A modified approach to the phomoidrides: synthesis of a late-stage intermediate containing a key carbon quaternary stereocenter

Article abstract of DOI:10.1016/j.tet.2007.02.106

A previously developed approach to the synthesis of the phomoidrides has been modified to incorporate all necessary carbon atoms prior to the key tandem carbonylation/Cope rearrangement reaction. This modification necessitated the synthesis of a challengi

Full text of DOI:10.1016/j.tet.2007.02.106

Tetrahedron 63 (2007) 5895–5902
A modified approach to the phomoidrides: synthesis of a late-stage
intermediate containing a key carbon quaternary stereocenter
*
Bastien Castagner and James L. Leighton
Department of Chemistry, Columbia University, 3000 Broadway, MC 3117, New York, NY 10027, United States
Received 23 January 2007; revised 21 February 2007; accepted 23 February 2007
Available online 28 February 2007
Abstract—A previously developed approach to the synthesis of the phomoidrides has been modified to incorporate all necessary carbon
atoms prior to the key tandem carbonylation/Cope rearrangement reaction. This modification necessitated the synthesis of a challenging
all-carbon quaternary stereocenter, which in turn rendered ineffective several reactions from the original synthesis. An oxidative radical cleav-
age of a spirocyclopropane ring system was developed that accomplishes the synthesis of the quaternary center, and a regioselective double
hydroboration reaction was devised that provides an alternate approach to a key sequence of functional group interconversions, where the
originally developed route was found to be ineffective.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
synthetic effort that has thus far culminated in four total syn-
theses from the Nicolaou,3 Shair,4 Fukuyama,5 and Dani-
shefsky6 groups as well as numerous synthetic approaches.7
In the context of a screening program, Kaneko and co-
workers identified two new natural products, phomoidrides
A (CP-225917) and B (CP-263114), which displayed mod-
erate activity against both RAS farnesyl transferase and
squalene synthase (Fig. 1).1 The discovery was followed a
few years later by the identification of two new secondary
metabolites in the fermentation broth, phomoidrides C and
D, both thought to derive from the same primary biosyn-
thetic product, phomoidride B.2 The intriguing and novel
structures of these natural products inspired intensive
We have previously described an approach to the synthesis of
phomoidride D based on a tandem carbonylation/silyloxy-
Cope rearrangement sequence exemplified by the conver-
sion of 1 to 2 (Scheme 1).8 Although there is precedent for
the conversion of the silyl enol ether into the requisite maleic
anhydride moiety, we became intrigued by the notion of
building the two missing carbon atoms of the anhydride
into the carbonylation/Cope precursor so as to produce
3 from 4. A straightforward and precedented oxidation
sequence9 would then be all that remained to carry out fol-
lowing the tandem reaction, minimizing the number of trans-
formations that would have to be carried out in the presence
of the sensitive pseudoester. While this looked like an attrac-
tive possibility on paper, it also necessitated a significantly
redesigned synthesis of the densely functionalized [2.2.1]-
bicycloheptane precursor to the tandem carbonylation/Cope
rearrangement reaction. Specifically, whereas thevinylgroup
of 1 was installed by a simple vinyl lithium addition to the
corresponding ketone, the modified synthetic plan neces-
sitated the design of a synthesis that would allow the efficient
construction of a carbon quaternary stereocenter (marked *
in structure 4, Scheme 1). In the retrosynthesis of 4 to 5, it
was assumed that what had worked in the previous route to
convert the endocyclic olefin into the b-trifloxy enone would
work in this series as well (as will be described, this assump-
tion proved unwarranted). Compound 5 was identified as an
initial target due to its straightforward, at least in principle,
disconnection into two simpler fragments by way of a
Diels–Alder (DA) cycloaddition. In this case, however, the
O
OH
HO
O
Me
O
7
O
Me
O
O
O
14
7(S) - Phomoidride A (CP-225, 917)
7(R) - Phomoidride C
CO2H
O
O
Me
Me
O
7
O
O
O
14
7(S) - Phomoidride B (CP-263, 114)
7(R) - Phomoidride D
CO2H
Figure 1. Phomoidrides A–D.
Keywords: Phomoidrides; Quaternary stereocenter; Radical; Hydrobora-
tion.
* Corresponding author. Tel.: +1 212 854 4262; fax: +1 212 932 1289;
e-mail: leighton@chem.columbia.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.106

5896
B. Castagner, J. L. Leighton / Tetrahedron 63 (2007) 5895–5902
TESO
OH
TESO
R'
TESO
R'
OTBDPS
Me
Me
Me
O
O
R
R
2
20 mol %
4
OTf
OTES
O
Pd(PPh3)4
115 °C
O
O
O
O
O
5
i-Pr2NEt,
Silyloxy-
Cope
OH
O
O
800 psi CO,
PhCN, 70 °C
1
78% yield
2
Rearr.
OTBDPS
R"
R"
Me
Me
OH
OPG
OPG
OPG
OPG
OPG
O
2
OPG
OPG
OPG
O
OPG
+
O
*
O
OPG
*
R'
*
O
O
Me
R'
R'
OTf
5
OPG
OPG
R'
N
O
O
7
4
3
OH
5
6
8
CO2Me
CO2Me
Bn
R"
Scheme 1. Modified retrosynthesis with all necessary carbon atoms built into the Cope rearrangement precursor.
disconnection leads back to a 5,5-disubstituted cyclopenta-
diene, and a DA reaction that would very likely be highly
problematic, at best. Thus, it was envisioned that the carbon
atoms of the target quaternary center would be ‘packaged’ as
a spirocyclopropane as in structure 6, which leads to diene 7
and dienophile 8 upon DA disconnection. This notion was
inspired by a demonstration by Corey that if constrained in
a cyclopropane ring along these lines, 5,5-dialkyl substituted
cyclopentadienes are competent partners in DA cycloaddi-
tions,10 and by a demonstration by Carreira that a cyclopro-
pane similar to 6 could be subjected to radical fragmentation
under oxidative conditions to install the requisite hydr-
oxymethyl group on the carbon quaternary center.11 An
additional benefit of this new retrosynthesis was that, in con-
trast to our earlier route, it would lend itself well to an enan-
tioselective version by employing the Evans Diels–Alder
protocol.12 Herein, we describe the successful realization
of this strategy in the form of a synthesis of a version of
compound 4 (wherein R00¼H and PG¼TBS) that efficiently
incorporates the requisite carbon quaternary stereocenter.
fully substituted fulvene 11 in 64% yield. Cyclopropanations
of fulvenes using dimethylsulfoxonium methylide15 had pre-
viously been demonstrated,16 and we were delighted to dis-
cover that the method worked well in the case of fulvene 11,
delivering the requisite spirocyclopropyl cyclopentadiene 12
in 78% yield. Diels–Alder cycloaddition of 8 and 12 using
the proscribed conditions of Evans12 proceeded smoothly
and delivered 13 in 84% yield, with excellent (>97:3) dia-
stereoselectivity. Removal of both benzyl groups could be
accomplished with BCl3, and gave diol 14 in 73% yield. In
anticipation of the radical cleavage of the cyclopropane
ring to reveal the fully elaborated carbon quaternary center,
it was necessary to convert one of the alcohols into an iodide,
to protect the other alcohol, and in addition it proved expe-
dient to remove the oxazolidinone auxiliary at this stage. Af-
ter some experimentation, a reliable four-step sequence was
worked out that led to 15 as a 1:1 mixture of diastereomers.
