Design, synthesis, and evaluation of azepine-based cryptophycin mimetics

Article abstract of DOI:10.1016/S0040-4020(03)00857-3

Cryptophycins, depsipeptides isolated from terrestrial blue-green algae, show potent activity against a variety of tumor cell lines. Given the potential of the cryptophycins for cancer therapy, we developed a new class of non-peptide peptidomimetic, designed to replace the 16-membered macrolide ring with a 7-membered azepine ring for attachment of the cryptophycin side chains with the required spatial orientation to mimic the conformation of the relevant region of the natural product. Monte Carlo conformational analysis revealed excellent overlay of the local minimum structural model 6 and X-ray structure of (+)-cryptophycin-3 (5). Starting from this structural model, we designed and synthesized compounds (+)-25, (+)-30, and (+)-34 as potential mimics of cryptophycins. Compounds (+)-25, (+)-30, and (+)-34 were tested for in vitro cytotoxicity against six human cancer cell lines. Although only modest activities were observed, these results suggested that a new series of bioactive cryptophycin analogues might be available by structural modification of the central ring system of the cryptophycins.

Full text of DOI:10.1016/S0040-4020(03)00857-3

Tetrahedron 59 (2003) 6991–7009
Design, synthesis, and evaluation of azepine-based
cryptophycin mimetics
a
b
a
,
Amos B. Smith, IIIa Young Shin Cho, G. Robert Pettit and Ralph Hirschmann
,
,
*
*
*
aDepartment of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter,
University of Pennsylvania, Philadelphia, PA 19104, USA
bThe Cancer Research Institute, Arizona State University, Tempe, AZ 85287, USA
Received 8 May 2003; revised 26 May 2003; accepted 29 May 2003
Dedicated to Professor K. C. Nicolaou, on the occasion of the 2002 Tetrahedron Prize, with admiration and respect, for his many seminal contributions to
chemistry including, in particular, his early involvement in the Nonpeptidal Peptidomimetic Program at the University of Pennsylvania
Abstract—Cryptophycins, depsipeptides isolated from terrestrial blue–green algae, show potent activity against a variety of tumor cell
lines. Given the potential of the cryptophycins for cancer therapy, we developed a new class of non-peptide peptidomimetic, designed to
replace the 16-membered macrolide ring with a 7-membered azepine ring for attachment of the cryptophycin side chains with the required
spatial orientation to mimic the conformation of the relevant region of the natural product. Monte Carlo conformational analysis revealed
excellent overlay of the local minimum structural model 6 and X-ray structure of (þ)-cryptophycin-3 (5). Starting from this structural model,
we designed and synthesized compounds (þ)-25, (þ)-30, and (þ)-34 as potential mimics of cryptophycins. Compounds (þ)-25, (þ)-30, and
(þ)-34 were tested for in vitro cytotoxicity against six human cancer cell lines. Although only modest activities were observed, these results
suggested that a new series of bioactive cryptophycin analogues might be available by structural modification of the central ring system of the
cryptophycins.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
known as cryptophycin A). Concurrently, a related
cytotoxin, (þ)-arenastatin A (2, cryptophycin-24), was
isolated from the Okinawa marine sponge Dysidea arenaria
by Kitagawa and Kobayashi.2 The structures and stereo-
chemistries of the cryptophycins, initially proposed on the
basis of chemical and spectroscopic studies,3 were later
revised by total synthesis.4
In 1990, Schwartz and co-workers reported a novel, cyclic
depsipeptide isolated from the terrestrial blue–green algae
Nostoc sp. ATCC 53789.1 Initially observed to have potent
antifungal activity against strains of Cryptococcus, which
frequently infect immunodeficient Acquired Immuno
Deficiency Syndrome (AIDS) and cancer patients, this
compound was named (þ)-cryptophycin-1 (1, Fig. 1; also
Cryptophycin-1 (1), the most abundant member of the
family, is a potent tumor-selective cytotoxin displaying
significant in vitro activity against tumor cell lines
(IC50¼9–20 pM).5 The broad spectrum of antitumor
activity of 1 against a variety of human tumor xenographs
andmurinesolidtumormodelsisparticularlynoteworthy.4,5a,6
Importantly, cryptophycin-1 demonstrates low suscep-
tibility to P-glycoprotein-mediated multiple drug resistance
when compared to currently utilized natural product anti-
cancer drugs.6b,c The KB human nasopharyngeal carcinoma
cell line which demonstrates resistance to vinblastine,
colchicines, and Taxolw, displays no resistance to crypto-
phycin-1. Thus, overexpression of P-glycoprotein does not
lead to resistance to 1.6b
Figure 1. The structure of cryptophycin-1 and cryptophycin-24.
Keywords: cryptophycin; microtubule; non-peptide peptidomimetics.
At the molecular level (þ)-cryptophycin-1 (1) inhibits
tubulin polymerization by binding to the ends of micro-
tubules, resulting in potent suppression of microtubule
*
Corresponding authors. Tel.: þ1-215-898-4860; fax: þ1-215-898-5129;
e-mail: smithab@sas.upenn.edu
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00857-3

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A. B. Smith, III et al. / Tetrahedron 59 (2003) 6991–7009
dynamics, which in turn induces apoptosis, and thereby the
observed antiproliferative activity.6,7
was therefore introduced to reduce this susceptibility.
Cryptophycin-52 (4), the most potent suppressor of micro-
tubule dynamics studied thus far, is very effective against
numerous human tumor cell lines.11 Compared to other
antimitotic agents, such as Taxolw, vinblastine, and
vincristine, the potency of 4 was shown to be maintained
against multidrug-resistant cells.
Further studies by Moore and co-workers led to the isolation
of 26 closely related cryptophycins providing important
structure–activity relationship (SAR) information,3,6a
suggesting the presence of several important pharma-
cophores3 (Fig. 2) including: (i) the intact macrolide ring,
(ii) the b-epoxide (C20, C30) in unit A, (iii) the chloro and
the methoxy substituents in unit B, and (iv) the C(6) methyl
group in unit C.
In view of the significant potential of the cryptophycins as
leads for new anticancer agents, there has been considerable
interest in recent years in addressing the synthetic challenges
associated with this structurally intriguing class of molecules.
The first reports on the total synthesis of cryptophycins
appeared in 1994 and 1995, respectively, from the research
groups of Kobayashi and Kitagawa,12 and Moore and Tius.4
Numerous approaches followed thereafter comprising both
formal and total syntheses. A strategy common to the reported
syntheses has been utilization of amide and ester linkages to
provide highly convergent approaches. A recent review by
Eggen and Georg13 summarized the synthetic efforts targeting
the cryptophycins over the last decade.
2. Results and discussion
2.1. First generation analogues based on the azepine
scaffold: strategy and design
Cognizant of the significant potential of the cryptophycins
for therapeutic use, we initiated a program to develop a new
class of analogues, exploiting the concept of non-peptide
peptidomimetics.14 We anticipated that the analogues
would have both better stability and bioavailability since
the designed scaffolds would lack the peptide bonds present
in the 16-membered depsipeptide of the cryptophycins;
peptides, in general, possess poor pharmacokinetic proper-
ties (e.g., poor transport properties and/or biliary secretion).
Furthermore, peptides recognized by proteolytic enzymes
are hydrolytically unstable.
Figure 2. Analogues of (þ)-cryptophycin-1 with improved therapeutic
index.
Efforts to develop cryptophycin analogues possessing
enhanced pharmacokinetic properties have produced (þ)-
cryptophycin-83,8 and cryptophycin-529 (3 and 4, respect-
ively; Fig. 2). The semisynthetic chlorohydrin (þ)-3 showed
similar in vitro cytotoxic activity relative to (þ)-1, but was
found to have an improved therapeutic index in several
animal models implying potential clinical activity.10 These
results suggested that (þ)-cryptophycin-8 might be a
prodrug, which can accumulate at the tumor site where it
is transformed into (þ)-cryptophycin-1.3 Indeed, the much
lower activity of (þ)-3 in an in vitro microtubule assembly
assay, compared to that of (þ)-1, indicated that the
chlorohydrin derivative has reduced or no biological
activity and that the observed activity results from the
generation of (þ)-1.10d Also noteworthy, (þ)-cryptophycin-
8 was curative for four of the tumor models evaluated
(mouse colon-38, human prostate TSU, human prostate
LNCaP, and human breast MX-1).10b,c
The broad concept of placing pharmacophoric groups on non-
peptide scaffolds was first proposed by Farmer in 1980.15a He
didnot,however,explorethepotentialofthisidea, norpropose
´
any specific scaffolds. In 1986 Belanger and DuFresne were
the first to implement this concept using a bicyclooctane
scaffold,15b but they did not develop this important achieve-
ment further. It remained for the researchers at the University
of Pennsylvania to finally put the full potential of this idea on a
firm basis. In particular Hirschmann, Nicolaou, and Smith
recognized the distinction in design required for peptidomi-
metics that are receptor ligands and those that are enzyme
inhibitors.16 This insight led them to design non-peptide
peptidomimetics based on glycoside17a,b and polypyrrolin-
one17c scaffolds respectively. Continuing efforts by Hirsch-
mann and Smith on the design and synthesis of non-peptide
peptidomimetics has produced: (a) potent b-D-glucose-based
agonists and antagonists for somatostatin (SRIF)18a,b and
substance P (NK-1)18c receptors, respectively; (b) pyrrolin-
one-based renin18d and HIV-1 protease inhibitors,18e–g the
latter having oral bioavailability in dogs, improved transport
properties, and potency comparable to Crixivanw against
several mutant HIV-1 viral strains;18e (c) pyrrolinone-based
matrix metalloprotease inhibitors;18h and (d) competent
Cryptophycin-52 (4), designed to enhance hydrolytic
stability relative to (þ)-1 while maintaining a favorable
profile of antitumor activity,9 is currently in phase II clinical
trials.9c As noted by Moore et al., the ester functionality
connecting units C and D of cryptophycin-1 is very
susceptible to base hydrolysis.3 Dimethyl substitution in 4

A. B. Smith, III et al. / Tetrahedron 59 (2003) 6991–7009
6993
Figure 4. Overlay of the X-ray structure of (þ)-cryptophycin-3 (5) and the
simplified model of analogue (6) utilizing an azepine-based scaffold.
ring as a scaffold, reasoning that a benzyl substituent on the
ring nitrogen would nicely overlay the substituted tyrosine
moiety in unit B (Fig. 4). To alleviate the possibility of
hydrophobic collapse induced by van der Waals interactions
between the two phenyl groups, a problem observed in our
initial modeling studies, we incorporated a urea subunit into
the side chain. An additional advantage of the urea moiety is
that it has the potential to mimic the carbonyl and NH
groups in the macrolide ring of the cryptophycins. Addition
of the remaining cryptophycin side chains onto the azepine
scaffold completed the model for the Monte Carlo
conformational analysis.20 To simplify the calculation, we
omitted the epoxide of unit A, as well as the chloro and
methoxy substituents of unit B as shown in Figure 4. In
addition, the relative disposition of the side chains in the
crystal structure of (þ)-cryptophycin-3 (5) was used as a
constraint in the conformational search. The analysis
located the global minimum for model structure 6, in
which the 7-membered ring adopted a bent half-chair
conformation. The results identified a conformer (Fig. 4)
displaying a similar chain topology at reasonably low
Figure 3. (a) b-D-glucose scaffold mimicking the b turn of the cyclic
hexapeptide L 363,301. (b) Peptidal HIV-1 protease inhibitor and
pyrrolinone-based inhibitor. (c) Peptidal inhibitor of renin developed by
Abbott and pyrrolinone-based inhibitor. (d) Peptidyl inhibitor of MMP
developed by Roche and pyrrolinone-based inhibitor.
non-peptide–peptide hybrid ligands for the human class II
MHC protein HLA-DR118i (Fig. 3).
Given these successes, we sought to develop a suitable
scaffold to replace the 16-membered macrolide ring of
cryptophycin-1 while maintaining the required spatial
orientation of the side chains to mimic the conformation
of the natural product. A serious caveat to this strategy was
that modification of the macrolide ring might result in a
conformational change of the side chains, and thereby
significantly reduce the cytotoxicity.4,5a Since little was
known about the bioactive conformations of the crypto-
phycins, our initial working hypothesis was that the
available X-ray structure of (þ)-cryptophycin-34 (5, Fig. 4)
would reasonably represent the solution conformation
permitting a template for scaffold design. Subsequently,
NOE studies reported by Moore and co-workers have shown
that the preferred side chain conformations of (þ)-
cryptophycin-3 in DMSO appear to be identical with those
shown in the crystal structure.4
Early computer modeling studies suggested that a 7-
membered ring could function as a viable depsipeptide
ring surrogate. Compounds possessing 7-membered rings
are quite prevalent as privileged structures19 in pharmaceu-
ticals (e.g. benzodiazepines). The efficacy of the 7-
membered ring is attributed to the puckered conformation,
in conjunction with a modest degree of flexibility to permit
induced fit into the receptor.
With these design criteria in mind, we chose the azepine
Figure 5. Proposed azepine-based cryptophycin analogues.

