂ
(c¼3.0, CHCl3); 1H NMR (300 MHz, CDCl3):
d 6.75 (s, 1H), 4.50 (m,
1H), 3.26 (m, 2H), 2.99 (m, 2H), 2.75 (dd, J¼18,10 Hz,1H), 2.56 (ddd,
J¼16, 4, 3 Hz, 1H), 2.39 (dd, J¼18, 3 Hz, 1H), 2.20 (ddd, J¼13, 6, 3 Hz,
1H), 1.89 (td, J¼14, 5 Hz, 1H), 1.66 (s, 3H), 1.20 (s, 3H); 13C NMR
(75 MHz, CDCl3):
d 208.0, 180.1, 174.1, 138.8, 128.4, 77.6, 52.3, 43.8,
43.2, 34.8, 31.8, 29.821.6, 13.9, 7.9; IR (film): 2935, 1786, 1712, 1636,
1458, 1419 cmꢀ1; EIMS: 404 (Mþ), 277 (MþꢀI). HRMS calcd for
C15H17IO5: m/z 404.2021. Found: 404.2001.
vide 0.10 g (95%) of hydroxy amide 46 as an oil having ½a D22
ꢀ53 (c
ꢂ
3.2, CHCl3); 1H NMR (300 MHz, CDCl3):
d 6.40 (s, 1H), 4.39 (m, 1H),
4.30 (m, 1H), 3.72 (m, 4H), 3.63 (s, 3H), 3.40 (t, 1H, J¼10 Hz), 3.22 (s,
3H), 2.95 (ddd, 1H, J¼17, 12, 5 Hz), 2.84 (d, 1H, J¼6 Hz), 2.53 (dt, 1H,
J¼13, 5 Hz), 2.29 (m, 2H), 2.02 (d (br), 1H, J¼17 Hz), 1.53 (td, 1H,
J¼13, 4 Hz), 1.39 (s, 3H), 1.30 (s, 3H); 13C NMR (75 MHz, CDCl3):
4.2.32. (1S,4aR,4bS,8aR)-1,2,3,4,4a,4b,5,6,7,8,8a,9-Dodecahydro-1-
carbomethoxy-1,4a-dimethyl-4,6-dioxo-7,9-dioxaphenanthrene
(44). To a solution of iodolactone 43 (1.3 g, 3.3 mmol) in tetrahy-
drofuran (15 mL) was added 0.5 M potassium hydroxide (13 mL,
6.6 mmol). The mixture was capped and stirred at ambient tem-
perature for 2 h. At this time the mixture was acidified (pH <2) with
concentrated hydrochloric acid, and stirred an additional 3 h. So-
dium chloride (solid) was added, and the reaction mixture was
extracted with tetrahydrofuran (4ꢃ10 mL). The organic layers were
combined, dried over sodium sulfate, and concentrated in vacuo. An
ethereal solution of diazomethanewas preparedbyadding an excess
d
212.0, 176.3, 174.2, 141.5, 115.3, 72.8, 60.7, 60.4, 52.0, 50.3, 43.0,
35.7, 34.5, 33.1, 32.0, 29.4, 28.1, 24.7; IR (film): 3396, 2949, 1723,
1711, 1641, 1434, 1390 cmꢀ1; EIMS: 308 (MþꢀHN(OMe)Me). This
material was of sufficient purity for use as obtained in the following
transformation.
4.2.35. (ꢀ)-(1S,2R,5S,8aR)-1,2,3,5,6,7,8,8a-Octahydro-5-carbometh-
oxy-5,8a-dimethyl-1-methylene carbo-N-methoxy-N-methylamido-
3-oxa-8-oxo-2-naphthaldehyde (47). To a solution of alcohol 46

R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
9803
(0.10 g, 0.28 mmol) in methylene chloride was added DesseMartin
periodinane (190 mg, 0.44 mmol) portionwise. The reaction mix-
ture was capped and stirred at ambient temperature for 2 h. The
mixture was then quenched with 10% sodium bicarbonate (2 mL)
and 10% sodium thiosulfate (2 mL). When a clear biphasic mixture
was obtained, the mixture was extracted with methylene chloride
(3ꢃ5 mL). The combined organic layers were dried over sodium
sulfate and concentrated in vacuo. Chromatography on silica gel
(elution by 2:1 ethyl acetate/hexanes) afforded 92 mg (90%) of al-
amido-3-oxa-8-oxo-2-naphthyl-30furyl ketone (50). To a solution of
3-tributylstannylfuran (35.7 mg, 0.10 mmol) in ether (0.8 mL) at
ꢀ78 ꢁC under argon was added n-BuLi (1.6 M in hexane, 0.16 mL,
0.10 mmol) and stirred for 1 h. At this time, a solution of epoxy al-
dehyde 49 (19 mg, 0.05 mmol) in toluene (0.5 mL) precooled to
ꢀ78 ꢁC was added dropwise by cannula. The reaction mixture was
then stirred at ꢀ78 ꢁC for an additional 1 h before being quenched
with saturated ammonium chloride solution and extracted with
methylene chloride (3ꢃ5 mL). The combined organic layers were
dried over sodium sulfate and concentrated in vacuo.
dehyde 47 as a pale yellow oil having ½a D22
ꢂ
ꢀ39 (c 1.6, CHCl3); 1H
NMR (300 MHz, CDCl3):
d
9.60 (s, 1H), 6.52 (s, 1H), 4.67 (s, 1H), 3.71
The resulting crude mixture of 2ꢁ alcohols was dissolved in
methylene chloride (2 mL) and DesseMartin periodinane (34 mg,
0.080 mmol) was added. The reaction mixture was stirred for 3 h
before being quenched with 10% sodium bicarbonate (2 mL) and
10% sodium thiosulfate (2 mL). When a clear solution resulted the
layers were separated and the aqueous phase washed with two
additional portions of methylene chloride (10 mL total volume).
The combined organic layers were dried over sodium sulfate and
concentrated in vacuo. Chromatography on silica gel (elution with
1:1 hexanes/ethyl acetate) provided 10.5 mg (48%) of 50 as a col-
(s, 3H), 3.59 (s, 3H), 3.23 (m, 1H), 3.11 (s, 3H), 2.89 (ddd, J¼17, 12,
5 Hz,1H), 2.51 (dt, J¼14, 5 Hz,1H), 2.31 (dt, J¼17, 5 Hz,1H), 2.23 (dd,
J¼17, 8 Hz, 1H), 2.10 (dd, J¼17, 1 Hz, 1H), 1.57 (td, J¼13, 4 Hz, 1H),
1.41 (s, 3H), 1.36 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 210.0, 196.4,
175.8, 171.8, 140.9, 116.2, 78.4, 60.7, 51.7, 49.4, 43.1, 36.3, 35.8, 32.6,
32.1, 29.6, 28.3, 24.8; IR (film): 2950, 1724, 1645, 1446, 1387 cmꢀ1
;
EIMS: 367 (Mþ), 307 (MþꢀN(OMe)Me). This material was used as
obtained in the next transformation.
4.2.36. (1R,2R,3S,7S,8S,9R,10RS)-2-Bromo-3-carbomethoxy-3,7-
dimethyl-10-hydroxy-8-methylenecarbo-N-methoxy-N-methyl-
amido-6-oxo-11,12-dioxatricyclo [6.2.1.02,7]dodecane (48). To a solu-
tion of aldehyde 47 (110 mg, 0.30 mmol) in 3:1 tetrahydrofuran/
water (3 mL) at rt was added N-bromoacetamide (43 mg,
0.30 mmol) in one portion. The reaction mixture was stirred for 4 h
before being quenched with 10% sodium thiosulfate (3 mL) and
extracted with methylene chloride (3ꢃ5 mL). The combined or-
ganic layers were dried over sodium sulfate and concentrated in
vacuo. Chromatography on silica gel (elution by 1:1 hexanes/ethyl
acetate) provided 85 mg, (61%) of bromolactol 48 as w6:1 mixture
orless oil having: ½a D22
ꢂ
þ9.4 (c 0.64, CHCl3); 1H NMR (300 MHz,
CDCl3):
d 8.17 (s, 1H), 7.43 (s, 1H), 6.77 (s, 1H), 5.17 (s, 1H), 4.98 (d,
J¼2 Hz, 1H), 3.83 (s, 3H), 3.72 (m, 1H), 3.57 (s, 3H), 3.22 (m, 1H),
3.04 (s, 3H), 2.80 (m, 1H), 2.70 (dd, J¼19, 6 Hz, 1H), 2.54 (ddd,
J¼19, 18, 4 Hz, 1H), 2.42 (d (br), J¼18 Hz, 1H), 1.90 (dd, J¼13, 4 Hz,
1H), 1.53 (s, 3H), 1.14 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 209.5,
198.0, 190.5, 175.2, 147.4, 144.4, 143.4, 125.4, 108.8, 79.1, 65.1, 60.6,
52.4, 51.4, 44.1, 40.5, 35.6, 32.2, 30.6, 29.5, 22.7, 22.1; IR (film):
2950, 1727, 1661, 1459, 1385 cmꢀ1
.
EIMS: 449 (Mþ), 389
(MþꢀN(OMe)Me). HRMS calcd for C22H27NO9: m/z 449.1680.