Thus, diol 14 could be smoothly mono-iodinated and the re-
maining alcohol was protected as its tert-butyldimethylsilyl
(TBS) ether. Sm(OTf)3-catalyzed methanolysis of the auxil-
iary followed, but was accompanied by a significant amount
of TBS ether deprotection. Simple reprotection of the alco-
hol as its TBS ether completed the four-step sequence and
delivered 15 in 63% overall yield from 14.
2. Results and discussion
Our studies began with syntheses of the requisite diene 7 and
dienophile 8 for the asymmetric Diels–Alder process. Thus,
Horner–Wadsworth–Emmons reaction between aldehyde 9
and phosphonate 1013 proceeded smoothly to provide di-
enophile 8 in 86% yield (Scheme 2). The synthesis of diene
7 was initiated with a condensation reaction of cyclopenta-
diene with dialkoxyacetones employing the conditions re-
ported by Little.14 We ultimately chose benzyl protecting
groups and the condensation reaction in this case gave the
With iodide 15 in hand, we turned our attention to the key
radical fragmentation process. Originally developed in a sim-
ilar context as a reductive process by Corey,10 this reaction
was adapted by Carreira11 such that the initially produced
primary homoallylic radical could be oxidatively trapped
to give the illustrated hydroxymethyl product using a Naka-
mura protocol17 (Scheme 3). It seemed a straightforward
matter to apply this procedure to our system, and indeed,
O
O
O
O
O
O
OTBS
I
OBn
OBn
OH
OH
NaH
THF
Me
(EtO)2P
+
H
N
O
R
N
O
5
9
10
8
1. I2, PPh3, imid-
azole, CH2Cl2
86%
R
R
R
Bn
Bn
OBn
OBn
Et2AlCl
BCl3
OBn OBn
2. TBSCl, imid-
azole, CH2Cl2
3. Sm(OTf)3
MeOH
4. TBSCl, imid-
azole, CH2Cl2
CH2Cl2
-20 °C
84%
CH2Cl2
-78 °C
OBn OBn
15
OMe
13
14
N
O
+
Me2S(O)CH2
DMSO
H
O
O
Xc
O
Xc
73%
11
MeOH
63%
12
R = (E)-MeCH=CH(CH2)5-
64%
78%
Scheme 2. The key enantioselective Diels–Alder cycloaddition with a 5,5-disubstituted cyclopentadiene.

B. Castagner, J. L. Leighton / Tetrahedron 63 (2007) 5895–5902
Carreira (ref. 11):
5897
OH
O
Corey (ref. 10):
CH3
I
I
n-Bu3SnH, AIBN
n-Bu3SnH, air
Benzene
Benzene
O
O
80%
O
O
86%
NPh
NPh
Me
Me
O
R = (E)-MeCH=CH(CH2)5-
OTBS
I
N
OTBS
OTBS
OTBS
OH
O
TBSO
R
Me Me
R
R
R
n-Bu3SnH, air
Toluene
42%
n-Bu3SnH, TEMPO
1. Zn, AcOH, H2O, THF
Benzene
2. TBSCl, imidazole, CH2Cl2
17
OMe
16
15
OMe
18
53% (overall from 15)
O
O
OMe
O
O
OMe
Scheme 3. A radical cleavage of the cyclopropane with an oxidative trap establishes the quaternary stereocenter.
subjection of 15 to these conditions did allow the isolation of
alcohol 16 in 42% yield. While the 42% yield in the transfor-
mation of 15 to 16 was disappointing, far more problematic
was the fact that this reaction was not entirely reliable, and
required constant attention for the more than 40 h it took
to perform. As it stood, the procedure was simply not
amenable to shepherding multi-gram quantities through the
sequence, and we were forced to stop and optimize the
procedure. The source of the problem seemed to be ineffi-
cient trapping of the primary radical by O2, as the concentra-
tion of the reaction and rate of bubbling of air through the
solution had to be very carefully controlled. We considered
other oxygen atom sources and TEMPO seemed a promising
candidate especially in light of Boger’s demonstration of the
trapping of a primary radical with TEMPO in a high-
yielding reaction.18 Gratifyingly, when 15 was subjected to
the action of tributyltin hydride in the presence of TEMPO,
smooth and reproducible conversion to 17 ensued. N–O
bond reduction was effected with Zn/AcOH, and TBS pro-
tection of the resulting alcohol furnished 18 in 53% overall
yield from 15. This three-step sequence proceeded in higher
overall yield than the original procedure, and, more impor-
tantly, allowed us to access multi-gram quantities of 18,
wherein the all-important carbon quaternary center has
been successfully incorporated.
The next task was the one-carbon homologation of the ester
and the regioselective functionalization of the endocyclic
olefin. Our previously reported route made use of an Arndt–
Eistert homologation followed by a mercuriolactonization-
reduction sequence,8a and we first attempted to apply this
sequence to ester 18. While the Arndt–Eistert sequence pro-
ceeded smoothly and gave homologated acid 19 in 67%
overall yield, all attempts to induce mercurio or halolactoni-
zation reactions followed by reduction of the organomercury
or halide species were met with complete failure (Scheme 4).