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A. B. Smith, III et al. / Tetrahedron 59 (2003) 6991–7009
energy costs, considering the flexibility of the model
structure. With this structural model available, we designed
compounds 7 and 8 as potential mimics of the cryptophycins
(Fig. 5). The synthetic plan permitted construction of 8, a
diastereomer of 7, through a parallel synthesis.
The synthesis of 7 and 8 began by converting known amine
11 to 12 (Scheme 2).21 Ring-closing metathesis using
Grubbs catalyst 13 led to olefin 14 in 90% yield,22 which
was epoxidized to furnish meso epoxide 10.
In 1995, Jacobsen reported that the chromium–salen
complex was a highly effective catalyst for the enantio-
selective ring opening of epoxides with azidotrimethyl-
silane.23 We adopted this chiral aminoalcohol synthesis to
introduce functionality in an enantioselective fashion onto
the azepine ring. Epoxide 10 was treated with trimethylsilyl
azide in the presence of the Jacobsen Cr(salen) catalyst
(S,S)-1523a (Scheme 3); reaction of the resultant azido silyl
ether with camphorsulfonic acid then provided hydroxy
azide (2)-16 in 98% yield and 87% ee (two steps).
Subsequent alkylation of the hydroxyl, followed by
simultaneous reduction of the azide and olefin afforded
amino ether (2)-18. The same sequence of reactions with
(þ)-16 furnished the enantiomer (þ)-18.
2.2. First generation analogues: synthesis
From the retrosynthetic perspective, we chose to install the
epoxide at the final stage of the synthesis (Scheme 1),
permitting an olefin precursor of 7, which would mimic (þ)-
cryptophycin-3 (5), to be available for bioassay. Disconnec-
tion of the side chains led to the azepine framework 10.
Scheme 1.
With both antipodes of the amino ether 18 in hand, the stage
was set for incorporation of the remaining side chains.
Coupling of amine (2)-18 with aldehyde (2)-1924 via
reductive amination (Scheme 4) led to the corresponding
secondary amine 20,25 which was protected as the tert-butyl
carbamate to furnish 21 in 59% yield over the two steps.
Unfortunately, NMR analysis indicated that partial
Scheme 2.
Scheme 3.
Scheme 4.

A. B. Smith, III et al. / Tetrahedron 59 (2003) 6991–7009
6995
epimerization of the methyl group at C(30) had occurred
during the reductive amination; the desired compound 21
however was the major component of an 8:1 mixture of
1
epimers determined by H NMR integration. Protection of
the amine with the bulky Boc group enabled separation via
HPLC later in the synthesis (vide infra). Hydrogenolysis of
the benzyl ether followed by oxidation to the corresponding
aldehyde and olefination utilizing the Wittig protocol26
provided olefin 22 in 75% yield for three steps as a 10:1
mixture of E- and Z-isomers. The Teoc group was then
removed with TBAF,27 and the resulting amine coupled
with commercially available 4-methoxybenzyl isocyanate
23 to furnish urea (þ)-24.28 At this juncture, purification by
Scheme 6.
nitrogen.29 A one-pot procedure involving BF3·amine
complexation and epoxidation was applied to both (þ)-25
and (þ)-30 (Scheme 6). Unfortunately, only the undesired
a-epoxides (2)-31 and (2)-32 were isolated after purifi-
cation using preparative TLC.30 We surmised that the
desired b-epoxides reacted intra-molecularly with the
tertiary amine either during the reaction or upon the
purification to generate a 5-membered ring, whereas the
undesired a-epoxides did not undergo this transformation.
2.3. First generation analogues: biological evaluation
Compounds (þ)-25, (þ)-30, (2)-31, and (2)-32 (Fig. 6)
were tested for in vitro cytotoxicity against six human
cancer cell lines.31 Mimic (þ)-25 displayed modest activity
against four human cell lines (Table 1), suggesting that the
side chains indeed occupied spatial orientation suitable for
activity. Compound (þ)-30, which differed from (þ)-25 in
the stereochemistry at the junction of the side chains and the
azepine ring, showed modest cytotoxicity against only two
human cancer cell lines. These data suggest that the
preferred trajectory of the side chains for activity was
Scheme 5.
reverse-phase HPLC led to (þ)-24 (.98% purity). Removal
of the Boc group (TFA) and subsequent reductive N-
methylation (HCHO, NaBH4)25 completed the synthesis of
(þ)-25. The same sequence of events was employed to
convert (þ)-18 to (þ)-30 (Scheme 5).
Attempts to install the epoxide in the presence of the tertiary
amine proved difficult, due to the high tendency of the
nitrogen to undergo oxidation. Protection of the tertiary
amine prior to epoxidation was therefore necessary.
Messeguer and co-workers reported that a tertiary amine
could be protected with a non-protic Lewis acid and that
such adducts possessing olefins could be epoxidized with
dimethyl dioxirane without the occurrence of oxidation at
Figure 6. First generation analogues of cryptophycin.

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A. B. Smith, III et al. / Tetrahedron 59 (2003) 6991–7009
Table 1. Biological evaluation of analogues, GI50 (mM)
Cell type
Cell-line
25
30
31
32
Pancreas-a
Breast adn
CNS gliobl
Lung-NSC
Colon
BXPC-3
MCF-7
SF268
NCI-H460
KM20L2
DU-145
4.8
.10
6.8
3.7
2.1
.10
.10
.10
13.2
2.5
.10
.10
10.2
.10
.10
.10
.10
.10
.10
.10
.10
40.3
Prostate
.10
.10
Figure 8. Proposed analogue 34.
obtained in (þ)-25 rather than in (þ)-30. Lack of activity for
epoxides (2)-31, and (2)-32 was expected as synthetic
cryptophycins with a-epoxides showed no biological
activity.
However, to obtain optimal overlap between the side chains of
(þ)-cryptophycin-3 (5) and the model (33), one additional
carbon in the epoxide side chain would be required.
We also suspect that the low potency of the analogues may
result from facile protonation of the tertiary amine, which in
turn would significantly change the orientation of the side
chain, as well as the ability of the compounds to cross the
cellular membrane. Although the analogues displayed only
modest or poor cytotoxicity compared to the extraordinarily
potent cryptophycins,32 we were encouraged by the initial
results which validated the utility of the azepine ring as an
analogue scaffold. To enhance the biological activity of the
analogues, we decided to redesign the side chains.
Grafting the required functional groups onto the simplified
model 33 gave proposed analogue 34 as shown in Figure 8.
2.5. Synthesis of a second generation analogue of
cryptophycin-1
With new structural constraints in mind, we turned to the
synthesis of analogue 34 as outlined retrosynthetically in
Scheme 7. In this approach, we would introduce the b-
epoxide via the Sharpless ‘one-pot’ conversion of vicinal
diols to epoxides.33
2.4. A second generation design strategy
Having demonstrated that incorporation of a tertiary amine
(6, Fig. 4) permitted excellent overlap with cryptophycin-3
(5), but that installation of the b-epoxide, required for potent
activity, was problematic due to the nucleophilic nitrogen,
we reasoned that an ether linkage between the functional
groups (Fig. 7) might enable us to install the desired epoxide
with the requisite stereochemistry mimicking the
cryptophycins.
Scheme 7.
Preparation of iodide (2)-35, a precursor of the side chain,
began with the Wittig olefination of aldehyde (þ)-37
(Scheme 8), followed by Sharpless dihydroxylation to
Figure 7. Overlay of the X-ray structure of (þ)-cryptophycin-3 (5) and the
simplified model of analogue (33) utilizing an azepine-based scaffold.
Scheme 8.

A. B. Smith, III et al. / Tetrahedron 59 (2003) 6991–7009
Table 2. Biological evaluation of analogue (þ)-34; GI50 (mM)
6997
furnish diol (2)-38.34 Protection of (2)-38 as the acetonide,
removal of the silyl protecting group and conversion of the
resultant alcohol to the iodide furnished (þ)-39. Homo-
logation proceeded smoothly via cyanide displacement to
give the desired nitrile, which in turn was subjected to a
two-step reduction sequence followed by iodination.
Cell type
Cell-line
(þ)-34
Pancreas-a
Breast adn
CNS gliobl
Lung-NSC
Colon
BXPC-3
MCF-7
SF268
NCI-H460
KM20L2
DU-145
3.2
5.4
.10
.10
7.8
Again, we employed the Jacobsen metal–salen catalyst to
install functional groups on the azepine ring enantioselec-
tively. Epoxide ring opening with iso-butanol in the
presence of (S,S)-15 afforded alcohol (2)-36 (Scheme
9).35 Although this operation proceeded with only modest
selectivity (25% ee), alkylation of the resulting alcohol (2)-
36 with iodide (2)-35 provided (2)-40 in 26% yield as the
major diastereomer (d.r.¼20:1). The side product [60%
yield from (2)-35] resulted from elimination of the iodide
to give an olefin. We speculated that a kinetic resolution
worked in our favor since the recovered starting alcohol 36
proved to be racemic. Removal of the Teoc protecting group
with TBAF,29,33 followed by reaction with 3-chloro-4-
methoxybenzyl isocyanate, generated in situ from 41,36
provided acetonide (2)-42.37 Hydrolysis of the acetonide
and treatment of the resulting diol with trimethyl orthoacetate
and TMSCl, followed by saponification of the acetate
intermediate completed the synthesis of b-epoxide (þ)-34.33
Prostate
.10
The poor activity of the second generation analogues may
be due to the flexibility of the azepine core compared to the
cryptophycins leading to increased conformational mobility
of the side chains. The longer side chains needed to
correctly position the requisite substituents in the oxygen
analogue may also have resulted in a conformational change.
3. Summary
We have designed and synthesized a series of azepine-based
cryptophycin analogues. Although only modest activities
were observed, these results hold the promise for a new
series of cryptophycin analogues with improved cytotox-
icity and pharmacokinetic properties available from a
scaffold which appropriately orients the cryptophycin side
chains, as has been achieved with the b-D-glucose scaffold
for the somatostatin (SRIF) and substance P (NK-1)
receptors.18a–c
4. Experimental
4.1. Materials and methods
All reactions were carried out under argon with dry, freshly
distilled solvents, oven- or flame-dried glassware, and
magnetic stirring, unless otherwise stated. All solvents
were reagent grade or HPLC grade. Diethyl ether (Et2O) and
tetrahydrofuran (THF) were distilled from sodium/benzo-
phenone under argon; benzene and toluene were distilled
from sodium, and dichloromethane (CH2Cl2) from calcium
hydride. Triethylamine (Et3N) and diisopropylethylamine
(DIEA) were distilled from calcium hydride and stored over
potassium hydroxide (KOH). Hexamethylphosphoramide
was freshly distilled from calcium hydride. Anhydrous
pyridine, dimethylformamide and dimethyl sulfoxide were
purchased from Aldirich and used without purification. n-
Butyllithium and t-butyllithium were purchased from
Aldrich and used without purification.
Except as indicated otherwise, reactions were magnetically
stirred and monitored by thin layer chromatography (TLC)
using 0.25-mm E. Merck pre-coated silica gel plates. Flash
chromatography was performed with the indicated solvents
and E. Merck silica gel 60 (particle size 0.040–0.063 mm).
Yields refer to chromatographically and spectroscopically
pure compounds, except as otherwise indicated.
Scheme 9.
2.6. Biological evaluation of (1)-34
Mimic (þ)-34 was submitted to in vitro cytotoxicity tests
against six human cancercell lines (Table 2). Althoughwehad
anticipated better activity from (þ)-34 due to the presence of
the b-epoxide in unit A and the chloride in unit B, compound
(þ)-34 displayed the same levels of modest activity.
All melting points were obtained on a Thomas–Hoover
apparatus. Infrared spectra were recorded on a Perkin–
Elmer Model 283B spectrophotometer. Proton and carbon