Found: 449.1680.
of lactol epimers: major epimer: ½a D22
ꢂ
ꢀ4.5 (c 2.2, CHCl3); 1H NMR
(300 MHz, CDCl3):
d
5.79 (s, 1H), 5.35 (d, J¼7 Hz, 1H), 4.20 (d,
4.2.39. (S)-(ꢀ)-Ethyl 4-oxo-1,2,3-trimethyl-2-cyclohexene-1-
J¼3 Hz, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.42 (m, 1H), 3.20 (s, 3H),
3.05e2.82 (m, 3H), 2.36e2.18 (m, 3H), 1.82 (d (br), J¼7 Hz, 1H), 1.52
carboxylate [(ꢀ)-53]26b. A mixture of 13.4 g of (S)-(ꢀ)-
a-methyl-
naphthylamine (78 mmol), 11.3 g (78 mmol) of ethyl 2-
methylacetoacetate and a catalytic amount (75 mg) of p-tol-
uensulfonic acid in 100 mL of dry toluene was heated at reflux for
20 h with azeotropic removal of water using a DeaneStark trap.
After cooling to rt, w200 mg of solid NaHCO3 was added and the
solution was filtered through a pad of silica gel using hexanes/
EtOAc 4:1 containing 2% Et3N as eluent. Evaporation of the solvent
at reduced pressure afforded 20.7 g (89%) of vinylogous carbamate
(s, 3H), 1.40 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 209.2, 175.0, 173.1,
101.1, 95.1, 81.4, 77.7, 61.0, 54.7, 51.8, 49.2, 38.7, 36.1, 32.7, 32.1, 28.1,
24.2, 21.8; IR (film): 3396, 2950, 1714, 1658, 1461, 1385 cmꢀ1; FAB
MS: 464 (79BrMþþH), 466 (81BrMþþH). This material was pure
enough for use directly in the next transformation.
4.2.37. (þ)-(1S,2R,4R,4aS,5S,8aR)-Decahydro-5-carbomethoxy-5,8a-
dimethyl-1-methylenecarbo-N-methoxy-N-methylamido-3-oxa-8-
oxo-2-naphthaldehyde (49). To a solution of bromolactol 48 (37 mg,
0.080 mmol) in acetonitrile (1.5 mL) was added triethylamine
(0.50 mL), and the mixture was heated to 65 ꢁC. Silver tetra-
fluoroborate (40 mg, 0.20 mmol) was added and the reaction
mixture was stirred at 65 ꢁC for 30 min. The mixture was cooled to
rt, quenched with 10% sodium bicarbonate (3 mL) and extracted
with methylene chloride (3ꢃ5 mL). The combined organic layers
were filtered through a plug of Celite, dried over sodium sulfate,
and concentrated in vacuo. The residue was quickly chromato-
graphed on silica (100% ethyl acetate) to provide 23 mg (75%) of
(½a 2D0
ꢂ
þ299 (c 5.5, CH3OH)).26b To a suspension of anhyd ZnCl2
(11 mg) in 4 mL of dry toluene was added 0.30 mL ethyl vinyl ke-
tone (2.73 mmol, 1.3 equiv) dropwise at 0 ꢁC and the resulting
mixture was stirred for 40 min. After cooling the reaction mixture
further to ꢀ30 ꢁC, a solution of 625 mg of carbamate (2.1 mmol) in
4 mL of dry toluene was added dropwise. The resulting reaction
mixture was stirred at ꢀ30 ꢁC for 1.5 h, then hydrolyzed by addition
of 5 mL of 10% aq HOAc with stirring and warming from 0 ꢁC to rt
overnight. The aqueous phase was separated and extracted thor-
oughly four times with EtOAc. The combined organic phases were
washed with brine, dried over Na2SO4, filtered, and the solvent
removed in vacuo. The residue was purified by chromatography
(with elution by hexanes/EtOAc 4:1) to afford 291 mg (61%) of
epoxy aldehyde 49 as an oil having: ½a D22
ꢂ
þ9.4 (c 1.7, CHCl3); 1H
NMR (300 MHz, CDCl3):
d
9.48 (s, 1H), 5.11 (s, 1H), 4.63 (d, J¼2 Hz,
1H), 3.81 (s, 3H), 3.74 (m, 1H), 3.63 (s, 3H), 3.21 (dd, J¼7, 5 Hz, 1H),
3.15 (s, 3H), 2.54 (m, 1H), 2.53 (m, 3H), 1.87 (dd, J¼13, 4 Hz, 1H), 1.46
diketone (ꢀ)-52,25
½
a 2D2
ꢂ
ꢀ6 (c 5.113, CHCl3), along with 49 mg of
a mixture of (ꢀ)-53 (minor amount) and its regioisomer 54 (11%
(s, 3H), 1.11 (s, 3H); 13C NMR (75 MHz, CDCl3):
d
209.7, 196.4, 175.0,
combined): 1H NMR (400 MHz, CDCl3):
d
4.20 (dq, J¼7.2, 0.9 Hz,
172.4, 78.9, 78.0, 65.1, 60.4, 52.3, 51.2, 44.0, 38.2, 35.5, 32.0, 30.4,
22.7, 21.9; IR (film): 2952, 1728, 1655, 1433, 1389 cmꢀ1; EIMS: 383
(Mþ), 323 (MþꢀN(OMe)Me).
2H), 2.42 (q, J¼7.3 Hz, 2H), 2.46e2.36 (m, 2H), 2.16 (ddd, J¼14.2, 9.5,
6.0 Hz, 1H), 2.16 (s, 3H), 2.06 (ddd, J¼14.2, 9.9. 5.9 Hz, 1H), 1.34 (s,
3H), 1.27 (t, J¼7.2 Hz, 3H), 1.05 (t, J¼7.3 Hz, 3H); 13C NMR (100 MHz,
This material was used as obtained in the following
transformation.
CDCl3): d 209.7, 205.0, 172.5, 61.2, 58.6, 37.0, 35.7, 28.4, 25.9, 19.1,
13.8, 7.6: IR (neat): 2981, 2940, 1713, 1461 cmꢀ1; APCI (þ): 229
([MþH]þ, 10), 211 (51), 183 (17), 145 (85), 139 (100).
4.2.38. (þ)-(1S,2R,4R,4aS,5S,8aR)-Decahydro-5-carbomethoxy-
A solution 286 mg (1.25 mmol) of (ꢀ)-52 in 15 mL dry toluene
was heated to reflux and then 0.31 mL (3.7 mmol) of pyrrolidine
5,8a-dimethyl-4(4a)-epoxy-1-methylene carbo-N-methoxy-N-methyl-

9804
R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
was added followed by addition of 0.28 mL (5 mmol) of glacial
HOAc. The mixture was stirred at reflux for 3 h with azeotropic
removal of water using a DeaneStark trap. After cooling to rt and
concentration at reduced pressure, the residue was purified by
chromatography (with elution by hexanes/EtOAc 4:1) to afford
229 mg (87%) of (S)-(ꢀ)-ethyl 4-oxo-1,2,3-trimethyl-2-cyclohe-
35.7, 28.4, 25.9, 19.1, 13.8, 7.6; IR (neat): 2981, 2940, 1713,
1461 cmꢀ1; APCI (þ): 229 ([MþH]þ, 10), 211 (51), 183 (17), 145 (85),
139 (100).
4.2.41.2. Ethyl R-(þ)-1,2,3-trimethyl-4-oxo-3-cyclohexenyl-
carboxylate (þ)-5326c. ½a D22
ꢂ
þ84 (c 2.155, CHCl3, 95% ee); 1H NMR
xene-1-carboxylate [(ꢀ)-53] (½a D22
ꢂ
ꢀ82 (c 0.989, CHCl3, 95% ee))
(400 MHz, CDCl3)
d
4.19 (dq, J¼7.2, 1.8 Hz, 2H), 2.55e2.36 (m, 3H),
as a yellow oil: 1H NMR (400 MHz, CDCl3)
d
4.19 (dq, J¼7.2, 1.8 Hz,
1.91 (ddd, J¼11.8, 6.8, 3.8 Hz, 1H), 1.89 (q, J¼0.9 Hz, 3H), 1.80 (q,
2H), 2.55e2.36 (m, 3H), 1.91 (ddd, J¼11.8, 6.8, 3.8 Hz, 1H), 1.89 (q,
J¼0.9 Hz, 3H), 1.80 (q, J¼0.9 Hz, 3H), 1.43 (s, 3H), 1.27 (t, J¼7.2 Hz,
J¼0.9 Hz, 3H),1.43 (s, 3H), 1.27 (t, J¼7.2 Hz, 3H); 13C NMR (400 MHz,
CDCl3): d 197.8, 180.6, 154.2, 132.7, 48.2, 33.7, 33.4, 22.2, 18.1, 11.4; IR
3H); 13C NMR (400 MHz, CDCl3):
d
197.8, 180.6, 154.2, 132.7, 48.2,
(neat): 2940, 1729, 1666 cmꢀ1; APCI (þ): 183 ([MþH]þ, 7), 139
33.7, 33.4, 22.2, 18.1, 11.4; IR (neat): 2940, 1729, 1666 cmꢀ1; APCI
(100), 111 (17).
(þ): 183 ([MþH]þ, 7), 139 (100), 111 (17).
4.2.41.3. 1,2,3-Trimethyl-4-oxo-cyclohex-2-enecarboxylic
acid
4.2.40. (S)-(ꢀ)-Methyl 4-oxo-1,2,3-trimethyl-2-cyclohexene-1-
carboxylate (ꢀ)-(51)26c. A mixture of 10.2 g (48 mmol) of (ꢀ)-53
in 60 mL of CH3OH and 32 mL (62.4 mmol, 1.3 equiv) of 2 M aq KOH
was heated at reflux for 3 h. After cooling to rt and acidification to
pH ꢄ1 with 10% aq hydrochloric acid, the solution was saturated
with solid NaCl and extracted thoroughly four times with EtOAc.