In some cases evidence for successful mercuriolactonization
(20) could be secured, but attempts at reduction invariably
caused reversion to carboxylic acid 19. As an alternative
strategy, hydroboration reactions were considered but it was
not clear how the regioselectivity would be controlled. Using
the ester group, or a related functional group, as a directing
group seemed worth considering and that ultimately inspired
the idea that we might orchestrate a double hydroboration
on diene 21 (prepared in three simple steps and 88%
overall yield from 18) with a primary borane (RBH2).19
Thus, the vinyl group would react first and the resulting
dialkylborane would undergo an intramolecular, and thereby
regiocontrolled, hydroboration of the endocyclic olefin. In
practice, treatment of diene 21 with thexylborane (prepared
in situ20), followed by an oxidative workup afforded
OTBS
OTBS
OTBS
OTBS
TBSO
R
TBSO
R
TBSO
R
TBSO
R
1. Me3SiOK, THF
2. LiOH; (COCl)2, CH2Cl2
HgOAc
Hg(OAc)2
THF
Many different
3. CH2N2, Et3N, CH2Cl2
4. h , dioxane, H2O
reduction attempts
20
18
19
19
CO2H
O
67%
O
OMe
CO2
O
1. LiAlH4, Et2O
2. Pyridine•SO3, DMSO,
88%
i-Pr2NEt, CH2Cl2
R = (E)-MeCH=CH(CH2)5-
3. Ph3P=CH2, THF
OTBS
OTBS
OTBS
OTBS
TBSO
TBSO
TBSO
R
TBSO
R
Thexylborane, THF;
R
R
1. TESCl, imidazole, CH2Cl2
H2O2, NaOH
+
2. Dess-Martin Periodinane, CH2Cl2
85%
O
o-NitrophenylSeCN,
OH
21
22
21%
23
34%
PBu3, THF
24
72%
OH
OH
OTES
Scheme 4. Regioselective functionalization of the endocyclic olefin by a double hydroboration reaction.

5898
B. Castagner, J. L. Leighton / Tetrahedron 63 (2007) 5895–5902
OTBS OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
CSA
OTBS
Cl
O
H
OTBS
TFAA
R
R
R
R
R
DMSO
Tf2N
N
OH
OH
OTf
OTf
LDA, THF
-78 °C
i-Pr2NEt
CH2Cl2
MeOH
THF
KHMDS
THF
O
O
O
O
O
50%
68%
24
81%
25
26
83%
27
28
OTES
OTES
(+26% rsm) OTES
(+15% rsm)
OTES
OH
R = (E)-MeCH=CH(CH2)5-
Scheme 5. Stereoselective installation of the tetrasubstituted b-trifloxy enone.
mono-hydroboration product 22 (which could be recycled
back to 21) in 20% yield, and the desired diol 23 in 34%
yield. Attempts to push the reaction to completion or to
screen other boranes did not lead to better results. Despite
the low yield of 23, we were delighted that, compared to our
original route, we had developed a significantly more step-
efficient process, and one that proceeded in comparable
overall yield relative to the Arndt–Eistert/mercuriolactoni-
zation/reduction sequence employed in the original route.
Selective protection of the primary alcohol as its triethylsilyl
(TES) ether, and oxidation of the secondary alcohol using
the Dess–Martin periodinane21 furnished ketone 24 in 85%
yield (over two steps).
prepare gram quantities of 28. With access to 28 secured,
we are now in a position to investigate the installation of
the remaining side chain, and the tandem carbonylation/
Cope rearrangement in this new more densely functionalized
context.
4. Experimental
4.1. General
All reactions were conducted under an atmosphere of nitro-
gen in flame-dried glassware with magnetic stirring unless
otherwise indicated. Degassed solvents were purified by pas-
sage through an activated alumina column. 1H NMR spectra
were recorded on a Bruker DPX-300 (300 MHz) or a DRX-
400 (400 MHz) spectrometer and are reported in parts
per million from CDCl3 internal standard (7.26 ppm). Data
are reported as follows: (s¼singlet, d¼doublet, t¼triplet,
q¼quartet, dd¼doublet of doublets; coupling constant(s)
in hertz; integration; assignment). Proton decoupled 13C
NMR spectra were recorded on a Bruker DPX-300
(75 MHz) or a DRX-400 (100 MHz) spectrometer and are
reported in parts per million from CDCl3 internal standard
(77.0 ppm). Infrared spectra were recorded on a Perkin–
Elmer Paragon 1000 FTIR spectrometer. Optical rotations
were recorded on a JASCO DIP-1000 digital polarimeter.
Low resolution mass spectra were obtained on a JEOL
HX110 mass spectrometer in the Columbia University
Mass Spectrometry Laboratory.
Completion of the synthesis of the target late-stage interme-
diate proved to be straightforward and followed from the
originally developed route. Thus, enolization of ketone 24
with LDA and subsequent aldol addition to 3-(tert-butyldi-
methylsilyloxy)-propionaldehyde gave 25 as a 2:1 mixture
of diastereomers in 81% yield (Scheme 5). Swern oxida-
tion22 to give enol 26 proceeded in 50% yield, along with
26% recovered starting material. Z-Selective triflation of
the enol was accomplished by deprotonation with KHMDS
and treatment of the resulting enolate with 2-[N,N-bis(tri-
fluoromethylsulfonyl)amino]-5-chloropyridine (Comins’ re-
agent23) to give triflate 26 in 68% yield, along with 15%
recovered starting material. In each of these last two reac-
tions, attempts to force full conversion led to significantly
lower yields. Nevertheless, significant quantities of material
could be brought through this sequence, and selective meth-
anolysis of the TES ether provided alcohol 27 in 83% yield.
This compound is poised for addition of an appropriately
configured side chain (R00 in structure 4, Scheme 1), and the
tandem carbonylation/Cope rearrangement reaction.
4.1.1. Dienophile 8. NaH (60% in mineral oil, 4.04 g,
101 mmol) was washed three times with hexanes and
suspended in THF (600 mL). Phosphonate 1012 (35.9 g,
101 mmol) was dissolved in 50 mL THF and added slowly
over 30 min to the NaH suspension (caution!! H2 evolu-
tion!). The mixture was stirred for an additional 5 h. The
clear solution was cooled to 0 ꢀC and aldehyde 9 was added
via cannula. The mixture was warmed to room temperature
and stirred overnight. The resulting solution was diluted with
Et2O and washed with satd aq NH4Cl, followed by brine.
The organic layer was dried over MgSO4, filtered, and con-
centrated. The residue was purified by flash chromatography
on silica (10% EtOAc/hexanes) to give 24.7 g of 8 (86%) as
a white solid. 1H NMR (400 MHz, CDCl3) d 7.35–7.21 (m,
7H), 5.42–5.40 (m, 2H), 4.72–4.70 (m, 1H), 4.20–4.15 (m,
2H), 3.33 (dd, J¼3.1, 13.4 Hz, 1H), 2.79 (dd, J¼9.6,
13.4 Hz, 1H), 2.30 (q, J¼7.1 Hz, 2H), 1.98 (br s, 2H), 1.64
(d, J¼3.3 Hz, 3H), 1.51 (quint, J¼7.0 Hz, 2H), 1.36–1.34
(m, 4H); 13C NMR (100 MHz, CDCl3) d 165.6, 153.9,
3. Conclusion
We have developed a modified route to a late-stage interme-
diate in a projected phomoidride synthesis. This modified
route required the synthesis of a challenging all-carbon qua-
ternary stereocenter, which in turn necessitated non-trivial
modifications to other parts of the established synthesis.