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A. B. Smith, III et al. / Tetrahedron 59 (2003) 6991–7009
NMR spectra were recorded on a Bruker AMX-500
spectrometer. Chemical shifts are reported in d values
relative to chloroform (d 7.24 for proton and d 77.0 for
carbon NMR), benzene (d 7.15 for proton and d 128.0
for carbon NMR), methanol (d 4.78 for proton and d 49.0
for carbon NMR), and dimethyl sulfoxide (d 2.49 for proton
and d 39.5 for carbon NMR). Optical rotations were
measured with a Perkin–Elmer Model 241 polarimeter in
the solvent indicated. High resolution mass spectra were
obtained at the University of Pennsylvania Mass Spec-
trometry Center by Dr Rakesh Kohli or Mr John Dykins on
either a VG Micromass 70/70H or VG ZAB-E spectrometer.
Microanalyses were performed at the University of
Pennsylvania elemental analysis center by Dr Rakesh
Kohli. Single-crystal X-ray structures were determined by
Dr Patrick Carroll at the University of Pennsylvania with an
Enraf Nonius CAD-4 automated diffractometer.
4.2.3. Epoxide 10. A solution of olefin 14 (2.91 g,
12.0 mmol) in CH2Cl2 (100 mL) was cooled to 08C and
treated with m-chloroperbenzoic acid (8.64 g, 4.00 equiv.).
The reaction mixture was stirred at 08C for 12 h and poured
into 10% NaHSO3 (100 mL). The layers were separated and
the aqueous phase was extracted with ether (3£150 mL).
The combined organic extracts were washed with saturated
NaHCO3 (200 mL) and brine (200 mL), dried (MgSO4),
filtered, and concentrated in vacuo. Flash chromatography
(hexanes–ether 3:1!1:1) gave epoxide 10 as a pale yellow
oil (2.57 g, 84% yield): Rf 0.32 (hexanes–EtOAc 3:1); IR
(CHCl3) 3680 (w, br), 3480 (w, br), 3000 (s), 2960 (s), 1670
(s), 1480 (s), 1420 (s), 1360 (m), 1300 (m), 1250 (s), 1210
(s), 1130 (m), 1100 (s), 1070 (s), 980 (m), 940 (s), 860 (s),
1
830 (s) cm21; H NMR (500 MHz, CDCl3) d 0.02 (s, 9H),
0.97 (t, J¼8.4 Hz, 2H), 2.06 (m, 1H), 2.19 (m, 3H), 2.76 (m,
2H), 3.17 (br s, 2H), 3.76 (br d, J¼14.6 Hz, 1H), 3.88 (br d,
J¼13.8 Hz, 1H), 4.13 (m, 2H); 13C NMR (125 MHz,
CDCl3) d 155.6, 63.4, 56.0, 55.8, 43.6, 43.0, 29.0, 28.3,
17.9, 21.5; HRMS (CI, methane) m/z 258.1523 [(MþH)þ;
calcd for C12H24NO3Si: 258.1525].
All calculations were performed on a Silicon Graphics Iris
4D/440 VGX (Unix operating system). The MacroModel
program [Version 6.5 (Iris)] was used for construction and
analysis of all modeled structures. The 10, 000 step Monte
Carlo conformational search in the gas phase was carried
out using the MM2 force field implanted in MacroModel.
4.2.4. Azido alcohol (2)-16. To a suspension of catalyst
(S,S)-15 (52 mg, 0.03 equiv.) in ether (1.0 mL) was added
epoxide 10 (746 mg, 2.90 mmol). After 15 min, azidotri-
methylsilane (0.420 mL, 1.09 equiv.) was added. The
reaction mixture was stirred for 6 days and then filtered
through a plug of silica gel (10 mL) with 100 mL of 30%
EtOAc–hexanes. The filtrate was concentrated in vacuo to
give azido silyl ether as an oil.
4.2. Preparative experiments
4.2.1. Diene 12. A solution of 2-(trimethylsilyl)ethoxycar-
bonyl chloride (8.96 g, 1.79 equiv.) in THF (20 mL) was
cooled to 2508C and a solution of N-benzyl-N,N-bisho-
moallylamine (4.48 g, 20.8 mmol) in THF (20 mL) was
added dropwise. The resultant mixture was warmed to room
temperature and stirred for 12 h. The reaction mixture was
concentrated in vacuo and flash chromatography on silica
gel (hexanes–ether 25:1!10:1!5:1) gave 3.26 g (59%
yield) of diene 12 as a colorless oil: Rf 0.35 (hexanes–
EtOAc 10:1); IR (CHCl3) 3680 (w, br), 3460 (w, br), 3080
(m), 3020 (s), 2980 (s), 1680 (s), 1480 (s), 1420 (s), 1370
(m), 1300 (m), 1230 (s), 1160 (m), 1080 (m), 1040 (m), 990
To a solution of the unpurified azido silyl ether in MeOH
(5.0 mL) was added 1S-(þ)-10-camphorsulfonic acid
(12 mg, 0.02 equiv.). The reaction mixture was stirred for
30 min and then concentrated to remove MeOH. The
residue was purified by flash chromatography on silica gel
using hexanes–ether (1:1) as eluant, to afford azido alcohol
(2)-16 as a colorless oil (647 mg, 98% yield): Rf 0.23
(hexanes–EtOAc 3:1); [a]2D0¼212.58 (c 2.94, CHCl3); IR
(CHCl3) 3560 (w, br), 3440 (w, br), 3000 (s), 2960 (s), 2890
(s), 2100 (s), 1680 (s), 1420 (s), 1350 (w), 1250 (s), 1200 (s),
1
(m), 920 (s), 840 (s) cm21; H NMR (500 MHz, CDCl3) d
0.02 (s, 9H), 0.98 (m, 2H), 2.27 (br d, J¼5.8 Hz, 4H), 3.26
(br s, 4H), 4.14 (m, 2H), 5.00 (m, 2H), 5.05 (dd, J¼1.4,
17.1 Hz, 2H), 5.75 (m, 2H), ; 13C NMR (125 MHz, CDCl3)
d 156.5, 135.4, 116.6, 63.3, 47.1, 46.7, 33.2, 32.7, 17.9,
21.5; HRMS (CI, methane) m/z 270.1887 [(MþH)þ; calcd
for C14H28NO2Si: 270.1889].
1130 (w), 1050 (m), 930 (w), 840 (s) cm21 1H NMR
;
(500 MHz, CDCl3) d 0.02 (s, 9H), 0.99 (m, 2H), 1.75 (m,
2H), 2.09 (m, 2H), 2.34 (d, J¼32.7 Hz, 1H), 3.24–3.41 (m,
3H), 3.57 (m, 1H), 3.68 (m, 1H), 4.16 (m, 2H); 13C NMR
(125 MHz, CDCl3) d 156.2, 74.0, 73.8, 67.7, 63.8, 41.3,
41.2, 40.9, 32.7, 32.6, 29.8, 29.6, 17.9, 21.5; HRMS (ESI)
m/z 323.1523 [(MþNa)þ; calcd for C12H24N4O3NaSi:
323.1515].
4.2.2. Olefin 14. A solution of diene 12 (3.78 g, 14.0 mmol)
in CH2Cl2 (150 mL) was treated with the Grubbs catalyst 13
(0.233 g, 0.020 equiv.) and the resulting mixture was heated
to reflux. After 24 h, the reaction mixture was cooled to
room temperature and concentrated in vacuo. Flash
chromatography using hexanes–ether (8:1) as eluant
afforded olefin 14 as a colorless oil (3.06 g, 90% yield): Rf
0.60 (hexanes–EtOAc 3:1); IR (CHCl3) 3780 (w, br), 3460
(w, br), 3000 (s), 2960 (s), 1770 (s), 1470 (s), 1430 (s), 1350
(m), 1310 (m), 1230 (s), 1110 (s), 1040 (m), 990 (m), 930
Determination of enantiomeric purity of (2)-16. HPLC
conditions: CHIRALPAK AD, hexanes–i-propanol 95:5,
1.0 mL/min, 258C, l¼210 nm.
(2)-16
Racemic
13.525 min
13.699 min
93.5%
50.4%
18.472 min
18.481 min
6.5%
49.6%
1
(s), 840 (s) cm21; H NMR (500 MHz, CDCl3) d 0.02 (s,
Determination of stereochemistry of (2)-16. (R)-(2)-a-
methoxy-a-trifluoromethylphenyl-acetyl chloride [(R)-
MTPACl, 7.9 mL, 1.2 equiv.] was added to a solution of
(2)-16 (10.2 mg, 0.0340 mmol), 4-(N,N, -dimethylamino)-
pyridine (DMAP, 5 mg), and triethylamine (10 mL,
2.1 equiv.) in CH2Cl2 (0.7 mL) at room temperature. The
9H), 0.99 (m, 2H), 2.27 (br d, J¼13.0 Hz, 4H), 3.47 (br dd,
J¼3.4, 12.8 Hz, 4H), 4.17 (m, 2H) 5.71 (br d, J¼1.9 Hz,
2H); 13C NMR (125 MHz, CDCl3) d 156.0, 129.9, 129.3,
63.3, 46.7, 29.9, 29.7, 17.9, 21.5; HRMS (CI, methane) m/z
242.1575 [(MþH)þ; calcd for C12H24NO2Si: 242.1576].