The combined organic phases were washed once with brine, dried
over Na2SO4, filtered, and the solvent removed in vacuo. An ana-
lytical sample of acid (ꢀ)-55 was purified by chromatography and
(þ)-5526c. ½a 2D2
ꢂ
þ96 (c 0.989, CHCl3); 1H NMR (400 MHz, CDCl3):
d
11.24 (s(br), 1H), 2.61e2.38 (m, 3H), 1.98e1.91 (m, 1H), 1.94 (d(br),
J¼0.7, 3H), 1.78 (d(br), J¼0.7, 3H), 1.44 (s,3H); 13C NMR (400 MHz,
CDCl3): d 197.8, 180.6, 154.2, 132.7, 48.2, 33.7, 33.4, 22.2, 18.1, 11.4; IR
(neat): 2940, 1729, 1666, 1452 cmꢀ1; APCI (þ): 183 ([MþH]þ, 7), 139
(100), 111 (17).
4.2.41.4. Methyl R-(þ)-1,2,3-trimethyl-4-oxo-cyclohex-2-
enecarboxylate (þ)-5126c. ½a D22
ꢂ
þ93 (c 1.523, CHCl3); 1H NMR
had ½a 2D2
ꢂ
ꢀ96 (c 0.989, CHCl3).26c Crude acid (ꢀ)-55 above was
(400 MHz, CDCl3): d 3.69 (3H, s), 2.49e2.32 (3H, m), 1.92e1.84 (1H,
dissolved in 200 mL of acetone and 33 g (240 mmol) of K2CO3 and
5.4 mL (57 mmol) of (CH3)2SO4 were added sequentially at rt and
the mixture was heated at reflux with stirring for 2 h. After cooling
to rt, 150 mL of 1.5 M aq NaOAc was added and stirring was con-
tinued at rt overnight. The biphasic mixture was separated and the
aqueous phase was extracted thoroughly four times with EtOAc.
The combined organic phases were washed once with brine, dried
over Na2SO4, filtered, and the solvent removed in vacuo. The resi-
due was purified by chromatography (with elution by a gradient of
hexanes/EtOAc 7:1 to 4:1) to afford 8.95 g of (S)-(ꢀ)-methyl 4-oxo-
1,2,3-trimethyl-2-cyclohexene-1-carboxylate [(ꢀ)-51]26c (95% from
m), 1.84 (3H, q, J¼0.9 Hz), 1.75 (3H, br s), 1.40 (3H, s); 13C NMR
(100 MHz, CDCl3):
d 197.1, 175.4, 154.2, 132.4, 52.3, 48.4, 33.7, 33.3,
22.0, 17.9, 11.3; IR (neat): 2951, 1732, 1669, 1428 cmꢀ1; APCI (þ): 197
([MþH]þ, 100), 169 (30), 137 (34).
4.2.42. 1S-(þ)-4-[(E)-50-tert-Butyldiphenylsilyloxy-40-methyl-20-
pentenyloxy]-1,3-dimethyl-2-methylene-cyclohex-3-ene (58). Allylic
triflate 31 was prepared in situ as follows: (E) 5-tert-butyldiphe-
nylsilyloxy-2-penten-1-ol (8.2 g, 24 mmol),41 and
a catalytic
amount of 1,10-phenantroline were dissolved in w60 mL of dry
ether and cooled to ꢀ78 ꢁC; n-BuLi was added until the equivalence
point then, after 5 min, Tf2O (4.2 mL, 25 mmol) was added quickly.
After stirring for 10 min at ꢀ78 ꢁC the reaction mixture was
transferred via cannula to a solution of the enolate as described
below. A solution of 4.25 g (21.7 mmol) of (ꢀ)-51 (ꢅ95% ee) in
40 mL of anhyd THF was added dropwise under Ar to KHMDS
(4.12 g, 20.6 mmol) in anhyd THF (50 mL) at ꢀ78 ꢁC followed by
addition of anhyd HMPA (20 mL) and the mixture was stirred for
30 min at ꢀ78 ꢁC, then warmed to rt and stirred for 2 h. After
recooling the reaction mixture to ꢀ78 ꢁC, the solution of 31, pre-
pared above, was added via cannula and stirring was continued for
30 min at ꢀ78 ꢁC. The reaction mixture was then poured into satd
aq NaHCO3 (350 mL) containing Et3N (10 mL) and the resulting
mixture was stirred at rt for 20 min. The reaction mixture was
extracted with three 200 mL portions of EtOAc, and the organic
layer was washed successively with water and brine, dried over
K2CO3, filtered, and the solvent removed in vacuo. The residue was
chromatographed on silica gel (hexanes/EtOAc 30:1 to 1:1 con-
(ꢀ)-53) as a yellow oil: ½a D22
ꢂ
ꢀ93 (c 1.523, CHCl3): IR (neat): 2951,
1732, 1669, 1428 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 3.69 (3H, s),
2.49e2.32 (3H, m), 1.92e1.84 (1H, m), 1.84 (3H, q, J¼0.9), 1.75 (3H,
br s), 1.40 (3H, s); 13C NMR (100 MHz, CDCl3):
d 197.2, 175.4, 154.1,
132.3, 52.3, 48.4, 33.7, 33.3, 22.1, 17.9, 11.3. APCI (þ): 197 ([MH]þ,
100), 169 (30), 137 (34).
4.2.41. The R series of derivatives 51e53 and 55, were prepared
starting with R(þ)-
a-methyl benzyl amine as shown below using the
procedures described for the S series above.
O
H
O
O
NH
O
ZnCl2
COOEt
then aq. HCl
COOEt
(+)-52
O
O
pyrrolidine
acetic acid
K2CO3
taining 2% of Et3N) to afford 6.90 g (65%) of (þ)-58 having ½a D22
ꢂ
þ37
aq KOH
MeOH, Δ
Me2SO4
acetone
Δ
(c 2.142, Et2O) and 1H NMR (400 MHz, C6D6):
d 7.86e7.84 (m, 4H),
tol, reflux
7.34e7.32 (m, 6H), 5.72 (dt, J1¼15.4, J2¼6.5 Hz,1H), 5.58 (dt, J1¼15.4,
J2¼5.5 Hz, 1H), 5.15 (s, 1H), 5.06 (s, 1H), 4.09 (d(br), J¼5.5 Hz, 2H),
3.73 (t, J¼6.5 Hz, 2H), 3.43 (s, 3H), 2.50e2.41 (m, 1H), 2.39 (dd,
J1¼12.7, J2¼6.0 Hz, 1H), 2.29 (q (br), J¼6.5 Hz, 2H), 2.14e2.05 (m,
1H), 2.09 (s, 3H), 1.58e1.53 (m, 1H), 1.50 (s, 3H), 1.26 (s, 9H); 13C
COOEt
(+)-53
COOH
(+)-55
COOMe
(+)-51
NMR (100 MHz, C6D6): d 176.0, 151.4, 147.9, 136.0, 134.2, 130.1, 129.9,
4.2.41.1. Ethyl R-(þ)-2-acetyl-2-methyl-5-oxo-heptanoate (þ)
128.6, 128.0, 113.4, 106.3, 68.0, 63.7, 51.5, 46.8, 36.0, 32.6, 27.1, 24.1,
23.2,19.4,11.7; IR (neat): 2931,1732,1643,1428 cmꢀ1; APCI (þ): 519
([MþH]þ, 7), 441 (100), 197 (8); APIES (þ): 519 ([MþH]þ, 85), 323
(28), 197 (100), 157 (79), 129 (42), 102 (23).
Owing to its sensitivity, this material was used as obtained for
the following transformation.