An efficient modification to the oxidative radical cleavage
of a tetrasubstituted cyclopropane was developed, and a re-
gioselective double hydroboration was developed as well
that gracefully provides a new path through some key func-
tional group interconversions. In all the synthesis of 28
required 19 steps from diene 12 and dienophile 8, and
proceeds efficiently enough that we have been able to

B. Castagner, J. L. Leighton / Tetrahedron 63 (2007) 5895–5902
5899
152.5, 135.8, 131.8, 129.9, 129.4, 127.7, 125.3, 120.7, 66.5,
55.8, 38.2, 33.2, 32.9, 29.8, 29.1, 28.4, 18.4; IR (CHCl3 soln)
3009, 2927–2844, 1779, 1768, 1679, 1628 cmꢁ1; [a]D +54.0
(c 1.19, CHCl3); LRMS (FAB+, M+H) calcd for C21H28NO3
342.21, found 342.21.
6H), 0.92 (d, J¼5.8 Hz, 1H), 0.84 (d, J¼5.8 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d 174.4, 153.9, 140.4, 139.33,
139.27, 135.9, 132.1, 130.9, 129.9, 129.5, 128.8, 128.2,
128.1, 127.9, 125.2, 73.4, 72.2, 71.9, 66.8, 55.9, 53.3,
51.3, 50.4, 49.7, 44.7, 38.8, 34.5, 33.1, 30.1, 29.8, 29.5,
24.9, 18.6, 18.3; IR (thin film) 3064–2856, 1778, 1697,
1497, 1454, 1383, 1352, 1216, 1097, 1074 cmꢁ1; [a]D
+53.8 (c 1.15, CH2Cl2); LRMS (FAB+, M+H) calcd for
C44H51NO5 673.38, found 674.3.
4.1.2. Cyclopentadiene 12. Dibenzyloxyacetone (47.6 g,
176 mmol) and freshly distilled cyclopentadiene (36.3 mL,
440 mmol) were dissolved in MeOH (175 mL). Freshly dis-
tilled pyrrolidine (22.3 mL, 264 mmol) was added, and the
mixture was stirred for 2 h, after which it was diluted with
Et2O (1.5 L), washed with 1 N HCl (300 mL), and then
washed with brine (100 mL). The organic layer was dried
with MgSO4, filtered, and concentrated. The resulting oil
was purified by flash chromatography on silica (10%
EtOAc/hexanes) to give 35.6 g of fulvene 11 (64%) as
a bright orange oil. Note: fulvene 11 is unstable, and the
workup and purification must be carried out quickly, and
the product was taken on to the next step without delay.
4.1.4. Diol 14. To a cooled (ꢁ78 ꢀC) solution of compound
13 (15.6 g, 23 mmol) in CH2Cl2 (180 mL) was added BCl3
(1.0 M in CH2Cl2, 69 mL, 69 mmol) over 2 min via addition
funnel (added by letting the solution slide on the cold flask-
side to cool it down before it is in contact with the solution).
The reaction mixture was allowed to stir for 15 min after
which MeOH (70 mL) was added in the same fashion. The
mixture was poured into cold (ca. ꢁ40 ꢀC) MeOH (300 mL)
containing solid NaHCO3. The mixture was allowed to warm
to room temperature with vigorous stirring and then con-
centrated. The residue was dissolved in Et2O, and satd
Rochelle’s salt was added. The bi-phasic mixture was stirred
overnight and then extracted three times with EtOAc. The
combined organic layers were washed with brine, dried
with MgSO4, filtered, and concentrated. The residue was pu-
rified by flash chromatography on silica (30–50% EtOAc/
hexanes) to give 8.33 g of diol 14 (73% yield) as a thick
NaH (60% suspension in mineral oil, 12.8 g, 320 mmol) was
washed twice with dry pentane, dried under a stream of dry
nitrogen, agitated into a free flowing powder, and suspended
in DMSO (100 mL). Trimethyl sulfoxonium iodide (73.2 g,
332.8 mmol) was added in portions over the course of 3 h
(caution!! H2 evolution!). Another portion of DMSO
(250 mL) was added after the addition, and then a solution
of fulvene 11 (40.6 g, 128 mmol) in DMSO (100 mL) was
added by way of an addition funnel over 20 min. After
14 h, the mixture was poured in an addition funnel contain-
ing CH2Cl2 (1.2 L) and the mixture was washed with water
(2ꢂ400 mL). The organic layer was dried with MgSO4,
filtered through a short silica pad, and concentrated. The
residue was purified by flash chromatography on silica (10%
Et2O/hexanes) to give 33.4 g of 12 (78%) as a slightly yellow
1
foamy oil. H NMR (300 MHz, CDCl3) d 7.36–7.20 (m,
5H), 6.63–6.60 (m, 1H), 6.03–6.01 (m, 1H), 5.47–5.35 (m,
2H), 4.70–4.65 (m, 1H), 4.23–4.14 (m, 2H), 3.88–3.76 (m,
3H), 3.52 (t, J¼10.6 Hz, 2H), 3.25 (dd, J¼3.1, 13.2 Hz,
1H), 3.11 (br s, 1H), 2.65 (dd, J¼10.2, 13.1 Hz, 1H), 2.46
(br s, 1H), 2.27 (s, 2H), 2.24–2.17 (m, 1H), 1.98–1.94 (m,
2H), 1.64 (d, J¼4 Hz, 3H), 1.63–1.58 (m, 2H), 1.35–1.21
(m, 6H), 0.88 (d, J¼5.8, 1H), 0.78 (d, J¼5.8 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d 174.2, 154.0, 141.4, 135.9,
132.1, 131.9, 129.9, 129.6, 128.0, 125.3, 67.9, 67.7, 66.9,
56.0, 53.9, 51.2, 50.3, 49.9, 44.5, 38.8, 34.6, 33.1, 30.1,
29.8, 29.5, 27.6, 18.6, 18.3; LRMS (FAB+, M+H) calcd for
C30H40NO5 494.29, found 494.23.
1
oil. H NMR (400 MHz, CDCl3) d 7.42–7.34 (m, 10H),
6.62–6.60 (m, 2H), 6.30–6.28 (m, 2H), 4.62 (d, J¼12 Hz,
2H), 4.56 (d, J¼12 Hz, 2H), 3.91 (d, J¼10 Hz, 2H), 3.76
(d, J¼10 Hz, 2H), 1.91 (s, 2H); 13C NMR (100 MHz,
CDCl3) d 138.7, 136.0, 130.5, 128.7, 128.1, 128.0, 73.4,
72.3, 46.1, 38.5, 22.3; IR (thin film) 3065, 3030, 2862,
1952 (w), 1871 (w), 1812 (w), 1496, 1482, 1454, 1365,
1146, 1094, 1076 cmꢁ1; LRMS (FAB+, M+H) calcd for
C23H24O2 333.19, found 333.31.