A. B. Smith, III et al. / Tetrahedron 59 (2003) 6991–7009
6999
reaction mixture was stirred for 3 h at room temperature and
concentrated in vacuo. Flash chromatography, using
CH2Cl2–MeOH (70:1) as eluant, gave 10.5 mg (60%
yield) of the (S)-MTPA ester of (2)-16 as a colorless oil:
1H NMR (500 MHz, CDCl3) d 0.02 (s, 9H), 0.97 (t,
J¼8.4 Hz, 2H), 1.80–1.94 (m, 2H), 2.02 (m, 1H), 2.16 (m,
1H), 3.32–3.45 (m, 2H), 3.54 (s, 3H), 3.48–3.58 (m, 1H),
3.67 (m, 2H), 4.15 (dd, J¼7.5, 16.3 Hz, 2H), 5.08 (m, 1H),
7.40 (m, 3H), 7.51 (m, 2H).
The reaction mixture was stirred for 12 h at room
temperature and filtered through a celite plug, then
concentrated in vacuo. Flash chromatography (CH2Cl2–
MeOH 8:1!4:1) afforded 372 mg (98% yield) of amine
(2)-18 as a colorless oil: Rf 0.22 (CH2Cl2–MeOH 10:1);
[a]2D0¼23.68 (c 2.1, CHCl3); IR (neat) 3540 (m, br), 3360
(m), 2940 (s), 2860 (s), 1690 (s), 1460 (s), 1420 (s), 1340
(m), 1280 (m), 1240 (s), 1180 (m), 1090 (s), 850 (s), 830
1
(s) cm21; H NMR (500 MHz, CDCl3) d 20.00 (s, 9H),
0.87 (d, J¼6.8 Hz, 3H), 0.88 (d, J¼7.4 Hz, 3H), 0.96 (m,
2H), 1.48–1.86 (m, 6H), 2.02 (m, 1H), 2.81 (m, 1H), 2.91
(m, 1H), 3.07 (m, 1H), 3.31 (dd, J¼6.4, 8.6 Hz, 1H), 3.14–
3.36 (m, 2H), 3.54 (m, 2H), 3.64 (m, 1H), 4.13 (m, 2H); 13C
NMR (125 MHz, CDCl3) d 156.3, 84.8, 84.6, 76.2, 76.1,
63.4, 56.1, 55.7, 41.9, 41.8, 41.2, 41.0, 32.9, 32.5, 30.1,
29.8, 28.8, 19.5, 19.4, 17.8, 21.5; HRMS (ESI) m/z
331.2402 [(MþH)þ; calcd for C16H35N2O3Si: 331.2417].
In similar fashion, the (R)-MTPA ester of (2)-16 was
obtained in 64% yield as a colorless oil: 1H NMR
(500 MHz, CDCl3) d 0.02 (s, 9H), 0.96 (m, 2H), 1.80 (m,
1H), 1.89 (m, 1H), 2.08 (m, 2H), 3.29–3.51 (m, 3H), 3.55 (s,
3H), 3.58–3.69 (m, 2H), 4.15 (t, J¼8.4 Hz, 2H), 5.02 (br m,
1H), 7.40 (m, 3H), 7.51 (m, 2H).
4.2.7. Azido alcohol (1)-16. To a suspension of catalyst
(R,R)-15 (52 mg, 0.03 equiv.) in ether (1.0 mL) was added
epoxide 10 (694 mg, 2.69 mmol). After 15 min, azidotri-
methylsilane (0.420 mL, 1.17 equiv.) was added. The
reaction mixture was stirred for 6 days and then filtered
through a plug of silica gel (10 mL) with 100 mL of 30%
EtOAc–hexanes. The filtrate was concentrated in vacuo to
give azido silyl ether as an oil.
(S)-MTPA ester (R)-MTPA ester
(S)–(R)
b1/b2 1.82/2.02
3.67
e1/e2 1.91/2.16
1.89/2.08
3.69
1.80/2.08
4.151
0.962
20.07/20.06
20.02
c
þ0.11/þ0.08
To a solution of the unpurified azido silyl ether in MeOH
(5.0 mL) was added 1S-(þ)-10-camphorsulfonic acid
(13 mg, 0.03 equiv.). The reaction mixture was stirred for
30 min and then concentrated to remove MeOH. The
residue was purified by flash chromatography on silica gel
using hexanes–ether (1:1) as eluant, to afford azido alcohol
(þ)-16 (605 mg, 95% yield) as a colorless oil: Rf 0.23
(hexanes–EtOAc 3:1); [a]2D0¼þ12.48 (c 2.85, CHCl3); IR
(CHCl3) 3580 (w, br), 3460 (w, br), 3010 (s), 2960 (s), 2900
(s), 2100 (s), 1670 (s), 1430 (s), 1350 (m), 1250 (s), 1210 (s),
g
h
i
4.153
0.973
0.022
þ0.002
þ0.011
0.019
þ0.003
4.2.5. Azido ether (2)-17. To a suspension of NaH (95%,
170 mg, 5.35 equiv.) in THF (10 mL) was added a solution
of azido alcohol (2)-16 (398 mg, 1.32 mmol) in THF
(3 mL) at room temperature. After 30 min, when gas
evolution had ceased, tetrabutylammonium iodide
(TBAI, 48.9 mg, 0.10 equiv.) was added followed by
dropwise addition of methallyl bromide (0.72 mL,
5.4 equiv.). The resulting mixture was stirred for 30 min
at room temperature, quenched by addition of water
(10 mL), and diluted with ether (30 mL). The layers were
separated and the aqueous phase was further extracted with
ether (2£30 mL). Combined extracts were dried (MgSO4),
filtered and concentrated in vacuo. Flash chromatography
(hexanes–ether 5:1) gave azido ether (2)-17 as a pale
yellow oil (413 mg, 88% yield): Rf 0.47 (hexanes–EtOAc
3:1); [a]2D0¼23.58 (c 2.67, CHCl3); IR (CHCl3) 3680 (w,
br), 3620 (w, br), 3020 (s), 2960 (s), 2100 (s), 1680 (s), 1420
(s), 1350 (m), 1220 (s), 1100 (s), 1060 (s), 910 (m), 840
(s) cm21; 1H NMR (500 MHz, CDCl3) d 0.02 (s, 9H), 0.98
(t, J¼8.5 Hz, 2H), 1.75 (s, 3H), 1.68–1.83 (m, 2H), 2.04 (m,
2H), 3.28 (m, 1H), 3.42 (m, 2H), 3.49 (m, 1H), 3.59 (m, 1H),
3.65 (m, 1H), 3.94 (m, 2H), 4.15 (m, 2H), 4.92 (d,
J¼43.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) d 156.2,
141.9, 112.6, 80.1, 80.0, 73.5, 64.6, 64.4, 63.6, 41.0, 40.9,
40.7, 29.7, 29.6, 20.3, 29.1, 19.5, 17.9, 21.5; HRMS (CI,
methane) m/z 355.2178 [(MþH)þ; calcd for C16H31N4O3Si:
355.2165].
1140 (m), 1050 (s), 930 (m), 840 (s) cm21 1H NMR
;
(500 MHz, CDCl3) d 0.03 (s, 9H), 0.99 (m, 2H), 1.75 (m,
2H), 2.09 (m, 2H), 2.33 (d, J¼34.2 Hz, 1H), 3.24–3.41 (m,
3H), 3.56 (m, 2H), 3.68 (m, 1H), 4.17 (m, 2H); 13C NMR
(125 MHz, CDCl3) d 156.2, 74.0, 73.8, 67.7, 63.7, 41.3,
41.2, 40.9, 32.7, 32.6, 29.8, 29.6, 17.9, 21.5; HRMS (ESI)
m/z 323.1517 [(MþNa)þ; calcd for C12H24N4O3NaSi:
323.1515].
Determination of enantiomeric purity of (þ)-16. HPLC
conditions: CHIRALPAK AD, hexanes–i-propanol 95:5,
1.0 mL/min, 258C, l¼210 nm.
(þ)-16
13.653 min
13.699 min
7.3%
50.4%
18.068 min
18.481 min
92.7%
49.6%
Racemic
4.2.8. Azido ether (1)-17. To a suspension of NaH (95%,
138 mg, 5.68 equiv.) in THF (10 mL) was added a solution
of azido alcohol (þ)-16 (335 mg, 1.01 mmol) in THF
(3 mL) at room temperature. After 30 min, when gas
evolution had ceased, tetrabutylammonium iodide
(TBAI, 42.3 mg, 0.11 equiv.) was added followed by
dropwise addition of methallyl bromide (0.61 mL,
6.0 equiv.). The resulting mixture was stirred for 30 min
at room temperature, quenched by addition of water
(10 mL), and diluted with ether (30 mL). The layers were
4.2.6. Amine (2)-18. To a solution of azido ether (2)-17
(406 mg, 1.15 mmol) in MeOH (15 mL) was added Pd/C
(10%, 57.4 mg) and the reaction flask was charged with H2.