-5226a. ½a 2D2
ꢂ
þ6 (c 5.113, CHCl3); 1H NMR (400 MHz, CDCl3):
d 4.20
(dq, J¼7.2, 0.9 Hz, 2H), 2.42 (q, J¼7.3 Hz, 2H), 2.46e2.36 (m, 2H),
2.16 (ddd, J¼14.2, 9.5, 6.0 Hz, 1H), 2.16 (s, 3H), 2.06 (ddd, J¼14.2, 9.9,
5.9 Hz, 1H), 1.34 (s, 3H), 1.27 (t, J¼7.2 Hz, 3H), 1.05 (t, J¼7.3 Hz, 3H);
13C NMR (100 MHz, CDCl3):
d 209.7, 205.0, 172.5, 61.2, 58.6, 37.0,

R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
9805
4.2.43. (ꢀ)-(4S)-2-[(E)-50-tert-Butylydiphenylsiloxypenten-30(R)-yl]-
2,4-dimethyl-3-methylene-4-carbomethoxycyclohexanone
(59). Freshly distilled TiCl4 (1.5 mL, 14.0 mmol) was dissolved in
anhyd CH2Cl2 (75 mL) containing suspended powdered activated
while temperature was slowly raised from rt to reflux and the
mixture heated at reflux 1 h. After cooling to 0 ꢁC water was
carefully added, followed by addition of NaBO3.4H2O (8.0 g,
52 mmol) and the mixture was stirred at rt for 20 h. After dilution
with water, the aqueous phase was extracted with Et2O; the com-
bined organic layers were washed with water and brine, dried over
Na2SO4, filtered, and the solvent removed in vacuo. The crude was
purified by flash chromatography on silica gel to yield 1.76 g (87%
ꢀ
4 A MS, and a 2 M solution of Me3Al in toluene (7.0 mL, 14.0 mmol)
was added under Ar at ꢀ65 ꢁC. After 10 min, a solution of 58 (2.72 g,
5.22 mmol) in 25 mL of anhyd CH2Cl2 containing suspended pow-
ꢀ
dered activated 4 A MS was added dropwise, and the deep purple
reaction mixture was stirred for 25 min before dilution with tech
Et2O. Water was added and, after warming to rt, the salts were
dissolved by addition of 1 N aq HCl. The aqueous phase was
extracted three times with portions of EtOAc and the organic layer
was washed successively with brine containing NaHCO3 and brine,
dried over Na2SO4, filtered, and the solvent removed in vacuo. The
residue was chromatographed using a gradient of hexanes/EtOAc
from (ꢀ)-59, three steps) of (þ)-62.having: ½a D22
þ120 (c 1.020,
ꢂ
THF); 1H NMR (C6D6, 400 MHz):
d 5.33 (s, 1H), 5.23 (s, 1H),
3.64e3.54 (m. 2H), 3.88e3.31 (m, 2H), 3.30 (s, 3H), 3.00 (s, 3H),
2.41e2.34 (m, 1H), 2.34 (ddd, J1¼13.1, J2¼4.3, J3¼2.8 Hz, 1H), 2.23
(dt, J1¼13.8, J1¼4.3 Hz, 1H), 2.15e2.04 (2H, m), 2.04e1.96 (2H, m),
1.86 (ddd, J1¼13.8, J2¼4.5, J3¼2.8 Hz, 1H), 1.65 (ddd, J1¼13.84,
J2¼13.1, J3¼4.5 Hz, 1H), 1.41e1.32 (m, 2H), 1.29 (s, 1H), 1.20 (s, 1H),
1.19e1.14 (m, 2H), 0.91 (s(br), 1H); 13C NMR (C6D6, 100 MHz):
(6:1 to 1:1) to afford 2.03 g (75%) of (ꢀ)-59 (½a D22
ꢀ26 (c 1.895,
ꢂ
CHCl3)); 1H NMR (400 MHz, CDCl3):
d
7.66e7.63 (m, 4H), 7.45e7.35
d 176.9, 150.0, 114.9, 101.8, 63.4, 61.6, 51.3, 49.3, 47.3, 47.0, 37.3, 35.7,
(m, 6H), 5.44 (dt, J1¼17.0, J2¼10.0 Hz, 1H), 5.30 (s,1H), 5.17 (s, 1H),
5.05 (dd, J1¼10.0, J2¼1.9 Hz, 1H), 4.96 (dd, J1¼17.0, J2¼1.9 Hz, 1H),
3.68 (ddd, J1¼10.1, J2¼6.4, J3¼3.4 Hz, 1H), 3.63 (s, 3H), 3.54 (dt,
J1¼10.1, J2¼4.6 Hz, 1H), 2.80 (ddd, J1¼11.8, J2¼10.0, J3¼2.2 Hz, 1H),
2.65 (ddd, J1¼18.1, J2¼12.2, J3¼7.8 Hz, 1H), 2.43 (ddd, J1¼18.1, J2¼7.3,
J3¼1.9 Hz, 1H), 2.28 (ddd, J1¼14.7, J2¼12.2, J3¼7.3 Hz, 1H), 2.09 (ddd,
J1¼14.7, J2¼7.8, J3¼1.9 Hz, 1H), 2.02e1.94 (m, 1H), 1.49 (s, 3H),
1.25e1.17 (m, 1H), 1.20 (s, 3H), 1.05 (s, 9H). 13C NMR (100 MHz,
32.2, 28.1, 27.6, 27.3, 22.9; IR (neat): 3440, 2951, 1727, 1634,
1436 cmꢀ1; APCI (þ): 281 ([MþH]þꢀMeOH, 100), 113 (19); APIES
(þ): 335 ([MþNa]þ, 100), 281 (18), 113 (11), 102 (43). HRMS (CI)
calcd for C17H28O5: m/z 312.1931. Found: 312.1943.
4.2.46. (þ)-(3R,4S,8R)-Methyl 4,8-dimethyl-7-oxo-8-[(4R)-tetrahy-
dro-2-oxo-2H-pyran-4-yl]-1-oxaspiro[2.5]octane-4-carboxylate
(63). A solution of 2.0 mL (28 mmol) of DMSO in 60 mL of anhyd
CH2Cl2 was treated with 7.0 mL (14 mmol) of a 2 M solution of
(COCl)2 in CH2Cl2 at ꢀ70 ꢁC under Ar and the mixture was stirred
for 30 min at ꢀ70 ꢁC. A solution of 1.76 g (5.6 mmol) of (þ)-62 in
35 mL of anhyd CH2Cl2 was then added and stirring was continued
at the same temperature for 30 min. A 6.2 mL portion of anhyd Et3N
(45 mmol) was then added. After stirring at 0 ꢁC for 20 min and
dilution with CH2Cl2, the reaction mixture was quenched with cold
water and the aqueous phase was extracted four times with CH2Cl2.
The organic phase was washed successively with 1 N aq HCl, satd
NaHCO3 and brine, dried over Na2SO4, filtered, and the solvent
removed in vacuo. The residue was dissolved in a mixture of t-
BuOH (50 mL) and 2-methyl-2-butene (6 mL) and a solution of 3.2 g
of 80% NaClO2 (28 mmol) and 6.4 g of NaH2PO4.H2O (45 mmol) in
25 mL of water was added at rt. The resulting mixture was stirred
for 15 min then diluted with brine. The aqueous phase was satu-
rated with NaCl and extracted thoroughly four times with EtOAc.
The combined organic phases were washed with brine, dried over
Na2SO4, filtered, and the solvent removed in vacuo. The residual
crude acid was dissolved in 60 mL of CH2Cl2 and 1.4 g of NaHCO3
(17 mmol) and 2.9 g of w85% m-CPBA (14 mmol) were added at rt.
The resulting reaction mixture was stirred overnight at rt before
quenching with satd aq NaHSO3 at 20 ꢁC (with water bath cooling).
The aqueous phase was extracted thoroughly with CH2Cl2, and the
combined organic phases were washed with brine, dried over
Na2SO4, filtered, and the solvent removed in vacuo. The residue was
then dissolved in 30 mL THF and 30 mL of 10% aq HCl solution was
added at 20 ꢁC (with water bath cooling) and the resulting mixture
was stirred at rt for 1.5 h. After thorough extraction of the reaction
mixture four times with CH2Cl2, the combined organic phases were
washed with satd NaHCO3 and brine, dried over Na2SO4, filtered,
and the solvent removed in vacuo. Flash chromatography (elution
with a gradient of hexanes/EtOAc from 1:1 to pure EtOAc) afforded
1.26 g of 15 (73% from 12) as a white solid having mp 174e176 ꢁC
CDCl3):
d 210.9, 176.3, 151.4, 137.6, 135.5, 133.7, 133.6, 129.6, 127.6,
118.0, 115.5, 61.4, 58.7, 52.1, 46.4, 45.2, 35.6, 30.4, 30.3, 27.2, 26.8,
19.1, 17.1. IR (neat): 2952, 1732, 1428 cmꢀ1; APCI (þ): 519 ([MþH]þ,
79), 441 (100), 395 (18), 263 (25). HRMS calcd for C32H43O4Si
(MþH)þ: m/z 519.2931. Found: 519.2929.
4.2.44. (þ)-(2S,5S,7R,8R)-5-Carbomethoxy-5,7-dimethyl-8-(1-
ethenyl)-2-methoxy-4-methylene-1-oxabicyclo[4.4.02,7]decane
(61). AcOH (0.37 mL, 6.5 mmol) and TBAF (1 M soln in THF,16.2 mL,
16.2 mmol) were added successively at rt to a solution of 15 (3.37 g,
6.5 mmol) in THF (20 mL). After stirring for 3 h, the reaction mix-
ture was diluted with Et2O and EtOAc and washed with brine. The
organic phase was dried over Na2SO4, filtered, and the solvent re-
moved in vacuo. Chromatography (hexanes/EtOAc 5:1 to 1:1)
afforded an isomeric mixture of hemiketals (1.85 g) that was di-
rectly protected by treatment with catalytic TsOH/H2O in CH3OH/
CH(OCH3)3 (25 mL, 1:1 v/v) at rt for 1 h. After quenching with solid
NaHCO3 and dilution with Et2O the organic phase was washed with
water and brine, dried over Na2SO4, filtered, and the solvent re-
moved in vacuo to afford (þ)-61 (1.90 g) as a single isomer. An
analytical sample was purified by recrystallization in hexanes to
afford pure (þ)-61 mp 76e78 ꢁC having ½a D22
ꢂ
þ147 (c 1.347, THF); 1H
NMR (CDCl3, 400 MHz):
d
6.33 (ddd, J1¼17.3, J2¼10.8, J3¼4.5 Hz,1H),
5.48 (1H, s), 5.21 (1H, s), 5.06 (td, J1¼4.5, J2¼2.1 Hz, 1H), 5.02 (td,
J1¼10.8, J2¼2.1 Hz, 1H), 3.71e3.67 (m, 2H), 3.61 (s, 3H), 3.16 (s, 3H),
3.02e2.95 (m, 1H), 2.18e2.07 (m, 2H), 1.99 (dt, J1¼13.7, J2¼4.4 Hz,
1H), 1.80 (ddd, J1¼13.7, J2¼4.4, J3¼2.8 Hz, 1H), 1.57e1.52 (m, 1H),
1.38 (dt, J1¼13.7, J2¼4.2 Hz, 1H), 1.28 (3H, s), 1.04 (3H, s); 13C NMR
(CDCl3, 100 MHz):
d 177.2, 149.7, 140.9, 115.0, 113.0, 101.1, 60.9, 51.7,
47.7, 47.2, 46.8, 42.5, 31.5, 27.2, 26.5, 24.8, 23.3; IR (neat): 3078,
2950, 2879,1728, 1634, 1460, 1435 cmꢀ1; APCI(þ): 295 ([MþH]þ, 2),
263 (100), 233 (18), 203 (29), 173 (13); APIES (þ): 317 ([MþNa]þ,
100).