4.1.5. Compound 15. To a solution of diol 14 (8.33 g,
16.9 mmol) in CH2Cl2 (200 mL) were added imidazole
(1.15 g, 16.9 mmol) and PPh3 (4.43 g, 16.9 mmol). The mix-
ture was cooled to ꢁ40 ꢀC and I2 (4.29 g, 16.9 mmol) was
added. The mixture was stirred at ꢁ40 ꢀC for 30 min during
which time most of the I2 dissolved. The mixture was then
warmed to room temperature over 1 h and then diluted
with Et2O. The mixture was washed with 1 N HCl, followed
by satd Na2SO3, and then brine. The organic layer was dried
with MgSO4, filtered through a small pad of silica, and
concentrated. The residue was purified by flash chromato-
graphy on silica (10–20% EtOAc/hexanes) to give a 1:1 dia-
stereomeric mixture of mono-iodinated compounds (8.36 g,
13.8 mmol, 82% yield), which was used immediately in the
next step.
4.1.3. Diels–Alder product 13. To a cooled (ꢁ78 ꢀC) solu-
tion of 8 (818 mg, 2.40 mmol) and 12 (1.12 g, 3.35 mmol) in
CH2Cl2 was added Et2AlCl (2.67 mL, 1.8 M in toluene,
4.8 mmol) and the mixture was left in a ꢁ20 ꢀC freezer over-
night. The mixture was added slowly to 1 N HCl (60 mL),
and the resulting bi-phasic mixture was extracted with
CH2Cl2. The organic layer was washed with satd aq
NaHCO3 (30 mL), dried over MgSO4, filtered, and concen-
trated. The residue was purified by flash chromatography on
silica gel (5–10% EtOAc/hexanes) to afford 1.36 g of 13
(84%) as a single (>95:5) diastereomer. 1H NMR
(300 MHz, CDCl3) d 7.44–7.24 (m, 15H), 6.57–6.54 (m,
1H), 5.96–5.94 (m, 1H), 5.52–5.38 (m, 2H), 4.74–4.64 (m,
1H), 4.60–4.47 (m, 4H), 4.21–4.16 (m, 2H), 3.82 (dd,
J¼3.4, 4.8 Hz, 1H), 3.61–3.41 (m, 4H), 3.28 (dd, J¼3.1,
13.2 Hz, 1H), 3.01 (br s, 1H), 2.69 (dd, J¼10.0, 13.1 Hz,
1H), 2.36 (br s, 1H), 2.23–2.16 (m, 1H), 2.03–1.95 (m,
2H), 1.70–1.68 (m, 3H), 1.65–1.52 (m, 2H), 1.41–1.22 (m,
To a solution of the mixture of iodides (8.36 g, 13.8 mmol)
in CH2Cl2 (100 mL) were added imidazole (3.80 g,
55.9 mmol) and TBSCl (4.16 g, 27.6 mmol). The mixture
was stirred overnight, diluted with Et2O, and washed with
1 N HCl followed by satd NaHCO3 and then brine. The
organic layer was dried over MgSO4, filtered, and

5900
B. Castagner, J. L. Leighton / Tetrahedron 63 (2007) 5895–5902
concentrated. The residue was purified by flash chromato-
graphy on silica (5–10% Et2O/hexanes) to give a 1:1 dia-
stereomeric mixture of mono-iodinated TBS ethers (9.25 g,
12.9 mmol, 93%) as a slightly yellow oil, which was used
immediately in the next step.
mixture was diluted with 200 mL CH2Cl2 and a solution of
NaOH (3.8 g) in H2O (150 mL) was added to neutralize
the solution. The mixture was extracted with CH2Cl2, and
the combined organic layers were washed with brine, dried
with MgSO4, filtered, and concentrated. The residue was
purified by flash chromatography on silica (30–50%
EtOAc/hexanes) and the material thus obtained was used
immediately in the next step.
To a solution of the mixture of mono-iodinated TBS ethers
(9.25 g, 12.9 mmol) in MeOH (100 mL) was added
Sm(OTf)3 (770 mg, 1.29 mmol) and the mixture was stirred
for 3 days at room temperature. The solution was then
concentrated and the residue was purified by flash chro-
matography on silica (5–30% Et2O/hexanes) to give a 1:1
diastereomeric mixture of methyl esters 15 (910 mg, 12%)
and 5.28 g of material wherein the TBS ether had been
hydrolyzed. To a solution of this desilylated material
in CH2Cl2 (100 mL) were added imidazole (2.35 g,
34.5 mmol) and TBSCl (2.60 g, 17.2 mmol). The mixture
was stirred overnight, diluted with Et2O, and washed with
1 N HCl followed by satd NaHCO3 and then brine. The or-
ganic layer was dried with MgSO4, filtered, and concen-
trated. The residue was purified by flash chromatography
on silica (5–10% Et2O/hexanes) to give 5.21 g of 15 (70%
yield) for a total of 82% yield. Epimer A: 1H NMR
(400 MHz, CDCl3) d 6.35–6.33 (m, 1H), 6.04–6.02 (m,
1H), 5.45–5.43 (m, 2H), 3.69–3.66 (m, 4H), 3.42–3.39 (m,
3H), 2.83 (br s, 1H), 2.66 (t, J¼4.6 Hz, 1H), 2.39 (br s,
1H), 2.03–1.97 (m, 2H), 1.90–1.82 (m, 1H), 1.68–1.66 (m,
3H), 1.65–1.50 (m, 2H), 1.41–1.30 (m, 6H), 0.92–0.88 (m,
10H), 0.60 (d, J¼5.8 Hz, 1H), 0.10 (s, 3H), 0.09 (s, 3H);
13C NMR (100 MHz, CDCl3) 174.8, 139.1, 132.8, 131.4,
125.0, 65.6, 57.7, 52.1, 51.5, 49.5, 49.1, 48.9, 46.2, 35.3,
33.2, 30.2, 29.9, 29.2, 28.0, 26.6, 26.5, 22.2, 18.9, 18.6,
16.2, ꢁ4.5; IR (solution in CHCl3) 2921, 2855, 1732,
To a solution of this material in CH2Cl2 were added imid-
azole (6 equiv) and TBSCl (3 equiv). Upon completion of
the reaction (as monitored by TLC) the mixture was diluted
with ether, washed with 1 N HCl, followed by NaHCO3 and
brine, dried with MgSO4, filtered, and concentrated. The res-
idue was purified by flash chromatography on silica (10%
EtOAc/hexanes) to give 370 mg of 18 (53% overall yield
1
from 15) as an oil. H NMR (300 MHz, CDCl3) d 6.25–
6.22 (m, 1H), 5.80, 5.77 (m, 1H), 5.48–5.36 (m, 2H), 5.15 (d,
J¼1.8 Hz, 1H), 4.86 (d, J¼1.8 Hz, 1H), 3.96 (s, 2H), 3.67–
3.23 (m, 5H), 3.13 (br s, 1H), 2.85 (dd, J¼3.5, 5.3 Hz, 1H),
2.79 (br s, 1H), 2.00–1.94 (m, 2H), 1.84–1.77 (m, 1H), 1.66–
1.62 (m, 5H), 1.39–1.28 (m, 6H), 0.91 (s, 9H), 0.90 (s, 9H),
0.05 (s, 6H), 0.004 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 176.2, 151.2, 140.1, 132.3, 130.6, 125.3, 110.7, 69.9,
66.9, 66.0, 52.3, 50.8, 49.6, 49.2, 45.1, 34.3, 33.2, 30.2,
30.0, 26.6, 19.0, 18.6, ꢁ4.7, ꢁ4.8; IR (thin film) 3061,
2926–2833, 1737, 1644, 1463, 1435, 1361, 1256, 1197,
1131, 1073 cmꢁ1; [a]D +7.4 (c 1.24, CHCl3); LRMS
(FAB+, M+H) calcd for C33H61O4Si2 577.4, found 577.0.