7000
A. B. Smith, III et al. / Tetrahedron 59 (2003) 6991–7009
separated and the aqueous phase was further extracted with
ether (2£30 mL). Combined extracts were dried (MgSO4),
filtered and concentrated in vacuo. Flash chromatography
(hexanes–ether 5:1) gave azido ether (þ)-17 as a pale
yellow oil (336 mg, 94% yield): Rf 0.47 (hexanes–EtOAc
3:1); [a]2D0¼þ3.38 (c 1.22, CHCl3); IR (CHCl3) 3680 (w, br),
3600 (w, br), 3020 (s), 2960 (m), 2100 (s), 1680 (s), 1420
(s), 1360 (m), 1220 (s), 1090 (m), 1050 (m), 900 (s), 830
(m) cm21; 1H NMR (500 MHz, CDCl3) d 0.02 (s, 9H), 0.99
(t, J¼8.4 Hz, 2H), 1.75 (s, 3H), 1.68–1.83 (m, 2H), 2.04
(m, 2H), 3.28 (m, 1H), 3.42 (m, 2H), 3.49 (m, 1H), 3.59 (m,
1H), 3.65 (m, 1H), 3.94 (m, 2H), 4.16 (m, 2H), 4.92
(d, J¼42.9 Hz, 2H); 13C NMR (125 MHz, CDCl3) d 156.2,
141.9, 112.6, 80.1, 80.0, 73.5, 64.6, 64.4, 63.6, 41.0, 40.9,
40.7, 29.7, 29.6, 29.3, 29.2, 19.5, 17.9, 21.5; HRMS (CI,
methane) m/z 355.2164 [(MþH)þ; calcd for C16H31N4O3Si:
355.2165].
61.6, 50.8, 42.2, 42.0, 40.6, 40.4, 34.0, 30.5, 30.2, 28.8,
28.4, 19.4, 17.9, 15.6, 21.5; HRMS (ESI) m/z found
493.3453 [(MþH)þ; calcd for C27H49N2O4Si: 493.3462].
4.2.11. tert-Butyl carbamate 21. 8:1 Mixture at C30. A
solution of secondary amine 20 (114 mg, 0.232 mmol) in
CH2Cl2 (5 mL) was treated with Et3N (37 mL, 1.1 equiv.)
and (Boc)2O (59 mL, 1.1 equiv.) and the resulting mixture
was stirred for 12 h at room temperature. The reaction
mixture was quenched by addition of 10% NaHSO4 (10 mL)
and extracted with ether (3£20 mL). Combined extracts
were dried (MgSO4), filtered, and concentrated in vacuo.
Flash chromatography (hexanes–EtOAc 13:1!4:1)
afforded 111 mg (81% yield) of tert-butyl carbamate 21 as
a colorless oil: Rf 0.5 (hexanes–EtOAc 3:1); IR (neat) 2940
(s), 2860 (s), 1690 (s), 1460 (m), 1420 (m), 1360 (m), 1320
(w), 1290 (w), 1240 (m), 1170 (m), 1150 (m), 1090 (m), 850
1
(m), 830 (m) cm21; H NMR (500 MHz, CDCl3) d 0.02
4.2.9. Amine (1)-18. To a solution of azido ether (þ)-17
(336 mg, 0.948 mmol) in MeOH (15 mL) was added Pd/C
(10%, 29.1 mg) and the reaction flask was charged with
H2. The reaction mixture was stirred for 12 h at room
temperature and filtered through a celite plug, then
concentrated in vacuo. Flash chromatography (CH2Cl2–
MeOH 8:1!4:1) afforded 328 mg (97% yield) of amine
(þ)-18 as a colorless oil: Rf 0.22 (CH2Cl2–MeOH 10:1);
[a]2D0¼þ2.88 (c 1.7, CHCl3); IR (neat) 3540 (m, br), 3360
(m), 2940 (s), 2860 (s), 1690 (s), 1460 (s), 1420 (s), 1340
(m), 1280 (m), 1240 (s), 1170 (m), 1090 (s), 850 (s), 830
(s, 9H), 0.84, (d, J¼6.5 Hz, 3H), 0.85 (d, J¼6.4 Hz, 3H),
0.93 (d, J¼6.6 Hz, 3H), 0.97 (t, J¼8.4 Hz, 2H), 1.40 (d,
J¼8.5 Hz, 9H), 1.53 (m, 1H), 1.68–2.28 (m, 5H), 2.92–
3.85 (m, 12H), 4.13 (m, 2H), 4.48 (m, 2H), 7.22–7.35 (m,
5H); 13C NMR (125 MHz, CDCl3) d 156.3, 155.5, 155.2,
138.8, 138.6, 128.9, 128.8, 128.4, 128.3, 127.5, 80.5, 80.4,
79.5, 79.4, 79.2, 79.1, 77.7, 77.6, 77.5, 76.9, 76.6, 73.7,
73.6, 73.1, 73.0, 65.7, 65.5, 65.4, 63.4, 54.1, 54.0, 53.7,
43.4, 43.3, 41.0, 40.9, 34.1, 33.8, 32.2, 32.1, 31.9, 31.7,
31.6, 31.4, 30.8, 30.6, 28.9, 28.7, 28.6, 28.5, 19.5, 17.9,
15.7, 15.4, 21.5; HRMS (ESI) m/z found 615.3823
[(MþNa)þ; calcd for C32H56N2O6 NaSi: 615.3805].
(s) cm21 1H NMR (500 MHz, CDCl3) d 0.02 (s, 9H),
;
0.89 (d, J¼6.8 Hz, 3H), 0.90 (d, J¼7.3 Hz, 3H), 0.98
(m, 2H), 1.51–1.87 (m, 6H), 2.04 (m, 1H), 2.84 (m, 1H),
2.94 (m, 1H), 3.09 (m, 1H), 3.33 (dd, J¼6.4, 8.6 Hz, 1H),
3.17–3.37 (m, 2H), 3.55 (m, 1H), 3.66 (m, 1H), 4.15
(m, 2H); 13C NMR (125 MHz, CDCl3) d 156.3, 84.8,
84.5, 76.3, 76.2, 63.4, 56.2, 55.8, 42.0, 41.8, 41.2, 41.0,
32.9, 32.5, 30.2, 29.9, 28.9, 19.5, 17.9, 21.5; HRMS (CI,
methane) m/z 331.2412 [(MþH)þ; calcd for
C16H35N2O3Si: 331.2417].
4.2.12. Olefin 22. trans–cis¼10:1. To a solution of tert-
butyl carbamate 21 (696 mg, 1.17 mmol) in MeOH (20 mL)
was added Pd/C (10%, 41.3 mg) and the reaction flask was
charged with H2. The reaction mixture was stirred for 12 h
at room temperature, filtered through a celite plug, and then
concentrated in vacuo. Flash chromatography (hexanes–
EtOAc 4:1) gave 537 mg (91% yield) of alcohol as a
colorless oil: Rf 0.28 (hexanes–EtOAc 2:1); IR (neat) 3460
(m, br), 2940 (s), 2860 (s), 1690 (s), 1470 (m), 1420 (m),
1360 (m), 1250 (m), 1170 (m), 1090 (m), 1040 (w), 990 (w),
4.2.10. Benzyl ether 20. To a solution of aldehyde (2)-19
(168 mg, 2.97 equiv.) and amine (2)-18 (105 mg,
˚
0.318 mmol) in MeOH (8 mL) were added crushed 4 A
930 (w), 850 (m), 830 (w) cm21 1H NMR (500 MHz,
;
CD3OD) d 0.07 (s, 9H), 0.90 (d, J¼6.7 Hz, 6H), 0.94 (d,
J¼6.8 Hz, 3H), 1.03 (t, J¼8.2 Hz, 2H), 1.47 (br s, 9H), 1.62
(m, 1H), 1.77 (m, 1H), 1.88 (m, 2H), 2.13 (m, 1H), 2.25
(m, 1H), 2.96 (m, 1H), 3.08 (m, 2H), 3.30–3.85 (m, 9H),
4.78 (m, 2H); 13C NMR (125 MHz, CD3OD) d 158.0, 157.7,
156.9, 81.5, 81.4, 81.3, 80.7, 80.5, 80.4, 79.4, 77.5, 66.6,
66.3, 65.5, 64.8, 54.5, 54.4, 43.9, 43.5, 42.5, 37.3, 36.4,
32.7, 32.6, 32.5, 32.4, 32.3, 32.2, 32.1, 31.7, 31.4, 30.1,
28.9, 23.7, 19.9, 18.7, 15.8, 15.7, 15.6, 21.4; HRMS (CI,
methane) m/z found 503.3505 [(MþH)þ; calcd for
C25H51N2O6Si: 503.3516].
molecular sieves (2 mL) and NaBH3CN (38.6 mg,
1.93 equiv.). The pH was adjusted to 6–7 with glacial
AcOH and the resultant mixture was stirred for 1 h at room
temperature. The reaction mixture was filtered through a
silica gel plug and concentrated in vacuo. Flash chroma-
tography (CH2Cl2–MeOH 40:1!10:1) afforded 114 mg
(73% yield) of secondary amine 20 as a colorless oil: Rf 0.33
(CH2Cl2–MeOH 10:1); IR (neat) 3320 (w), 2960 (s), 2860
(s), 1690 (s), 1470 (s), 1410 (s), 1350 (m), 1240 (s), 1200
1
(m), 1090 (s), 990 (w), 930 (w), 850 (s), 830 (s) cm21; H
NMR (500 MHz, CDCl3) d 0.01 (s, 9H), 0.86 (d, J¼6.7 Hz,
3H), 0.87 (d, J¼6.6 Hz, 3H), 0.89 (d, J¼7.8 Hz, 3H), 0.97
(t, J¼8.4 Hz, 2H), 1.49 (m, 1H), 1.63 (m, 1H), 1.78 (m, 1H),
1.90–2.05 (m, 3H), 2.17 (br s, 1H), 2.32p [dd, J¼6.9,
11.3 Hz, 1H, minor diastereomer at C(3)], 2.54 (m, 3H),
2.73p (dd, J¼6.1, 11.3 Hz, 1H), 3.05 (m, 1H), 3.14 (m, 1H),
3.19 (m, 1H), 3.28–3.38 (m, 4H), 3.56 (m, 2H), 4.14
(t, J¼8.4 Hz, 2H), 4.47 (s, 2H), 7.22–7.33 (m, 5H); 13C
NMR (125 MHz, CDCl3) d 156.3, 138.6, 128.3, 128.2,
127.5, 127.4, 81.9, 81.7, 76.0, 75.9, 74.4, 73.0, 63.3, 62.1,
A solution of alcohol (519 mg, 1.03 mmol) in CH2Cl2
(20 mL) was treated with pyridine (0.28 mL, 3.4 equiv.) and
Dess–Martin periodinane (527 mg, 1.1 equiv.), then the
resultant mixture was stirred for 30 min at room tempera-
ture. The reaction mixture was poured into 20% Na2S2O3-
saturated NaHCO3 (1:1¼V:V, 60 mL) and after separation,
the aqueous phase was extracted with ether (3£80 mL).
Combined extracts were washed with saturated CuSO4
(3£60 mL), water (60 mL), and brine (60 mL), dried