The crude mixed ketal, which a single compound by NMR, was
used as obtained for the following transformation.
(from heptane/CH2Cl2) and ½a D22
ꢂ
þ19 (c 0.975, CHCl3): 1H NMR
(CDCl3, 400 MHz):
d
4.44 (dt, J1¼11.5, J2¼4.4 Hz, 1H), 4.22 (ddd,
J1¼11.5, J2¼10.4, J3¼3.7 Hz, 1H), 3.70 (s, 3H), 3.09 (d, J¼3.9 Hz, 1H),
2.95 (ddd, J1¼17.9, J2¼11.5, J3¼5.9 Hz, 1H), 2.75 (d, J¼3.9 Hz, 1H),
2.66 (dt, J1¼14.8, J2¼5.5 Hz, 1H), 2.56 (dt, J1¼18.0, J2¼4.9 Hz, 1H),
2.51e2.40 (m, 3H), 1.99e1.76 (m, 3H), 1.43 (s, 3H), 1.00 (s, 3H). 13C
4.2.45. (þ)-(2S,5S,7R,8S)-5-Carbomethoxy-5,7-dimethyl-8-(2-
hydroxyethyl)-2-methoxy-4-methylene-1-oxabicyclo[4.4.02,7]decane
(62). A solution of 61 (1.90 g, 6.5 mmol) in anhyd THF (35 mL) was
added dropwise (argon atmosphere, rt) to a solution of 9-BBN
(1.60 g, 13 mmol) in anhyd THF (25 mL). The mixture was stirred
NMR (CDCl3, 100 MHz):
d 210.2, 172.8, 170.5, 67.5, 61.1, 54.6, 52.1,
47.1, 46.6, 36.2, 33.9, 32.4, 28.1, 24.5, 24.1, 11.1. IR (neat): 2955, 1731,

9806
R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
1466, 1406 cmꢀ1. APCI (þ): 311 ([MþH]þ, 100), 293 (10), 233 (6).
HRMS calcd for C16H23O6 (MþH)þ: m/z 311.1495. Found: 311.1504.
stirred at reflux (DeaneStark system containing 3 A MS in the trap)
ꢀ
for 19 h. After cooling and addition of solid NaHCO3 the mixture
was diluted with EtOAc and water was added, the aqueous phase
was extracted with EtOAc and the combined organic layers were
washed with brine, dried (Na2SO4) and concentrated. Chromatog-
raphy of the crude product on silica gel (elution by hexanes/EtOAc
2:1 to 1:2) afforded 26.4 mg (45%) of 67 as an oil having: 1H NMR
4.2.47. (þ)-(3R,4S,8R)-Methyl 4,8-dimethyl-8-[(1R)-3-(3-furanyl)-1-
(2-methylene carboxy)-3-oxopropyl]-7-oxo-1-oxaspiro[2.5]octane-4-
carboxylate (65). A solution of 1.50 g of 3-tributylstannylfuran25
(4.2 mmol) in anhyd 5 mL of THF was cooled to ꢀ78 ꢁC and
2.3 mL of a 1.6 M solution of n-BuLi in hexanes (3.7 mmol) was
added and the resulting mixture was stirred for 1.5 h at ꢀ78 ꢁC. At
which time, a solution of (þ)-63 (501 mg, 1.6 mmol) in 15 mL of
anhyd THF was added and stirring was continued at the same
temperature for 15 min. The reaction mixture was then quenched
with satd aq NH4Cl, then the cold bath was removed. After warming
to rt, the phases were separated and the aqueous phase was
extracted thoroughly four times with EtOAc. The combined organic
phases were washed with brine, dried over Na2SO4, filtered, and the
solvent removed in vacuo.
Oxalyl chloride (2 M solution in CH2Cl2, 0.4 mL, 0.81 mmol) was
added, at ꢀ70 ꢁC and under argon atmosphere, over DMSO
(0.11 mL, 1.6 mmol) in anhyd CH2Cl2 (2.5 mL) and the mixture was
stirred for 30 min; a solution of a portion of the crude lactol/alcohol
64 (100 mg, 0.27 mmol) prepared above in anhyd CH2Cl2 (2.5 mL)
was then added and stirring was continued at the same tempera-
ture for 30 min before Et3N (0.34 mL, 2.43 mmol) was added. After
stirring at 0 ꢁC for 20 min and dilution with CH2Cl2 the reaction was
quenched with cold water and the aqueous phase was extracted
with CH2Cl2; the organic phase was washed with 1 N aq HCl, satd
NaHCO3 and brine, dried over Na2SO4, filtered, and the solvent
removed in vacuo. The residue was dissolved in t-BuOH (7 mL) and
2-methyl-2-butene (1 mL) and an aq solution (3.5 mL) of NaClO2
(80%, 209 mg,1.8 mmol) and NaH2PO4.H2O (408 mg, 3.0 mmol) was
added at rt; the mixture was stirred for 15 min before brine was
added, the aqueous phase was saturated with NaCl and extracted
with EtOAc; the organic phase was washed with brine (once), dried
over Na2SO4, filtered, and the solvent removed in vacuo to afford
74 mg (70%) of the crude title acid 65, which was used as obtained
in the following transformation.
(400 MHz, CDCl3):
d
7.42 (m, 2H), 6.18 (t, J¼1.4 Hz, 1H), 4.55 (dd(br),
J1¼7.4, J2¼2.4 Hz, 1H), 4.23 (d, J¼10.4 Hz, 1H), 4.06 (d, J¼10.4 Hz,
1H), 3.52 (s, 3H), 3.16 (s, 3H), 3.06 (s, 3H), 2.88 (dd, J1¼18.8,
J2¼6.0 Hz, 1H), 2.54 (dd, J1¼17.4, J2¼7.4 Hz, 1H), 2.27 (dd, J1¼18.8,
J2¼11.9 Hz, 1H), 2.21e2.13 (m, 1H), 1.90 (dd, J1¼17.4, J2¼2.4 Hz, 1H),
1.87 (dd, J1¼14.5, J2¼9.6 Hz, 1H), 1.80 (dd, J1¼14.5, J2¼2.2 Hz, 1H),
1.16 (s, 3H), 1.05 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 181.2, 168.8,
156.8, 143.7, 141.6, 126.0, 108.5, 101.5, 92.7, 91.3, 75.4, 55.0, 48.8,
48.5, 47.0, 43.2, 36.8, 32.9 (ꢃ2), 30.4, 23.0, 9.6. IR (neat): 2939, 1778,
1745, 1660 cmꢀ1; APCI (þ): 389 ([M-CH3OH]þ, 100), 195 (33), 151
(10); APIES (positive): 443 ([MþNa]þ, 99), 301(65), 233 (100), 123
(74), 102 (46).
This material was used in the following transformation as
obtained.
4.2.50. (1S,4S,5R,6R,10S)-2,12-Dioxa-3,11-dioxo-5-[2,2-
dimethoxyethyl-2-(3-furanyl)]-7-methoxy-4,6,10-trimethyl-tricyclo
and (1S,4R,5R,6R,10S)-2,12-dioxa-
3,11-dioxo-5-[2,2-dimethoxyethyl-2-furanyl]-7-methoxy-4,6,10-
trimethyl-tricyclo[7.4.01,6.01,10]tridec-7-ene (68
). A 0.1 M solution
[7.4.01,6.01,10]tridec-7-ene (68
b
)
a
of LDA in THF/hexanes (1.5 mL, 3 equiv) was added at ꢀ78 ꢁC under
inert atmosphere over a stirred solution of 67 (21 mg, 0.05 mmol)
in anhyd THF (1.5 mL) and anhyd HMPA (0.25 mL). After stirring for
1 h excess of CH3I (0.75 mL, freshly filtered over Al2O3) was added
and the mixture was stirred for 1 h while warming to rt, then
quenched with satd aq NH4Cl (3 mL). The layers were separated and
the organic phase was extracted with ether; the combined organic
layers were washed with brine, dried over Na2SO4 and the solvent
removed in vacuo. The crude material was chromatographed
(elution with hexanes/EtOAc 3:1 to 2:1) to obtain 18.2 mg (84%) of
68 (68b/68a w3:1). Alternatively the reaction was carried out at
4.2.48. (1S,5R,6R,10S)-6,10-Dimethyl-2,12-dioxa-3,7,11-trioxo-5-[2-
oxoethyl-2-(3-furanyl)]tricyclo[7.4.01,6.01,10]tridecane (66). A sample
of the preceding crude carboxylic acid 65 (145 mg, 0.37 mmol) was
dissolved in CH3CN (10 mL) and BF3-Et2O (0.27 mL, 2.1 mmol) was
added at rt After stirring for 10 min the reaction was quenched with
satd aq NaHCO3 and the aqueous phase extracted with EtOAc; the
organic phase was washed with brine, dried over Na2SO4, filtered,
and the solvent removed in vacuo. Flash chromatography (elution
by hexanes/EtOAc 2:1 to 1:1) yielded 55 mg (38%) of dilactone 66 as
ꢀ78 ꢁC to obtain, after chromatography, 71% of 68
b
/68
a
w6:1 and
:
23% of 67 as an oil having for the major isomer 68
b
1H NMR
(400 MHz, CDCl3):
d
7.41 (t, J¼1.7 Hz, 1H), 7.34 (s(br), 1H), 6.25 (dd,
J1¼1.7, J2¼0.7 Hz, 1H), 4.48 (dd(br), J1¼7.3, J2¼2.5 Hz, 1H), 4.24 (d,
J¼10.3 Hz, 1H), 3.48 (s, 3H), 3.25 (s, 3H), 3.18 (s, 3H), 2.82 (dt, J1¼7.6,
J2¼7.6 Hz, 1H), 2.52 (dd, J1¼17.4, J2¼7.3 Hz, 1H), 2.39 (dd(br),
J1¼10.2, J2¼7.6 Hz, 2H), 2.29 (dd, J1¼14.3, J2¼10.2 Hz, 1H), 1.91 (dd,
J1¼17.4, J2¼2.5 Hz, 1H), 1.68 (d(br), J¼14.3 Hz, 1H), 1.45 (d, J¼7.6 Hz,
3H), 1.25 (s, 3H), 1.07 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 181.4,
an oil having: 1H NMR (400 MHz, CDCl3):
d
8.02 (dd, J1¼1.4,
178.8, 156.9, 143.4, 140.8, 126.3, 109.3, 102.2, 92.5, 91.7, 75.5, 54.8,
49.8, 48.5, 47.1, 44.1, 36.5, 33.5, 33.0, 32.6, 23.1, 17.2, 12.3; IR (neat):
2926, 1784, 1715, 1674, 1563, 1463, 1386 cmꢀ1; APCI (þ): 403
([MþH]þꢀCH3OH, 100), 279 (7), 195 (51), 165 (12); APIES (þ): 457
([MþNa]þ, 100).