4.1.7. Compound 21. To a cooled (0 ꢀC) solution of com-
pound 18 (1.36 g, 2.35 mmol) in 25 mL of Et2O was added
LiAlH4 (1.0 M in Et2O, 2.47 mL, 2.47 mmol). After 30 min
the mixture was warmed to room temperature and stirred for
an additional 30 min. The reaction was quenched by the ad-
dition of 94 mL of water followed by 190 mL of 15% NaOH
and then an additional 282 mL of water was added. The mix-
ture was stirred for 3 h, dried over MgSO4, filtered, and con-
centrated. The residue was purified by flash chromatography
on silica (10% Et2O/CH2Cl2) to give 1.29 g of the primary
1
1602, 1463, 1362, 1322, 1098 cmꢁ1. Epimer B: H NMR
(400 MHz, CDCl3) d 6.27–6.25 (m, 1H), 5.94–5.91 (m,
1H), 5.40–5.32 (m, 2H), 3.62–3.57 (m, 4H), 3.37–3.26 (m,
3H), 2.76 (br s, 1H), 2.56–2.54 (m, 1H), 2.25 (br s, 1H),
1.94–1.86 (m, 2H), 1.83–1.77 (m, 1H), 1.58–1.45 (m, 5H),
1.31–1.20 (m, 6H), 0.83 (s, 9H), 0.73 (d, J¼5.8 Hz, 1H),
0.59 (d, J¼5.8 Hz, 1H), 0.01 (s, 3H), 0.00 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 174.8, 138.9, 132.9, 131.8,
125.0, 65.8, 57.4, 52.1, 51.7, 49.6, 48.9, 45.7, 35.1, 33.2,
30.2, 29.9, 29.2, 27.8, 26.5, 22.2, 18.9, 18.6, 16.0, ꢁ4.6;
IR (thin film) 3062, 2928–2856, 1737, 1463, 1435,
1252, 1178, 1091 cmꢁ1; LRMS (FAB+, M+H) calcd for
C27H46ISi1O3 573.23, found 573.4.
1
alcohol product (99% yield). H NMR (300 MHz, CDCl3)
d 6.17–6.14 (m, 1H), 5.87–5.84 (m, 1H), 5.42–5.39 (m,
2H), 5.15 (d, J¼1.8 Hz, 1H), 4.86 (d, J¼1.8 Hz, 1H), 3.97
(s, 2H), 3.74 (d, J¼10.0 Hz, 1H), 3.65 (d, J¼10.0 Hz, 1H),
3.56–3.44 (m, 1H), 3.29 (t, J¼9.6 Hz, 1H), 2.91 (br s, 1H),
2.73 (br s, 1H), 2.23–2.19 (m, 1H), 2.00, 1.94 (m, 2H),
1.66–1.56 (m, 5H), 1.40–1.25 (m, 7H), 0.91 (s, 9H), 0.89
(s, 9H), 0.05 (s, 6H), ꢁ0.003 (s, 3H), ꢁ0.008 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 151.6, 138.9, 131.9, 130.2,
125.0, 109.8, 69.7, 66.8, 66.7, 65.6, 50.6, 47.7, 47.2, 44.7,
34.3, 33.2, 30.6, 30.3, 30.0, 26.63, 26.60, 19.02, 18.97,
18.6, ꢁ4.6, ꢁ4.7, ꢁ4.8; IR (thin film) 3326 (br), 2928–
2856, 1643, 1463, 1255, 1106, 1074 cmꢁ1; [a]D ꢁ10.1 (c
1.76, CHCl3); LRMS (FAB+, M+H) calcd for C32H61Si2O3
549.42, found 549.05.
4.1.6. Compound 18. To a solution of compound 15
(692 mg, 1.21 mmol) and 10 mL benzene was added
TEMPO (0.567 g, 3.63 mmol), followed by tributyltin hy-
dride (320 mL, 1.21 mmol). The mixture was heated to reflux
and additional TEMPO (0.567 g, 3.63 mmol) and tributyltin
hydride (1.28 mL, 4.84 mmol) were added simultaneously
over 1 h in four portions. The mixture was stirred an addi-
tional 20 min, cooled to room temperature, and concen-
trated. The residue was purified by flash chromatography
on silica (0–5% Et2O/hexanes) to give 17, which was used
immediately in the next step.
To a solution of the alcohol (1.35 g, 2.45 mmol) in CH2Cl2
(30 mL) were added DMSO (1.04 mL, 14.7 mmol), diiso-
propylethylamine (1.71 mL, 9.8 mmol), and Pyr$SO3
(1.15 g, 7.35 mmol). The mixture was stirred for 30 min, di-
luted with Et2O, and washed with 1 N HCl followed by satd
NaHCO3 and then brine. The organic layer was dried over
MgSO4, filtered, and concentrated. The residue was purified
To a solution of compound 17 in THF (2 mL) and H2O
(2 mL) were added acetic acid (6 mL) and zinc powder
(820 mg). The mixture was heated to 70 ꢀC with vigorous
stirring for 2 h and then cooled to room temperature. The

B. Castagner, J. L. Leighton / Tetrahedron 63 (2007) 5895–5902
5901
by flash chromatography on silica (10% Et2O/hexanes) and
the aldehyde thus obtained was used immediately in the next
step.