A. B. Smith, III et al. / Tetrahedron 59 (2003) 6991–7009
7001
(MgSO4), filtered, then concentrated in vacuo. Flash
chromatography (hexanes–ether 4:1!1:1) afforded alde-
hyde as a colorless oil (470 mg, 88% yield): Rf 0.30
(hexanes–EtOAc 2:1); IR (neat) 2960 (s), 2860 (s), 2720
(w), 1690 (s), 1460 (m), 1420 (m), 1360 (m), 1310 (w), 1250
24 as a mixture (356 mg, 81% yield). The mixture was
further purified by preparative HPLC using a reverse phase
DYNAMAXw C18 column [21.1 mm, MeCN–0.1% TFA in
water (3:1), 4.0 mL/min] to give (þ)-24 (92.8 mg, 21%
yield) as a colorless oil: Rf 0.40 (CH2Cl2–MeOH 10:1);
[a]2D0¼þ56.58 (c 1.30, CHCl3); IR (neat) 3340 (m, br), 2960
(s), 1690 (s), 1630 (s), 1510 (s), 1460 (m), 1360 (m), 1240
(s), 1170 (s), 1090 (m), 1030 (m), 910 (m) cm21; 1H NMR
(500 MHz, CDCl3) d 0.85 (d, J¼6.4 Hz, 3H), 0.86 (d,
J¼6.1 Hz, 3H), 1.06 (d, J¼6.7 Hz, 3H), 1.39 (s, 9H), 1.52
(m, 1H), 1.73 (m, 2H), 1.90 (m, 1H), 2.09–2.35 (m, 2H),
2.56 (m, 1H), 2.99–3.06 (m, 4H), 3.13 (m, 1H), 3.27
(m, 1H), 3.49 (m, 2H), 3.62 (m, 1H), 3.73 (m, 1H), 3.77
(s, 9H), 3.86 (m, 1H), 4.31 (m, 2H), 4.43 (m, 1H), 6.10
(m 1H), 6.31 (d, J¼15.9 Hz, 1H), 6.84 (d, J¼8.6 Hz, 2H),
7.12–7.30 (m, 7H); 13C NMR (125 MHz, CDCl3) d 158.9,
157.5, 155.4, 155.1, 137.7, 137.5, 134.6, 134.1, 131.7,
129.3, 129.1, 129.0, 128.5, 128.4, 127.0, 126.8, 126.0,
125.9, 114.0, 113.9, 80.6, 79.5, 79.3, 79.1, 76.6, 65.5, 56.5,
55.3, 44.5, 43.0, 40.1, 37.6, 37.5, 32.3, 32.1, 31.5, 30.7,
28.8, 28.5, 28.4, 19.5, 19.4, 18.0; HRMS (ESI) m/z
found 616.3733 [(MþNa)þ; calcd for C35H51N3O5Na:
616.3726].
(m), 1170 (m), 1090 (m), 930 (w), 860 (m), 830 (m) cm21
;
1H NMR (500 MHz, CDCl3) d 0.00 (s, 9H), 0.83 (d, J¼3.5,
6.7 Hz, 3H), 0.84 (d, J¼6.7 Hz, 3H), 0.96 (t, J¼8.4 Hz, 2H),
1.04p [d, J¼7.2 Hz, 3H, minor diastereomer at C(30)], 1.05
(d, J¼7.0 Hz, 3H), 1.40 (br s, 9H), 1.51 (m, 1H), 1.72 (m,
1H), 1.83 (m, 1H), 2.05 (m, 1H), 2.27 (m, 1H), 2.57 (m, 1H),
3.25 (dd, J¼6.4, 8.7 Hz, 1H), 2.95–3.37 (m, 6H), 3.51–3.71
(m, 3H), 3.84 (m, 1H),.4.13 (t, J¼8.4 Hz, 2H), 9.59 (br s,
1H), 9.65p (d, J¼1.6 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 203.7, 203.5, 156.2, 155.3, 154.4, 80.4, 80.2, 80.1, 80.0,
79.2, 79.1, 76.6, 76.4, 65.7, 65.5, 63.4, 51.7, 51.4, 46.9,
46.8, 43.2, 42.9, 41.0, 40.8, 32.2, 32.1, 31.8, 31.4, 31.2,
30.6, 30.3, 28.8, 28.5, 28.4, 19.4, 17.8, 12.0, 11.8, 21.5;
HRMS (ESI) m/z found 523.3181 [(MþNa)þ; calcd for
C25H48N2O6 NaSi: 523.3179].
To a solution of benzyltriphenylphosphonium chloride
(435 mg, 1.19 equiv.) in benzene (10 mL) at 08C was
added n-BuLi (0.79 mL, 1.2 equiv.) in hexanes (1.4 M)
dropwise and the resulting solution was warmed to room
temperature then stirred for 1 h. The solution was cooled to
08C and treated with a solution of aldehyde (470 mg,
0.939 mmol) in benzene (5 mL). The reaction mixture was
warmed to room temperature and stirred for 5 h. The
reaction mixture was quenched with saturated NH4Cl
(50 mL) and extracted with ether (4£50 mL). Combined
extracts were washed with brine (50 mL), dried (MgSO4),
filtered and concentrated in vacuo. Flash chromatography
(hexanes–ether 5:1!4:1!2:1) afforded olefin 22 as a pale
yellow oil (507 mg, 94% yield): Rf 0.42 (hexanes–EtOAc
3:1); IR (neat) 2960 (s), 1680 (s), 1470 (m), 1420 (m), 1360
(m), 1250 (m), 1170 (m), 1090 (m), 960 (m), 930 (m), 850
(m), 830 (m) cm21; 1H NMR (500 MHz, CDCl3) d 0.01p [s,
9H, minor diastereomer at C(30)], 0.02 (s, 9H), 0.85 (m, 6H),
0.97 (t, J¼8.4 Hz, 2H), 1.04 (m, 3H), 1.37 (s, 9H), 1.42p (s,
9H), 1.52 (m, 1H), 1.73 (m, 1H), 1.81–2.29 (m, 3H), 2.57
(m, 1H), 2.94–3.22 (m, 5H), 3.27 (m, 1H), 3.39–3.88 (m,
4H), 4.11p (t, J¼8.3 Hz, 2H), 4.14 (t, J¼8.3 Hz, 2H), 6.08
(m, 1H), 6.31 (d, J¼15.9 Hz, 1H), 6.36p (d, J¼15.9 Hz, 1H),
7.15–7.30 (m, 5H); 13C NMR (125 MHz, CDCl3) d 156.3,
156.2, 155.3, 154.9, 137.7, 137.4, 134.6, 134.5, 134.1,
134.0, 129.8, 129.4, 129.3, 128.5, 128.4, 128.3, 128.2,
127.1, 127.0, 126.8, 126.0, 125.9, 80.6, 80.5, 79.4, 79.2,
79.0, 76.9, 76.6, 70.5, 65.2, 63.4, 56.4, 56.3, 43.4, 43.3,
40.9, 40.7, 40.6, 40.5, 37.6, 32.5, 32.4, 32.2, 32.0, 31.7,
30.9, 30.5, 28.8, 28.5, 28.4, 19.4, 18.2, 17.8, 21.5; HRMS
(ESI) m/z found 597.3707 [(MþNa)þ; calcd for C32H54N2-
O5NaSi: 597.3700].
4.2.14. Analogue (1)-25. To a solution of urea (þ)-24
(15.0 mg, 0.0253 mmol) in CH2Cl2 (1.2 mL) was added
trifluoroacetic acid (TFA, 0.65 mL) and the resulting
mixture was stirred at room temperature for 10 min. The
reaction mixture was diluted with CH2Cl2 (100 mL),
washed with water (30 mL), and saturated NaHCO3
(30 mL), dried (Na2SO4), filtered then concentrated in
vacuo. Preparative TLC [0.5 mm£20 cm£20 cm, CH2Cl2-
(saturated with NH3)–MeOH (10:1)] afforded 11.7 mg
(94% yield) of secondary amine as a colorless oil: Rf 0.35
(CH2Cl2–MeOH 10:1); [a]2D0¼þ25.08 (c 0.585, CHCl3); IR
(neat) 3320 (m, br), 2940 (s), 1620 (s), 1500 (s), 1460 (m),
1360 (m), 1350 (w), 1290 (w), 1240 (m), 1170 (m), 1090
(m), 1030 (m), 960 (m), 800 (m) cm21; 1H NMR (500 MHz,
CDCl3) d 0.66 (d, J¼6.7 Hz, 3H), 0.67 (d, J¼6.7 Hz, 3H),
1.09 (d, J¼6.7 Hz, 3H), 1.48–1.65 (m, 3H), 2.05 (m, 2H),
2.37 (dd, J¼9.0, 10.8 Hz, 2H), 2.50 (m, 1H), 2.56 (m, 1H),
2.73 (dd, J¼5.0, 10.8 Hz, 1H), 2.98 (dd, J¼6.3, 8.7 Hz, 1H),
3.10–3.25 (m, 4H), 3.57 (m, 1H), 3.64 (m, 1H), 3.77 (s, 3H),
4.32 (m, 2H), 4.49 (t, J¼5.2 Hz, 1H), 6.01 (dd, J¼8.5,
15.8 Hz, 1H), 6.45 (d, J¼15.8 Hz, 1H), 6.84 (d, J¼8.6 Hz,
2H), 7.15–7.35 (m, 7H); 13C NMR (125 MHz, CDCl3) d
158.9, 157.5, 137.2, 133.8, 131.7, 130.7, 129.1, 128.4,
127.1, 126.1, 114.0, 82.1, 76.9, 76.2, 62.9, 55.3, 53.3, 44.6,
41.8, 39.9, 38.1, 30.7, 28.8, 28.7, 19.3, 19.2, 19.0; HRMS
(ESI) m/z found 494.3378 [(MþH)þ; calcd for C30H44N3O3:
494.3383].
To a solution of secondary amine (11.7 mg, 0.0237 mmol)
and 37% formaldehyde (5.1 mg, 2.6 equiv.) in MeOH
˚
(1 mL) were added crushed 4 A molecular sieves (0.3 mL)
4.2.13. Urea (1)-24. Under argon, TBAF (1.6 equiv.) in
THF (1.2 mL, 1.0 M) was added to a solution of 22 (425 mg,
0.740 mmol) in THF (20 mL) at room temperature. The
reaction mixture was stirred for 12 h at room temperature,
and then treated with 4-methoxybenzyl isocyanate 23
(318 mg, 2.6 equiv.). The resulting mixture was then stirred
for 2 h, and quenched with MeOH (0.5 mL). The solution
was concentrated in vacuo and purified by flash chroma-
tography using CH2Cl2–MeOH (40:1) as eluant, to furnish
and NaBH3CN (4.2 mg, 2.8 equiv.). The pH was adjusted to
6–7 with glacial AcOH and the resultant mixture was stirred
for 24 h at room temperature. The reaction mixture was
filtered through a silica gel plug and concentrated in vacuo.
Preparative TLC [0.5 mm£20 cm£20 cm, CH2Cl2-
(saturated with NH3)–MeOH (10:1)] afforded 9.8 mg
(67% yield) of amine (þ)-25 as a colorless oil: Rf 0.33
(CH2Cl2–MeOH 10:1); [a]2D0¼þ178 (c 0.55, CHCl3); IR