J2¼0.9 Hz, 1H), 7.47 (dd, J1¼1.9, J2¼1.4 Hz, 1H), 6.72 (dd, J1¼1.9,
J2¼0.9 Hz, 1H), 4.34 (d, J¼10.9 Hz, 1H), 4.02 (d, J¼10.9 Hz, 1H),
3.50e3.43 (m, 1H), 2.94 (dd, J1¼18.7, J2¼6.2 Hz, 1H), 2.93 (ddd,
J1¼15.4, J2¼12.6, J3¼5.5 Hz, 1H), 2.69 (dd, J1¼17.9, J2¼4.1 Hz, 1H),
2.53 (dd, J1¼17.9, J2¼7.3 Hz, 1H), 2.39e2.25 (m, 3H), 1.93 (ddd,
J1¼14.4, J2¼12.3, J3¼4.4 Hz, 1H), 1.66 (s, 3H), 1.14 (s, 3H); 13C NMR
This material was used in the following transformation as
obtained.
(100 MHz, CDCl3):
d 208.7, 190.9, 177.7, 166.6, 147.5, 144.6, 126.9,
108.2, 92.7, 72.8, 50.9, 47.1, 33.3, 32.3, 30.3, 30.1, 17.6, 10.1. IR (neat):
3138, 2924, 1784, 1715, 1681, 1564, 1511 cmꢀ1; APCI (þ): 361
([MþH]þ, 100).
4.2.51. (1S,4S,5R,6R,10S)-6,10-Trimethyl-2,12-dioxa-5-[2-oxoethyl-2-
(3-furanyl)]-3,7,11-trioxotricyclo[7.4.01,6.01,10]tridecane (69
b
), (1S,4R,
5R,6R,10S)-2,12-dioxa-5-[2-oxoethyl-2-furanyl]-4,6,10-trimethyl-
3,7,11-trioxotricyclo[7.4.01,6.01,10
tridecane (69
and (þ)saudin
(1). Major diastereomer 68 was deprotected by treatment with
dilute hydrochloric acid in CH3OH, controlling the temperature to
prevent epimerization at C-4 by dissolving a few mg of 68 in
This material was used in the following transformation as
obtained.
]
a)
b
4.2.49. (1S,5R,6R,10S)-6,10-Dimethyl-2,12-dioxa-3,11-dioxo-5-[2,2-
dimethoxy ethyl-2-(3-furanyl)]-7-methoxy-tricyclo[7.4.01,6.01,10]tri-
dec-7-ene (67). Toluensulfonic acid hydrate (70 mg, 0.37 mmol)
was added to a solution of bis-lactone 66 (50 mg, 0.14 mmol) in
CH3OH (8 mL) and CH(OCH3)3 (1.5 mL) at rt. The mixture was
b
CH3OH (0.5 mL) and aq 1 N HCl (0.5 mL) was added at rt. The
mixture was stirred at rt for 18 h, then at 45 ꢁC (oil bath temper-
ature) for 4 days. 1H NMR after evaporation to dryness showed
a
clean mixture of 69 and (þ)-saudin (69
b
/69a
/(þ)-saudin

R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
9807
w2.5:1:1). Spectroscopic data for the major isomer 69
b
:
1H NMR
22.7, 21.1, 18.9; IR (neat): 2954, 1732, 1604 cmꢀ1; APCI (þ): 421
([MþH]þ, 6), 361 (100), 123 (14); APIES (þ): 443 ([MþNa]þ, 100).
HRMS calcd for C22H29O8: m/z 421.1862. Found: 421.1860.
(400 MHz, CDCl3): 8.07 (s(br), 1H), 7.48 (s(br), 1H), 6.75 (d(br),
d
J¼1.5 Hz, 1H), 4.34 (d, J¼10.9 Hz, 1H), 3.60 (ddd, J1¼9.1, J2¼7.8,
J3¼3.7 Hz, 1H), 3.16 (dt, J1¼7.8, J2¼7.8 Hz, 1H), 2.95 (dd, J1¼18.1,
J2¼9.1 Hz, 1H), 2.86 (ddd, J1¼15.4, J2¼12.9, J3¼6.0 Hz, 1H), 2.44 (dd,
J1¼18.1, J2¼3.7 Hz, 1H), 2.39 (dt, J1¼15.4, J2¼4.6 Hz, 2H), 2.23 (ddd,
J1¼14.1, J2¼6.0, J3¼4.6 Hz, 1H), 1.89 (ddd, J1¼14.1, J2¼12.9, J3¼4.6 Hz,
1H), 1.66 (s, 3H), 1.29 (d, J¼7.8 Hz, 3H), 1.17 (s, 3H); 13C NMR
4.2.54. (1S,4R,6S,13S,14S)-13-Carbomethoxy-13,14-dimethyl-4-(3-
furanyl)-8-oxo-3,9,15-trioxatetracyclo[8.3.1.11,4.06,14]tetradec-10-ene
(ꢀ)-75. Solid K2CO3 (800 mg, 5.8 mmol) was added at 0 ꢁC to
a solution of 485 mg of (þ)-72 (1.15 mmol) in 10 mL of CH3OH, then
1 mL of H2O was added and the mixture was stirred for 1 h at rt.
After dilution of the reaction mixture with EtOAc, the organic phase
was washed with H2O and brine, dried over Na2SO4, filtered, and
the solvent removed in vacuo. The crude primary alcohol 73
(438 mg) was directly oxidized to carboxylic acid 74 as previously
described above for the transformation of 64 into 65.
(100 MHz, CDCl3):
d 209.1, 191.1, 177.6, 171.3, 147.4, 144.7, 126.8,
108.3, 92.2, 72.9, 51.5, 47.0, 36.6, 34.9, 33.1, 29.9, 17.2, 15.7, 12.4; IR
(neat): 2925, 1784, 1716, 1677, 1463, 1385, 1262, 1156, 1089, 1018,
970, 801 cmꢀ1. APCI (þ): 375 ([MþH]þ, 100), 200 (13), 122 (11).
4.2.52. (ꢀ)-(3R,4S,8R)-Methyl 8-[(1R)-1-[2-(acetyloxy)ethyl]-3-(3-
furanyl)-3-oxopropyl]-4,8-dimethyl-7-oxo-1-oxaspiro[2.5]octane-4-
carboxylate (71). A solution of 1.50 g of 3-tributylstannylfuran25
(4.2 mmol) in anhyd 5 mL of THF was cooled to ꢀ78 ꢁC and
2.3 mL of a 1.6 M solution of n-BuLi in hexanes (3.7 mmol) was
added and the resulting mixture was stirred for 1.5 h at ꢀ78 ꢁC. At
which time, a solution of (þ)-63 (501 mg, 1.6 mmol) in 15 mL of
anhyd THF was added and stirring was continued at the same
temperature for 15 min. The reaction mixture was then quenched
with satd aq NH4Cl, then the cold bath was removed. After warming
to rt, the phases were separated and the aqueous phase was
extracted thoroughly four times with EtOAc. The combined organic
phases were washed with brine, dried over Na2SO4, filtered, and the
solvent removed in vacuo. The resulting crude alcohols 64 (and/or
70) was dissolved in 10 mL of CH2Cl2 and acetylated under standard
conditions by treatment with 0.4 mL of Ac2O, a catalytic amount of
DMAP, and 1 mL of pyridine at rt for 1 h. After quenching the re-
action mixture with satd aq NaHCO3, the aqueous phase was
extracted thoroughly four times with CH2Cl2 and the combined
organic phases were washed successively with 1 N aq HCl, satd
NaHCO3, and brine, dried over Na2SO4, filtered, and the solvent
removed in vacuo. Flash chromatography (elution with a gradient
of hexanes/EtOAc from 1.5:1 to 1:2) afforded 550 mg of (ꢀ)-71 (81%
The resulting crude acid 74 (w1.15 mmol) was dissolved in
10 mL of anhyd CH2Cl2 in the presence of 471 mg of anhyd NaOAc
(5.7 mmol) and the mixture cooled to 0 ꢁC. A 1 mL portion of
(CF3CO)2O (7.0 mmol) was added at 0 ꢁC, and the reaction mixture
was stirred for 1 h while warming slowly from 0 ꢁC to rt. After
quenching the reaction mixture with satd aq NaHCO3, the aqueous
phase was separated and extracted thoroughly four times with
CH2Cl2. The combined organic phases were washed with brine,
dried over Na2SO4, filtered, and the solvent removed in vacuo. Flash
chromatography (a gradient of hexanes/EtOAc from 2:1 to 1:1)
yielded 289 mg of (ꢀ)-75 (67% for four steps from (þ)-72) as
a white solid having mp 128e130 ꢁC (from hexanes/Et2O/CH2Cl2)
and ½a 2D2
ꢂ
ꢀ31 (c 0.995, CHCl3): 1H NMR (CDCl3, 400 MHz):
d 7.51
(s(br), 1H), 7.41 (t, J¼1.9 Hz, 1H), 6.45 (d(br), J¼1.9 Hz, 1H), 5.35 (dd,
J1¼4.6, J2¼3.2 Hz, 1H), 4.32 (d, J¼9.0 Hz, 1H), 4.28 (d, J¼9.0 Hz, 1H),
3.71 (s, 3H), 3.07 (dd, J1¼18.2, J2¼4.6 Hz, 1H), 3.06 (dd, J1¼18.9,
J2¼6.8 Hz, 1H), 2.48e2.40 (m, 2H), 2.20 (dd, J1¼18.2, J2¼3.2 Hz, 1H),
2.09 (dd, J1¼13.0, J2¼5.7 Hz, 1H), 1.85 (t, J¼13.0 Hz, 1H), 1.41 (s, 3H),
1.19 (s, 3H); 13C NMR (CDCl3, 100 MHz):
d 175.2, 165.9, 149.4, 143.4,
140.1, 125.6, 108.1, 105.5, 103.4, 85.9, 67.7, 52.3, 45.2, 40.2, 37.9, 32.0,
31.5, 22.8, 22.1; IR (neat): 2919, 1732, 1691, 1602 cmꢀ1; APCI (þ):
375 ([MþH]þ, 100), 279 (60). HRMS calcd for C20H23O7 (MþH)þ: m/
z 375.1444. Found: 375.1459.