To a solution of the mono-TES ether (123.8 mg,
0.178 mmol) in CH2Cl2 (5 mL) was added Dess–Martin pe-
riodinane (113.2 mg, 0.267 mmol). After 30 min the mixture
was treated with satd NaHCO3 and after 5 min the mixture
was extracted with Et2O. The organic layer was dried over
MgSO4, filtered, and concentrated. The residue was purified
by flash chromatography on silica (5% Et2O/hexanes) to
To a cooled (ꢁ78 ꢀC) solution of triphenylmethylphospho-
nium bromide (1.05 g, 2.94 mmol) in THF (20 mL) was
added potassium tert-butoxide (1.0 M in THF, 2.70 mL,
2.70 mmol) and the resulting mixture was warmed to room
temperature, stirred for 10 min, and then recooled to
ꢁ78 ꢀC. A solution of the aldehyde in 5 mLTHF was added
and the mixture was warmed to 0 ꢀC and stirred for 1.5 h.
The mixture was diluted with Et2O and washed with satd
NH4Cl and with brine. The organic layer was dried over
MgSO4, filtered through a small pad of silica, and concen-
trated. The residue was purified by flash chromatography
on silica (2% Et2O/hexanes) to give 1.19 g of 21 (89% over-
1
give 123 mg of 24 (85% overall yield from 23). H NMR
(300 MHz, CDCl3) d 5.47–5.35 (m, 2H), 5.29 (s, 1H), 4.89
(s, 1H), 4.12–4.32 (m, 1H), 4.05 (d, J¼14 Hz, 1H), 3.80–
3.73 (m, 2H), 3.70–3.55 (m, 2H), 2.68 (br s, 1H), 2.47–
2.22 (m, 3H), 2.00–1.92 (m, 2H), 1.68–1.12 (m, 16H),
0.95 (t, J¼8 Hz, 9H), 0.89–0.87 (m, 18H), 0.58 (q,
J¼8 Hz), 0.04 (s, 6H), 0.00 (s, 3H), ꢁ0.003 (s, 3H); IR
(thin film) 2955, 2929, 2879, 2857, 1749, 1462, 1255,
1097, 1007 cmꢁ1; [a]D +39.9 (c 1.0, CHCl3); LRMS
(FAB+, M+H) calcd for C39H77Si3O4 693.5, found 693.3.
1
all yield from the primary alcohol). H NMR (400 MHz,
CDCl3) d 6.22–6.20 (m, 1H), 5.88–5.86 (m, 1H), 5.60–
5.51 (m, 1H), 5.45–5.42 (m, 2H), 5.17 (d, J¼2 Hz, 1H),
5.03 (dd, J¼1.3, 17.0 Hz, 1H), 4.90–4.86 (m, 2H), 4.04–
3.94 (m, 2H), 3.74 (s, 2H), 2.79 (s, 1H), 2.74 (s, 1H),
2.61–2.57 (m, 1H), 2.01–1.96 (m, 2H), 1.67 (m, 3H),
1.60–1.57 (m, 2H), 1.39–1.29 (m, 6H), 1.20–1.15 (m, 1H),
0.93–0.90 (m, 18H), 0.05 (s, 6H), 0.01 (s, 6H); 13C NMR
(100 MHz, CDCl3) d 151.3, 143.0, 138.2, 131.4, 130.2,
124.4, 113.4, 109.2, 69.2, 66.3, 65.3, 51.3, 50.4, 48.6,
47.8, 33.5, 32.7, 29.80, 29.76, 29.5, 26.1, 18.54, 18.48,
18.1, ꢁ5.13, ꢁ5.19; IR (thin film) 3062, 2928–2856, 1638,
1463, 1255, 1090, 1073, 1006 cmꢁ1; [a]D +1.6 (c 1.32,
CHCl3); LRMS (FAB+, M+H) calcd for C33H61Si2O2
545.42, found 545.09.
4.1.9. Compound 27. To a cooled (ꢁ78 ꢀC) solution of
i-Pr2NH (510 mL, 3.64 mmol) in THF (1 mL) was added
n-BuLi (2.5 M in hexanes, 1.46 mL, 3.64 mmol). The solu-
tion was warmed to 0 ꢀC for 30 min and then recooled to
ꢁ78 ꢀC. To this solution was added a solution of compound
24 (1.94 g, 2.80 mmol) in 15 mL of THF by cannula. After
30 min a solution of 3-(tert-butyldimethylsilyloxy)-propion-
aldehyde (1.37 g, 7.28 mmol) in THF (2 mL) was added
dropwise. The reaction mixture was stirred at ꢁ78 ꢀC for
40 min. The mixture was then diluted with Et2O and washed
with satd NH4Cl followed by brine. The organic layer was
dried over MgSO4, filtered, and concentrated. The residue
was purified by flash chromatography on silica (2–8%
Et2O/hexanes with 0.2% Et3N) to give 2.00 g of 25 (81%)
as an unassigned 2:1 mixture of diastereomers, which was
used immediately in the next step.
4.1.8. Compound 23. To a cooled (ꢁ20 ꢀC) solution of com-
pound 21 (574 mg, 1.05 mmol) in THF (40 mL) was added
thexylborane (1.0 M in THF, 1.05 mL, 1.05 mmol) drop-
wise. After 45 min the mixture was warmed to 0 ꢀC for 1 h
and then to room temperature for 30 min. The reaction
was quenched by the addition of 1 mL of 3 N NaOH fol-
lowed by H2O2 (30% aq, 500 mL). The resulting mixture
was stirred for 1 h. Satd Rochelle’s salt was added and the
mixture was stirred for 1 h, and then extracted three times
with EtOAc. The combined organic layers were dried over
MgSO4, filtered, and concentrated. The residue was purified
by flash chromatography on silica (10–30% EtOAc/hexanes)
to give 206 mg of 23 (34%) and 124 mg of 22 (21% yield).
Compound 22 was dehydrated as described in Scheme 4, and
21 was used immediately in the next step.
To a cooled (ꢁ60 ꢀC) solution of DMSO (0.065 mL,
0.917 mmol) in 4 mL CH2Cl2 was added trifluoroacetic
anhydride (0.0556 mL, 0.394 mmol). After 1 h a solution
˚
of 25 (116 mg, 0.131 mmol) in CH2Cl2 (4 mL) over 4 A
molecular sieves was added. After 35 min Hunig’s base
(0.183 mL, 1.05 mmol) was added and the resulting solution
was allowed to warm to room temperature and stirred for
40 min. The solution was then diluted with Et2O and washed
with water. The organic layer was dried over MgSO4, fil-
tered, and concentrated. The residue was purified by flash
chromatography on silica (2–4% Et2O/hexanes) to give
57.6 mg of 26 (50%) and 30 mg (26%) of recovered 25.