7002
A. B. Smith, III et al. / Tetrahedron 59 (2003) 6991–7009
(neat) 3340 (m, br), 2940 (s), 1630 (s), 1500 (s), 1460 (m),
1390 (w), 1350 (w), 1290 (w), 1240 (m), 1170 (m), 1080
(m), 1030 (m), 950 (m), 810 (m) cm21; 1H NMR (500 MHz,
CDCl3) d 0.858 (d, J¼6.7 Hz, 3H), 0.862 (d, J¼6.6 Hz, 3H),
1.05 (m, 3H), 1.61 (m, 1H), 1.69–1.81 (m, 2H), 1.89 (m,
1H), 1.97 (m, 1H), 2.28 (br s, 3H), 2.48 (br s, 3H), 2.62 (br s,
1H), 3.10–3.17 (m, 2H), 3.19–3.26 (m, 2H), 3.38 (dt,
J¼3.0, 8.1 Hz, 1H), 3.54 (m, 1H), 3.61 (m, 1H), 3.77 (s,
3H), 4.33 (d, J¼5.3 Hz, 2H), 4.49 (br s, 1H), 6.15 (dd,
J¼6.4, 16.0 Hz, 1H), 6.35 (d, J¼16.0 Hz, 1H), 6.84 (d,
J¼8.6 Hz, 2H), 7.14–7.32 (m, 7H); 13C NMR (125 MHz,
CDCl3) d 158.9, 157.6, 138.0, 131.8, 129.1, 128.4, 128.3,
126.8, 126.0, 114.0, 79.9, 75.9, 68.0, 61.9, 55.3, 44.6, 42.5,
40.6, 38.0, 35.8, 30.9, 29.0, 28.3, 19.6, 18.3; HRMS (ESI)
m/z found 508.3525 [(MþH)þ; calcd for C31H46N3O3:
508.3539].
156.3, 155.6, 155.3, 138.7, 128.3, 127.5, 79.4, 79.3, 79.2,
79.1, 77.6, 77.5, 77.4, 73.7, 73.1, 65.7, 65.6, 65.4, 63.4,
54.2, 43.3, 41.0, 40.9, 34.3, 34.2, 34.1, 33.8, 32.2, 32.0,
31.9, 31.6, 31.1, 30.8, 30.7, 28.9, 28.6, 28.5, 19.5, 17.9,
15.5, 15.4, 21.5; HRMS (CI, methane) m/z found 593.3972
[(MþH)þ; calcd for C32H57N2O6Si: 593.3986].
4.2.17. Olefin 28. trans–cis¼10:1. To a solution of tert-
butyl carbamate 27 (765 mg, 1.29 mmol) in MeOH (20 mL)
was added Pd/C (10%, 34.0 mg) and the reaction flask was
charged with H2. The reaction mixture was stirred for 17 h
at room temperature, filtered through a celite plug, and then
concentrated in vacuo. Flash chromatography (hexanes–
EtOAc 5:1!2:1!1:1) gave 558 mg (86% yield) of alcohol
as a colorless oil: Rf 0.28 (hexanes–EtOAc 2:1); IR (neat)
3440 (m, br), 2940 (s), 2860 (s), 1690 (s), 1460 (m), 1410
(m), 1360 (m), 1240 (m), 1170 (m), 1090 (m), 1030 (w), 990
(w), 930 (w), 850 (m), 830 (w) cm21; 1H NMR (500 MHz,
CDCl3) d 0.01 (s, 9H), 0.84 (d, J¼6.7 Hz, 6H), 0.89 (d,
J¼7.0 Hz, 3H), 0.97 (t, J¼8.4 Hz, 2H), 1.43 (s, 9H), 1.56
(m, 1H), 1.69 (s, 1H), 1.70–2.02 (m, 3H), 2.05 (m, 2H),
3.03–3.33 (m, 7H), 3.51–3.68 (m, 4H), 3.84 (m, 1H), 4.14
(t, J¼8.3 Hz, 2H); 13C NMR (125 MHz, CDCl3) d 157.0,
156.2, 80.6, 80.4, 79.9, 79.7, 78.0, 77.4, 76.6, 76.4, 65.5,
65.4, 65.3, 63.7, 63.5, 43.1, 43.0, 41.3, 41.1, 35.7, 35.6,
31.6, 31.4, 31.3, 31.1, 28.8, 28.5, 19.5, 19.4, 19.3, 17.9,
15.0, 21.5; HRMS (ESI) m/z found 525.3356 [(MþNa)þ;
calcd for C25H50N2O6NaSi: 525.3336].
4.2.15. Benzyl ether 26. To a solution of aldehyde (2)-19
(664 mg, 1.49 equiv.) and amine (þ)-18 (826 mg,
˚
2.50 mmol) in MeOH (8 mL) were added crushed 4 A
molecular sieves (3 mL) and NaBH3CN (32.9 mg,
2.10 equiv.). The pH was adjusted to 6–7 with glacial
AcOH and the resultant mixture was stirred for 1 h at room
temperature. The reaction mixture was filtered through a
silica gel plug and concentrated in vacuo. Flash chroma-
tography (CH2Cl2–MeOH 40:1!10:1) afforded 763 mg
(62% yield) of benzyl ether 26 as a colorless oil: Rf 0.33
(CH2Cl2–MeOH 10:1); IR (neat) 3320 (w), 2940 (s), 2860
(s), 1690 (s), 1470 (s), 1420 (s), 1360 (m), 1250 (s), 1200
1
(m), 1090 (s), 990 (w), 940 (w), 860 (s), 830 (s) cm21; H
A solution of alcohol (446 mg, 0.887 mmol) in CH2Cl2
(10 mL) was treated with pyridine (0.28 mL, 3.9 equiv.) and
Dess–Martin periodinane (376 mg, 1.00 equiv.), and the
resultant mixture was stirred for 30 min at room tempera-
ture. The reaction mixture was poured into 20% Na2S2O3–
saturated NaHCO3 (1:1¼V:V, 60 mL) and after separation,
the aqueous phase was extracted with ether (4£80 mL).
Combined extracts were washed with saturated CuSO4
(3£80 mL), water (50 mL), and brine (50 mL), dried
(MgSO4), filtered, then concentrated in vacuo. Flash
chromatography (hexanes–ether 4:1!1:1) afforded alde-
hyde as a colorless oil (377 mg, 85% yield): Rf 0.30
(hexanes–EtOAc 2:1); IR (neat) 2960 (s), 2860 (s), 2700
(w), 1690 (s), 1470 (m), 1420 (m), 1360(m), 1320 (w), 1250
NMR (500 MHz, CDCl3) d 0.01 (s, 9H), 0.87 (d, J¼6.6 Hz,
3H), 0.88 (d, J¼6.5 Hz, 3H), 0.94 (d, J¼6.8 Hz, 3H), 0.97
(t, J¼8.4 Hz, 2H), 1.49 (m, 1H), 1.63 (m, 1H), 1.78 (m, 1H),
1.90–2.05 (m, 3H), 2.17 (br s, 1H), 2.32 (dd, J¼6.9,
11.3 Hz, 1H), 2.55 (m, 1H), 2.72 (dd, J¼6.1, 11.3 Hz, 1H),
3.04 (m, 1H), 3.14 (m, 1H), 3.20 (m, 1H), 3.32 (m, 3H), 3.38
(dd, J¼6.3, 9.2 Hz, 1H), 3.57(m, 2H), 4.14 (m, 2H), 4.47 (s,
2H), 7.22–7.33 (m, 5H); 13C NMR (125 MHz, CDCl3) d
156.3, 138.6, 128.3, 127.5, 127.4, 81.9, 81.7, 76.0, 75.9,
74.3, 73.1, 73.0, 63.3, 62.5, 61.9, 50.8, 42.2, 42.1, 40.6,
40.4, 34.2, 30.4, 30.2, 29.0, 28.8, 28.6, 19.5, 19.4, 17.9,
15.6, 21.5; HRMS (ESI) m/z found 493.3464 [(MþH)þ;
calcd for C27H49N2O4Si: 493.3462].
(m), 1180 (m), 1090 (m), 930 (w), 850 (m), 830(m) cm21
;
4.2.16. tert-Butyl carbamate 27. 4:1 Mixture at C30. A
solution of benzyl ether 26 (676 mg, 1.37 mmol) in CH2Cl2
(15 mL) was treated with Et3N (0.21 mL, 1.1 equiv.) and
(Boc)2O (0.34 mL, 1.1 equiv.) and the resulting mixture was
stirred for 16 h at room temperature. The reaction mixture
was quenched by addition of 10% NaHSO4 (60 mL) and
extracted with ether (3£50 mL). Combined extracts were
dried (MgSO4), filtered, and concentrated in vacuo. Flash
chromatography (hexanes–ether 5:1!4:1!3:1!2:1)
afforded 765 mg (94% yield) of tert-butyl carbamate 27 as
a colorless oil: Rf 0.5 (hexanes–EtOAc 3:1); IR (neat) 2940
(s), 2860 (s), 1690 (s), 1450 (m), 1420 (m), 1360 (m), 1320
(w), 1290 (w), 1250 (m), 1170 (m), 1150 (m), 1090 (m), 850
1H NMR (500 MHz, CDCl3) d 0.00 (s, 9H), 0.83
(d, J¼6.7 Hz, 3H), 0.84 (d, J¼6.6 Hz, 3H), 0.96 (t,
J¼8.40Hz, 2H), 1.00p [d, J¼7.2 Hz, 1H, minor diastereomer
at C(3 )] 1.04 (d, J¼7.2 Hz, 1H), 1.40 (s, 9H), 1.54 (m, 1H),
1.72 (m, 1H), 1.81 (m, 1H), 2.06 (m, 1H), 2.20 (m, 1H),
2.55–2.75 (m, 1H), 2.98–3.42 (m, 7H), 3.52–3.77 (m, 3H),
4.13 (t, J¼8.4 Hz, 2H), 9.59p (br s, 1H), 9.66 (br s, 1H); 13
C
NMR (125 MHz, CDCl3) d 203.7, 203.5, 156.3, 155.5,
154.7, 80.2, 80.0, 79.1, 78.9, 76.5, 76.3, 65.8, 65.7, 65.6,
63.5, 51.0, 50.9, 47.1, 46.9, 43.1, 41.0, 31.8, 31.6, 31.4,
30.9, 30.6, 28.8, 28.5, 28.4, 19.4, 17.9, 12.0, 11.9, 11.8,
21.5; HRMS (CI, methane) m/z found 501.3350 [(MþH)þ;
calcd for C25H49N2O6Si: 501.3360].
1
(m), 830 (m) cm21; H NMR (500 MHz, CDCl3) d 0.02
(s, 9H), 0.85 (d, J¼6.6 Hz, 3H), 0.86 (d, J¼6.3 Hz, 3H),
0.92 (d, J¼6.7 Hz, 3H), 0.97 (t, J¼8.4 Hz, 2H), 1.48
(d, J¼5.0 Hz, 9H), 1.53 (m, 1H), 1.70–2.30 (m, 5H), 3.01–
3.85 (m, 12H), 4.13 (t, J¼8.8 Hz, 2H), 4.48 (m, 2H), 7.25
(m, 1H), 7.30 (br s, 4H); 13C NMR (125 MHz, CDCl3) d
To a solution of benzyltriphenylphosphonium chloride
(510 mg, 1.21 equiv.) in benzene (10 mL) at 08C was
added n-BuLi (0.85 mL, 1.1 equiv.) in hexanes (1.4 M)
dropwise and the resulting solution was warmed to room
temperature then stirred for 1 h. The solution was cooled to