From the less polar fractions, 58 mg of the primary tri-
fluoroacetate of alcohol 73 (12%) was also recovered which was
recycled by hydrolysis to 73.
overall from (þ)-63) having ½a D22
ꢂ
ꢀ4 (c 1.785, CHCl3): 1H NMR
(CDCl3, 400 MHz):
d
8.02 (s(br),1H), 7.42 (s(br),1H), 6.69 (s(br),1H),
4.11e3.99 (m, 2H), 3.66 (s, 3H), 3.26e3.17 (m, 1H), 3.16 (dd, J1¼18.5,
J2¼6.2 Hz, 1H), 3.09 (d, J¼3.9 Hz, 1H), 2.93e2.81 (m, 1H), 2.75 (d,
J¼3.9 Hz, 1H), 2.63 (dd, J1¼18.5, J2¼3.1 Hz, 1H), 2.52e2.43 (m, 3H),
2.04e1.97 (m, 1H), 1.97 (s, 3H), 1.60 (s, 3H), 1.55e1.46 (m, 1H), 0.84
4.2.55. (1S,4R,6S,7R,13S,14S)-13-Carbomethoxy-4-(3-furanyl)-8-oxo-
7,13,14-trimethyl-3,9,15-trioxatetracyclo[8.3.1.11,4.06,14]tetradec-10-
(s, 3H); 13C NMR (CDCl3, 100 MHz):
d 212.5, 193.1, 173.4, 170.7, 147.0,
144.2, 127.0, 108.4, 62.0, 60.8, 55.8, 51.9, 46.9 (ꢃ2), 40.3, 37.0, 31.0,
29.5, 27.8, 24.8, 20.7, 10.1; IR (neat): 3139, 2955, 1732, 1681, 1563,
1368, 1156, 1044, 954, 735 cmꢀ1; APCI (þ): 421 ([MþH]þ, 56), 316
(100), 343 (10), 123 (9); HRMS calcd for C22H29O8 (MþH)þ: m/z
421.1862. Found: 421.1877.
ene (ꢀ)-(76
a). A 1.45 M solution of n-BuLi in hexane (0.56 mL,
0.81 mmol) was added dropwise at ꢀ78 ꢁC under Ar to a solution of
0.15 mL of 2,2,6,6-tetramethylpiperidine (0.92 mmol) in 5 mL of
anhyd THF and the resulting mixture was stirred for 1 h. At ꢀ78 ꢁC,
a solution of 193 mg (0.52 mmol) of (ꢀ)-75 in 10 mL of anhyd THF
was then added dropwise at such a rate that the temperature did
not rise. After stirring the resulting mixture for 2.5 h at ꢀ78 ꢁC,
0.56 mL of HMPA (3.2 mmol) was added dropwise, followed after
5 min by rapid addition of 3 mL of CH3I (excess) via syringe. The
temperature of the reaction mixture was slowly raised to ꢀ50 ꢁC
and stirring was continued for 35 min at w ꢀ50 ꢁC. After quenching
the reaction mixture at wꢀ45 ꢁC with 10 mL of satd aq NH4Cl and
warming to rt, the aqueous phase was separated and extracted
thoroughly four times with EtOAc. The combined organic phases
were washed with brine, dried over Na2SO4, filtered, and the sol-
vent removed in vacuo. Flash chromatography on silica gel (elution
using a gradient of hexanes/EtOAc from 2:1 to 1:1) afforded 59 mg
4.2.53. 7-(2-Acetyloxyethyl)-2-carboxymethyl-2,6-dimethyl-9-(3-
furanyl)-10,12-dioxa tricyclo [7.2.1.02,6]dodecane (þ)-(72). A 0.2 mL
portion of BF3$Et2O (1.6 mmol) was added at rt to a solution of
84 mg of (ꢀ)-71 (0.2 mmol) in 5 mL of CH3CN. After stirring for
10 min at rt, the reaction mixture was quenched with satd aq
NaHCO3 and the aqueous phase extracted thoroughly four times
with EtOAc. The combined organic phases were washed with brine,
dried over Na2SO4, filtered, and the solvent removed in vacuo. Flash
chromatography on silica gel (elution with a gradient of hexanes/
EtOAc from 2:1 to 1:1) provided 76 mg of (þ)-72 (90%) having ½a D22
ꢂ
þ46 (c 1.250, CHCl3): 1H NMR (CD3CN, 400 MHz):
d 7.57 (s(br), 1H),
7.44 (t, J¼1.8 Hz, 1H), 6.46 (d(br), J¼1.8 Hz, 1H), 4.25 (d, J¼9.3 Hz,
1H), 4.17 (d, J¼9.3 Hz, 1H), 4.06e3.99 (m, 2H), 3.71 (s, 3H), 2.92 (dt,
J1¼14.1, J2¼6.5 Hz, 1H), 2.40 (ddd, J1¼13.6, J2¼6.5, J3¼2.3 Hz, 1H),
2.14e1.80 (m, 7H), 1.98 (s, 3H), 1.31 (s, 3H), 1.11 (s, 3H); 13C NMR
(29%) of 76
a, and 92 mg (46%) of 76b. Treatment of the 92 mg
(0.24 mmol) sample of 76
b
in 5 mL of anhyd THF at ꢀ78 ꢁC with
1.5 mL (0.85 equiv) of a 0.14 M solution of LDA in anhyd THF and
warming with stirring to 0 ꢁC over 1.5 h then continued stirring at
0 ꢁC for 2 h followed by quenching, isolation, and purification as
(CD3CN, 100 MHz):
d 212.3, 176.1, 171.7, 144.4, 141.5, 127.5, 109.4,
105.6, 91.3, 68.9, 64.3, 56.0, 52.9, 47.4, 39.5, 37.2, 36.5, 33.7, 30.3,
above afforded 82 mg (88%) of (ꢀ)-76
a or a combined yield of 70%

9808
R.K. Boeckman Jr. et al. / Tetrahedron 67 (2011) 9787e9808
having ½a 2D2
ꢂ
ꢀ14 (c 1.390, CHCl3): 1H NMR (CDCl3,
7. Labadie, G. R.; Cravero, R. M.; Gonzalez Sierra, M. Molecules 2000, 5,
321e322.
8. Labadie, G. R.; Luna, L. E.; Gonzalez-Sierra, M.; Cravero, R. M. Eur. J. Org. Chem.
2003, 3429e3434.
9. Tambar, U. K.; Kano, T.; Stoltz, B. M. Org. Lett. 2005, 7, 2413e2416.
10. Tambar, U. K.; Kano, T.; Zepernick, J. F.; Stoltz, B. M. J. Org. Chem. 2006, 71,
8357e8364.
11. Boeckman, R. K., Jr.; Nelson, S. G.; Gaul, M. D. J. Am. Chem. Soc. 1992, 114,
2258e2260.
12. (a) Neeb, M. Ph.D. Dissertation, University of Rochester, 1995; (b) Fang, Y. Ph.D.
Dissertation, University of Rochester, 1991.
13. Boeckman, R. K., Jr.; Neeb, M. J.; Gaul, M. D. Tetrahedron Lett. 1995, 36, 803e806.
14. Berti, G. Top. Stereochem. 1973, 7, 93e251.
15. Heathcock, C. H.; Young, S. D.; Hagen, J. P.; Pilli, R.; Badertscher, U. J. Org. Chem.
1985, 50, 2095e2105.
16. Bartmann, E. Angew. Chem., Int. Ed. Engl. 1986, 25, 629e631.
17. Cohen, T.; Jeong, I. H.; Mudryk, K.; Bhupathy, M.; Awad, M. M. A. J. Org. Chem.
1990, 55, 1528e1536.