Compound 26 was used immediately in the next step.
To a cooled (ꢁ20 ꢀC) solution of diol 23 (116 mg,
0.20 mmol) in CH2Cl2 (5 mL) was added imidazole
(40.8 mg, 0.60 mmol) and TESCl (33.6 mL, 0.20 mmol).
The mixture was allowed to warm to room temperature
slowly and monitored by TLC. The mixture was recooled
to ꢁ20 ꢀC, and an additional portion of TESCl (13.4 mL,
0.080 mmol) was added and the mixture was warmed to
room temperature. TLC analysis showed complete con-
sumption of the starting material, and the mixture was then
diluted with Et2O and washed with satd NH4Cl followed
by satd NaHCO3 and then brine. The organic layer was dried
over MgSO4, filtered, and concentrated. The residue was pu-
rified by flash chromatography on silica (5% Et2O/hexanes)
to give 124 mg of the mono-TES ether, which was used
immediately in the next step.
To a cooled (ꢁ78 ꢀC) solution of 26 (74.7 mg, 0.085 mmol)
in Et2O (2 mL) was added KHMDS (0.256 mL, 0.128 mmol,
0.50 M in Et2O). After 30 min a solution of 2-[N,N-bis(tri-
fluoromethylsulfonyl)amino]-5-chloropyridine (Comins’ re-
agent22) (50 mg, 0.127 mmol) in Et2O (1 mL) was added by
cannula. The mixture was warmed to room temperature and
stirred for 5 h. The mixture was diluted with Et2O and
washed with aq NH4Cl and then brine. The organic layer
was dried over MgSO4, filtered, and concentrated. The resi-
due was purified by flash chromatography on silica (2%
Et2O/hexanes) to give 58.5 mg (68%) of 27 and 11.5 mg
1
(15%) of recovered 26. Data for 27: H NMR (300 MHz,
CDCl3) d 5.43–5.40 (m, 2H), 5.32 (s, 1H), 4.89 (s, 1H),
4.16 (d, J¼14 Hz, 1H), 3.98 (d, J¼14 Hz, 1H), 4.01–3.78

5902
B. Castagner, J. L. Leighton / Tetrahedron 63 (2007) 5895–5902
Nicolaou, K. C.; Jung, J.; Yoon, W. H.; Fong, K. C.; Choi,
H. S.; He, Y.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc.
2002, 124, 2183–2189; (e) Nicolaou, K. C.; Baran, P. S.;
Zhong, Y.-L.; Fong, K. C.; Choi, H. S. J. Am. Chem. Soc.
2002, 124, 2190–2201; (f) Nicolaou, K. C.; Zhong, Y.-L.;
Baran, P. S.; Jung, J.; Choi, H. S.; Yoon, W. H. J. Am. Chem.
Soc. 2002, 124, 2202–2211.
(m, 4H), 3.70–3.60 (m, 2H), 3.13 (br s, 1H), 2.86 (br s, 1H),
2.64–2.55 (m, 2H), 2.46–2.38 (m, 1H), 2.01–1.95 (m, 2H),
1.68–1.28 (m, 14H), 0.97 (t, J¼8 Hz, 9H), 0.9 (m, 27H),
0.60 (q, J¼8 Hz, 6H), 0.05–0.00 (m, 18H); IR (thin film)
2955, 2930, 2883, 2858, 1745, 1672, 1472, 1463, 1421,
1413, 1254, 1205, 1103, 1007 cmꢁ1; [a]D +29.2 (c 2.0,
CHCl3); LRMS (FAB+, M+H) calcd for C49H93F3SSi4O8
1011.6, found 1011.4.
4. (a) Chen, C.; Layton, M. E.; Shair, M. D. J. Am. Chem. Soc.
1998, 120, 10784–10785; (b) Chen, C.; Layton, M. E.;
Sheehan, S. M.; Shair, M. D. J. Am. Chem. Soc. 2000, 122,
7424–7425.
5. (a) Waizumi, N.; Itoh, T.; Fukuyama, T. Tetrahedron Lett. 1998,
39, 6015–6018; (b) Waizumi, N.; Itoh, T.; Fukuyama, T. J. Am.
Chem. Soc. 2000, 122, 7825–7826; (c) Hayashi, Y.; Itoh, T.;
Fukuyama, T. Org. Lett. 2003, 5, 2235–2238.
6. (a) Meng, D.; Tan, Q.; Danishefsky, S. J. Angew. Chem., Int. Ed.
1999, 38, 3197–3201; (b) Tan, Q.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2000, 39, 4509–4511.
7. For a comprehensive review of all approaches to the synthesis
of the phomoidrides, see: Spiegel, D. A.; Njardarson, J. T.;
McDonald, I. M.; Wood, J. L. Chem. Rev. 2003, 103, 2691–
2727.
4.1.10. Compound 28. To a cooled (0 ꢀC) solution of com-
pound 27 (46.7 mg, 0.046 mmol) in THF (1 mL) was added
CSA (0.1 M in MeOH, 0.092 mL, 0.0092 mmol). After 1.5 h
the reaction was quenched by the addition of satd NaHCO3
and after 5 min the mixture was extracted with Et2O. The
organic layer was dried over MgSO4, filtered, and concen-
trated. The residue was purified by flash chromatography
on silica (30% Et2O/hexanes) to give 34.1 mg (83%) of
28. 1H NMR (400 MHz, CDCl3) d 5.44–5.40 (m, 2H), 5.32
(s, 1H), 4.90 (s, 1H), 4.15 (d, 1H), 4.00–3.78 (m, 5H), 3.69
(m, 2H), 3.14 (br s, 1H), 2.97 (br s, 1H), 2.64–2.52 (m,
2H), 2.37–2.3 (m, 1H), 2.00–1.94 (m, 2H), 1.72–1.63 (m,
5H), 1.58–1.25 (m, 1H), 0.89 (s, 9H), 0.89 (s, 9H), 0.88 (s,
9H), 0.05–0.01 (m, 18H); IR (thin film) 3425 (br), 2955,
2927, 2850, 1742, 1672, 1462, 1427, 1251, 1202,
1104 cmꢁ1; [a]D +28.9 (c 1.83, CHCl3); LRMS (FAB+,
M+H) calcd for C43H80F3SSi3O8 897.5, found 897.3.
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