18. McChesney, J. D.; Thompson, T. N. J. Org. Chem. 1985, 50, 3473e3481.
19. (a) Darling, S. D.; Devgan, O. N.; Cosgrove, R. E. J. Am. Chem. Soc. 1970, 92,
696e697; (b) Brown, H. C.; Dodson, V. H. J. Am. Chem. Soc. 1957, 79, 2302e2306.
20. (a) Gasa, S.; Hamanaka, N.; Matsunaga, S.; Okuno, T.; Takeda, N.; Matsumoto, T.
Tetrahedron Lett. 1976, 17, 553e556; (b) Kamata, S.; Uyeo, S.; Haga, N.; Nagata,
W. Synth. Commun. 1973, 3, 265e272.
21. (a) Ziegler, F. E.; Kneisley, A.; Thottathil, J. K.; Wester, R. T. J. Am. Chem. Soc. 1988,
110, 5434e5442; (b) Ziegler, F. E.; Thottathil, J. K. Tetrahedron Lett. 1982, 23,
3531e3534.
22. (a) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12, 989e993; (b)
Lipton, M. F.; Basha, A.; Weinreb, S. M. Org. Synth. 1980, 59, 49e53; (c) Basha, A.;
Lipton, M. F.; Weinreb, S. M. Tetrahedron Lett. 1977, 18, 4171e4174.
23. (a) Boeckman, R. K., Jr.; Shao, P.; Mullins, J. J. Org. Synth. 2000, 77, 141e152; (b)
Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899; (c) Dess, D. B.; Martin, J. C. J.
Org. Chem. 1983, 48, 4155e4156.
24. (a) Boehm, M. F.; Prestwich, G. D. J. Org. Chem. 1986, 51, 5447e5450; (b) Dubey,
S. K.; Kumar, S. J. Org. Chem. 1986, 51, 3407e3412; (c) Koppenhoefer, B.; Weber,
R.; Schurig, V. Synthesis 1982, 316e318.
of (ꢀ)-76
a
400 MHz):
d
7.52 (s(br), 1H), 7.40 (t, J¼1.8 Hz, 1H), 6.46 (d(br),
J¼1.8 Hz, 1H), 5.29 (dd, J1¼4.4, J2¼3.5 Hz, 1H), 4.30 (d, J¼9.0 Hz, 1H),
4.27 (d, J¼9.0 Hz, 1H), 3.71 (s, 3H), 3.17 (dq, J1¼7.1, J2¼6.1 Hz, 1H),
3.11 (dd, J1¼18.4, J2¼4.4 Hz, 1H), 2.32 (ddd, J1¼11.7, J2¼6.1,
J3¼5.5 Hz, 1H), 2.17 (dd, J1¼18.4, J2¼3.5 Hz, 2H), 2.13 (dd, J1¼13.3,
J2¼5.5 Hz, 2H), 1.56 (t(br), J¼12.7, 1H), 1.41 (s, 3H), 1.25 (d, J¼7.1 Hz,
1H), 1.24 (s, 3H); 13C NMR (CDCl3, 100 MHz):
d 175.3, 169.5, 149.8,
143.3, 140.0, 125.9, 108.1, 104.9, 103.5, 86.0, 67.7, 52.3, 45.1, 39.5,
37.6, 35.3, 34.6, 31.5, 23.1, 22.3, 13.0; IR (neat): 2918, 1732,
1693 cmꢀ1; APCI (þ): 389 ([MþH]þ, 100). HRMS calcd for C21H25O7
(MþH)þ: m/z 389.1600. Found: 389.1615.
Traces of gem-dimethyl product 77 arising from polyalkylation
and minor by-products arising from an additional alkylation of
a position on the furan ring were observed to be present in the
crude alkylation product by 1H NMR.
4.2.56. (þ)-Saudin (1). A suspension of 56 mg of 76a (0.14 mmol)
in 10 mL of 2 N aq KOH was degassed with Ar and heated at reflux
for 3.5 h. After cooling to rt and acidification with 10% hydrochloric
acid to pH ꢄ1, the resulting aqueous phase was saturated with solid
NaCl and extracted thoroughly four times with EtOAc. The com-
bined organic phases were washed once with brine, dried over
Na2SO4, filtered, and the solvent removed in vacuo. The resulting
58 mg of crude diacid 78 was directly dissolved in 10 mL of anhyd
1,2-dichloroethane under Ar, and 0.7 mL of a 0.5 M solution of
TMSOTf in 1,2-dichloroethane (0.35 mmol) was added at rt. After
stirring for 1 h at rt, an additional 0.3 mL of the 0.5 M solution of
TMSOTf in 1,2-dichloroethane (0.14 mmol) was added and stirring
was continued for an additional 1 h. At which point, the reaction
mixture was quenched with satd aq NaHCO3, the phases separated,
and the aqueous phase extracted thoroughly four times with EtOAc.
The combined organic phases were washed once with brine, dried
over Na2SO4, filtered, and the solvent removed in vacuo. Flash
chromatography of the residue afforded 36 mg (70%) of (þ)-Saudin
25. Fleming, I.; Taddei, M. Synthesis 1985, 898.
26. (a) Clariana, J.; Galvez, N.; Marchi, C.; Moreno-Manas, M.; Vallribera, A.; Molins,
~
E. Tetrahedron 1999, 55, 7331e7334; (b) White, J. D.; Sung, W. L. J. Org. Chem.
1974, 39, 2323e2328; (c) White, J. D.; Takabe, K.; Prisbylla, M. P. J. Org. Chem.
1985, 50, 5233e5244.
27. (a) Nour, M.; Tan, K.; Jankowski, R.; Cave, C. Tetrahedron: Asymmetry 2001, 12,
765e769; (b) Tan, K.; Alvarez, R.; Nour, M.; Cave, C.; Chiaroni, A.; Riche, C.;
d’Angelo, J. Tetrahedron Lett. 2001, 42, 5021e5023.
28. Narasaka, K.; Bald, E.; Mukaiyama, T. Chem. Lett. 1975, 4, 1041e1044.
29. (a) Mancuso, A. J.; Brownfain, D. S.; Swern, D. J. Org. Chem. 1979, 44, 4148e4150;
(b) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480e2482.
30. Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37, 2091e2096.
31. Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 399e402.
32. (a) Zahra, J.-P.; Chauvet, F.; Cost-Maniere, I.; Martres, P.; Perfetti, P.; Waegell, B.
Bull. Soc. Chim. Fr. 1997, 134, 1001e1024; (b) McDonald, F. E.; Wang, X.; Do, B.;
Hardcastle, K. I. Org. Lett. 2000, 2, 2917e2919.
(1) having mp 204e206 ꢁC from Et2O/EtOAc and ½a D22
þ14 (c 0.460,
ꢂ
CHCl3). All spectroscopic properties [IR, 1H NMR, 13C NMR, APCI
(positive)] except the sign of the optical rotation were identical to
those of an authentic sample of natural (ꢀ)-Saudin kindly provided
by Professor Mossa.1,2
33. Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J.
J. Org. Chem. 1999, 64, 2564e2566.
34. Caine, D. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Ox-
ford, 1991; Vol. 3, p 1; and references cited therein.
Supplementary data
35. (a) Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc. 1994, 116, 7949e7950; (b) Re-
menar, J. F.; Lucht, B. L.; Kruglyak, D.; Romesberg, F. E.; Gilchirst, J. H.; Collum,
D. B. J. Org. Chem. 1997, 62, 5748e5754.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.09.067.
36. Grieco, P. A.; Ohfune, Y.; Yokoyama, Y.; Owens, W. J. Am. Chem. Soc. 1979, 101,
4749e4752.
References and notes
37. Watanabe, H.; Machida, K.; Itoh, D.; Nagatsuka, H.; Kitahara, T. Chirality 2001,
13, 379e385.
38. Boeckman, R. K.; Laci, M. A.; Johnson, A. T. Tetrahedron: Asymmetry 2001, 12,
205e217.
1. Mossa, J. S.; Cassady, J. M.; Antoun, M. D.; Byrn, S. R.; McKenzie, A. T.; Kozlowski,
J. F.; Main, P. J. Org. Chem. 1985, 50, 916e918.
2. Mossa, J. S.; El-Denshary, E.; Hindawi, R.; Ageel, A. Int. J. Crude Drug Res. 1988,
26, 81e87.
39. Delorme, D.; Girard, Y.; Rokach, J. J. Org. Chem. 1989, 54, 3635e3640.
40. (a) Nicolaou, K. C.; Petasis, N. A.; Li, W. S.; Ladduwahetty, T.; Randall, J. L.;
Webber, S. E.; Hernandez, P. E. J. Org. Chem. 1983, 48, 5400e5403; (b) Marron,
B. E.; Spanevello, R. A.; Elisseou, M. E.; Serhan, C. N.; Nicolaou, K. C. J. Org. Chem.
1989, 54, 5522e5527.
3. Winkler, J. D.; Doherty, E. M. Tetrahedron Lett. 1998, 39, 2253e2256.
4. Winkler, J. D.; Doherty, E. M. J. Am. Chem. Soc. 1999, 121, 7425e7526.
5. Boeckman, R. K., Jr.; Rico Ferreira, M. d. R.; Mitchell, L. H.; Shao, P. J. Am. Chem.
Soc. 2002, 124, 190e191.
6. Labadie, G. R.; Cravero, R. M.; Gonzalez-Sierra, M. Synth. Commun. 1996, 26,
4671e4684.
41. Mitchell, I. S.; Pattenden, G.; Stonehouse, J. Org. Biomol. Chem. 2005, 3,
4412e4431.