A. B. Smith, III et al. / Tetrahedron 59 (2003) 6991–7009
7003
08C and treated with a solution of aldehyde (543 mg,
1.08 mmol) in benzene (5 mL). The reaction mixture was
warmed to room temperature and stirred for 5 h. The
reaction mixture was quenched with saturated NH4Cl
(50 mL) and extracted with ether (4£50 mL). Combined
extracts were washed with brine (50 mL), dried (MgSO4),
filtered and concentrated in vacuo. Flash chromatography
(hexanes–ether 5:1!4:1!2:1) afforded olefin 28 as a pale
yellow oil (580 mg, 93% yield): Rf 0.42 (hexanes–EtOAc
3:1); IR (neat) 2940 (s), 1690 (s), 1460 (m), 1420 (m), 1360
(m), 1250 (m), 1170 (m), 1090 (m), 960 (m), 930 (m), 860
was stirred at room temperature for 14 min. The reaction
mixture was diluted with CH2Cl2 (200 mL), washed with
water (40 mL), and saturated NaHCO3 (40 mL), dried
(Na2SO4), filtered then concentrated in vacuo. Preparative
TLC [0.5 mm£20 cm£20 cm, CH2Cl2 (saturated with
NH3)–MeOH (10:1)] afforded 13.6 mg (90% yield) of
secondary amine as a colorless oil: Rf 0.35 (CH2Cl2–MeOH
10:1); [a]2D0¼þ51.58 (c 0.635, CHCl3); IR (neat) 3320 (m,
br), 2980 (s), 1640 (s), 1500 (s), 1460 (m), 1380 (m), 1340
(w), 1290 (w), 1240 (s), 1170 (m), 1080 (m), 1030 (m), 960
1
(m), 810 (m) cm21; H NMR (500 MHz, CDCl3) d 0.82
1
(m), 830 (m) cm21; H NMR (500 MHz, CDCl3) d 0.01
(d, J¼6.7 Hz, 6H), 1.09 (d, J¼6.3 Hz, 3H), 1.53–1.69 (m,
2H), 1.72 (m, 1H), 2.03 (m, 3H), 2.48 (m, 2H), 2.66 (m, 2H),
3.04 (dd, J¼6.6, 8.7 Hz, 1H), 3.15–3.24 (m, 3H), 3.28 (dd,
J¼6.4, 8.7 Hz, 1H), 3.55 (m, 1H), 3.61 (m, 1H), 3.77 (s, 3H),
4.30 (m, 2H), 4.49 (t, J¼5.2 Hz, 1H), 6.09 (dd, J¼7.3,
15.9 Hz, 1H), 6.39 (d, J¼15.9 Hz, 1H), 6.83 (d, J¼8.5 Hz,
2H), 7.15–7.32 (m, 7H); 13C NMR (125 MHz, CDCl3) d
158.9, 157.6, 137.5, 134.2, 131.8, 129.7, 129.1, 128.4,
127.0, 126.1, 114.0, 81.6, 76.6, 76.0, 61.8, 55.3, 53.0, 44.5,
41.7, 39.8, 37.5, 30.4, 28.8, 28.7, 19.4, 18.4; HRMS (ESI)
m/z found 494.3393 [(MþH)þ; calcd for C30H44N3O3:
494.3383].
(s, 9H), 0.02p [s, 9H, minor diastereomer at C(30)], 0.85
(m, 6H), 0.96 (m, 2H), 1.04 (d, J¼6.7 Hz, 3H), 1.37p (s, 9H),
1.43 (s, 9H), 1.52 (m, 1H), 1.73 (m, 1H), 1.86 (m, 1H),
2.01–2.30 (m, 2H), 2.57 (m, 1H), 2.94–3.21 (m, 5H), 3.26
(m, 1H), 3.36–3.84(m, 4H), 4.13 (m, 2H), 6.06 (m, 1H),
6.32p (d, J¼15.9 Hz, 1H), 6.37 (d, J¼15.9 Hz, 1H), 7.17–
7.32 (m, 5H); 13C NMR (125 MHz, CDCl3) d 156.2, 155.4,
155.1, 137.5, 137.3, 134.3, 134.1, 133.8, 133.6, 129.8,
128.5, 128.3, 128.2, 127.1, 127.0, 125.9, 80.7, 80.6, 79.5,
79.3, 79.1, 66.4, 66.2, 63.4, 63.3, 57.5, 57.4, 43.5, 43.3,
40.7, 38.1, 37.8, 37.7, 37.6, 32.1, 31.7, 31.5, 31.0, 30.7, 28.8,
28.6, 28.5, 28.3, 19.4, 18.2, 17.9, 21.5; HRMS (ESI) m/z
found 597.3693 [(MþNa)þ; calcd for C32H54N2O5NaSi:
597.3700].
To a solution of secondary amine (12.7 mg, 0.0257 mmol)
and 37% formaldehyde (4.1 mg, 2.0 equiv.) in MeOH
˚
(2.0 mL) were added crushed 4 A molecular sieves
4.2.18. Urea (1)-29. Under argon, TBAF (1.0 mL,
1.3 equiv.) in THF (1.0 M) was added to a solution of
olefin 28 (464 mg, 0.807 mmol) in THF (40 mL) at room
temperature. The reaction mixture was stirred for 18 h at
room temperature, and then treated with 4-methoxybenzyl
isocyanate (420 mg, 3.2 equiv.). The resulting mixture was
then stirred for 2 h, and quenched with MeOH (0.2 mL).
The solution was concentrated in vacuo and purified by flash
chromatography using CH2Cl2–MeOH (40:1) as eluant, to
furnish urea (þ)-29 as a mixture (307 mg, 64% yield). The
mixture was further purified by preparative HPLC using a
reverse phase DYNAMAXw C18 column [21.1 mm,
MeCN–0.1% TFA in water (3:1), 4.0 mL/min] to give
(þ)-29 (75.3 mg, 16% yield) as a colorless oil: Rf 0.40
(CH2Cl2–MeOH 10:1); [a]2D0¼þ59.08 (c 1.36, CHCl3); IR
(neat) 3340 (m, br), 2940 (s), 1680 (s), 1630 (s), 1500 (s),
1460 (m), 1360 (m), 1240 (s), 1170 (s), 1090 (m), 1030 (m),
(0.5 mL) and NaBH3CN (3.2 mg, 2.0 equiv.). The pH was
adjusted to 6–7 with glacial AcOH and the resultant
mixture was stirred for 16 h at room temperature. The
reaction mixture was filtered through a silica gel plug and
concentrated in vacuo. Preparative TLC [0.5 mm£20
cm£20 cm, CH2Cl2(saturated with NH3)–MeOH (10:1)]
afforded 9.7 mg (74% yield) of analogue (þ)-30 as a
colorless oil: Rf 0.33 (CH2Cl2–MeOH 10:1); [a]2D0¼þ188 (c
0.46, CHCl3); IR (neat) 3320 (m, br), 2940 (s), 1620 (s),
1500 (s), 1460 (m), 1380 (w), 1340 (w), 1290 (w), 1240 (w),
1160 (m), 1080 (m), 1030 (m), 960 (m), 810 (m) cm21; 1H
NMR (500 MHz, CDCl3) d 0.87 (d, J¼6.7 Hz, 6H), 1.04
(d, J¼6.5 Hz, 3H), 1.58–1.82 (m, 4H), 1.89 (m, 1H), 1.95
(m, 1H), 2.29 (br s, 3H), 2.40 (m, 1H), 2.47 (m, 1H), 2.54
(m, 1H), 2.60 (m, 1H), 3.08 (m, 1H), 3.14 (dd, J¼6.4,
8.6 Hz, 1H), 3.21 (dd, J¼6.6, 8.6 Hz, 1H), 3.24 (m, 1H),
3.38 (dt, J¼2.9, 8.1 Hz, 1H), 3.53 (m, 1H), 3.61 (m, 1H),
3.77 (s, 3H), 4.32 (d, J¼5.3 Hz, 2H), 4.48 (t, J¼5.0 Hz, 1H),
6.16 (dd, J¼7.0, 16.0 Hz, 1H), 6.36 (d, J¼16.0 Hz, 1H),
6.84 (d, J¼8.7 Hz, 2H), 7.13–7.35 (m, 7H); 13C NMR
(125 MHz, CDCl3) d 158.9, 157.6, 138.0, 135.6, 131.8,
129.1, 128.4, 126.8, 125.9, 114.0, 79.9, 75.8, 68.3, 61.9,
55.3, 44.6, 42.4, 40.6, 38.1, 35.8, 30.9, 29.0, 28.6, 19.6,
18.0; HRMS (ESI) m/z found 508.3542 [(MþH)þ; calcd for
C31H46N3O3: 508.3539].
960 (m) cm21 1H NMR (500 MHz, CDCl3) d 0.84 (d,
;
J¼6.7 Hz, 3H), 0.85 (d, J¼6.4 Hz, 3H), 1.01 (d, J¼6.7 Hz,
3H), 1.38 (m, 1H), 1.44 (s, 9H), 1.72 (m, 1H), 1.81 (m, 1H),
2.05–2.39 (m, 2H), 2.55 (m, 1H), 2.62 (m, 1H), 2.76–2.99
(m, 3H), 3.02 (m, 2H), 3.26 (m, 1H), 3.57 (m, 1H), 3.77 (s,
3H), 3.73–3.89 (m, 1H), 3.90 (m, 1H), 4.06 (m, 1H), 4.18
(dd, J¼5.1, 14.4 Hz, 1H), 4.28 (dd, J¼5.6, 14.4, 1H), 6.02
(m, 1H), 6.34 (d, J¼15.8 Hz, 1H), 6.85 (d, J¼8.7 Hz, 2H),
6.98–7.32 (m, 7H); 13C NMR (125 MHz, CDCl3) d 158.8,
157.4, 155.2, 154.9, 137.5, 137.3, 134.9, 134.3, 131.9,
129.8, 129.7, 128.9, 128.5, 128.4, 128.2, 127.1, 127.0,
125.8, 113.9, 80.5, 79.6, 79.1, 76.8, 67.2, 58.7, 55.2, 44.3,
43.3, 38.7, 38.4, 32.8, 32.6, 31.3, 30.5, 28.8, 28.7, 28.6,
28.5, 19.4, 18.0, 17.9; HRMS (ESI) m/z found 616.3716
[(MþNa)þ; calcd for C35H51N3O5Na: 616.3726].
4.2.20. a-Epoxide (2)-31. To a solution of olefin (þ)-25
(12.4 mg, 0.0244 mmol) in ether (5.0 mL) at 2788C was
added BF3·OEt2 (6.2 mL, 2.0 equiv.) and the resulting
mixture was warmed to room temperature, then stirred for
16 h. The reaction mixture was concentrated in vacuo,
dissolved in CH2Cl2 (0.5 mL), and cooled to 08C. A solution
of dimethyldioxirane in acetone (9 mL) was added to the
reaction mixture and the resulting mixture was stirred at 08C
for 1.5 h. The reaction mixture was concentrated in vacuo,
diluted with CH2Cl2 (170 mL), washed with 10% NaHSO3
4.2.19. Analogue (1)-30. To a solution of urea (þ)-29
(18.2 mg, 0.0306 mmol) in CH2Cl2 (2.0 mL) was added
trifluoroacetic acid (TFA, 1.0 mL) and the resulting mixture

7004
A. B. Smith, III et al. / Tetrahedron 59 (2003) 6991–7009
(3£30 mL), and saturated NaHCO3 (40 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. Preparative
TLC [0.5 mm£20 cm£20 cm, CH2Cl2(saturated with NH3)-
MeOH (9:1)] afforded epoxide (2)-31 (2.5 mg, 20% yield)
as a colorless oil: Rf 0.27 (CH2Cl2–MeOH 10:1);
[a]2D0¼29.68 (c 0.49, CHCl3); IR (neat) 3340 (m, br),
2960 (s), 1620 (s), 1510 (s), 1460 (m), 1390 (w), 1350 (w),
1290 (w), 1240 (s), 1170 (m), 1090 (m), 1030 (m), 880 (m),
37 (9.17 g, 28.1 mmol) in benzene (50 mL), workup, and
flash chromatography (hexanes–ether 150:1!100:1!10:1)
gave olefin as a colorless oil (6.70 g, 60% yield): Rf 0.47
(hexanes–EtOAc 40:1); [a]2D0¼þ11.18 (c 0.595, CHCl3); IR
(CHCl3) 3020 (m), 2960 (m), 2940 (m), 2860 (m), 1430 (w),
1200 (s), 1120 (s), 960 (w), 920 (w) cm21 1H NMR
;
(500 MHz, CDCl3) d 1.09 (s, 9H), 1.15 (d, J¼2.4 Hz, 3H),
2.59 (m, 1H), 3.64 (m, 2H), 6.18 (dd, J¼7.4, 16.0 Hz, 1H),
6.42 (d, J¼16.0 Hz, 1H), 7.19–7.44 (m, 11H), 7.69 (m, 4H);
13C NMR (125 MHz, CDCl3) d 137.8, 135.67, 135.66,
134.0, 133.4, 129.5, 128.4, 127.6, 126.9, 126.0, 68.7, 39.8,
26.9, 19.3, 16.7. Anal. calcd for C27H32OSi: C, 80.95; H,
8.05. Found: C, 81.29; H, 8.12.
810 (m) cm21 1H NMR (500 MHz, CDCl3) d 0.879
;
(d, J¼6.7 Hz, 3H), 0.883 (d, J¼6.7 Hz, 3H), 0.97
(d, J¼6.9 Hz, 3H), 1.58–1.81 (m, 5H), 1.89 (m, 1H), 1.96
(m, 1H), 2.27 (s, 3H), 2.55 (dd, J¼7.6, 12.7 Hz, 1H), 2.61
(m, 1H), 2.66 (dd, J¼6.5, 12.8 Hz, 1H), 2.83 (dd, J¼2.1,
6.6 Hz, 1H), 3.11 (m, 1H), 3.15 (dd, J¼6.4, 8.7 Hz, 1H),
3.21 (dd, J¼6.7, 8.4 Hz, 1H), 3.23 (m, 1H), 3.38 (dt, J¼3.0,
8.2 Hz, 1H), 3.55 (m, 1H), 3.61 (m, 1H), 3.64 (d, J¼2.0 Hz,
1H), 3.66 (s, 3H), 4.33 (t, J¼5.3 Hz, 2H), 4.50 (t, J¼5.2 Hz,
1H), 6.83 (d, J¼8.6 Hz, 2H), 7.16–7.31 (m, 7H); 13C NMR
(125 MHz, CDCl3) dd 158.9, 157.6, 138.1, 131.8, 129.1,
128.4, 127.9, 125.6, 114.0, 79.9, 75.9, 67.9, 66.3, 59.5, 56.6,
55.3, 44.6, 42.6, 40.6, 37.9, 35.0, 30.9, 29.0, 28.5, 19.7,
19.6, 14.5; HRMS (ESI) m/z found 524.3502 [(MþH)þ;
calcd for C31H46N3O4: 524.3488].
To a solution of olefin (1.51 g, 3.77 mmol) in t-BuOH–
water (1:1, 32 mL) at 08C were added methanesulfonamide
(359 mg, 1.00 equiv.) and AD-mix-b (5.86 g). The resulting
mixture was stirred at 08C vigorously for 5 days. Solid
Na2SO3 (6.5 g) was added and the mixture was warmed to
room temperature with stirring then extracted with EtOAc
(3£100 mL). Combined extracts were washed with 10%
NaOH (100 mL), dried (MgSO4), filtered, concentrated in
vacuo, and purified by flash chromatography (hexanes–
ether 6:1!4:1!3:1!1:1) to give diol (2)-38 as a colorless
oil (1.40 g, 85% yield): Rf 0.23 (hexanes–EtOAc 3:1);
[a]2D0¼24.28 (c 1.6, CHCl3); IR (CHCl3) 3500 (w, br), 3020
(s), 2960 (s), 2940 (s), 2860 (m), 1430 (w), 1200 (s), 1110
(s) cm21; 1H NMR (500 MHz, CDCl3) d 0.92 (d, J¼7.0 Hz,
3H), 1.03 (s, 9H), 1.54 (m, 1H), 2.92 (d, J¼3.3 Hz, 1H),
3.00 (m, 1H), 3.56–3.63 (m, 2H), 3.97 (dt, J¼2.9, 7.6 Hz,
1H), 4.64 (dd, J¼2.6, 7.6 Hz, 1H), 7.24–7.40 (m, 11H),
7.55–7.62 (m, 4H); 13C NMR (125 MHz, CDCl3) d 140.9,
135.5, 135.4, 133.1, 129.7, 128.4, 127.9, 127.7, 127.0, 75.4,
67.6, 36.0, 26.8, 19.1, 10.2; HRMS (CI, methane) m/z
435.2343 [(MþH)þ; calcd for C27H35O3Si: 435.2355].
4.2.21. a-Epoxide (2)-32. To a solution of olefin (þ)-30
(10.0 mg, 0.0197 mmol) in ether (10 mL) at 2788C was
added BF3·OEt2 (5.0 mL, 2.0 equiv.) and the resulting
mixture was warmed to room temperature, then stirred for
16 h. The reaction mixture was concentrated in vacuo,
dissolved in CH2Cl2 (0.5 mL), and cooled to 08C. A solution
of dimethyldioxirane in acetone (9 mL) was added to the
reaction mixture and the resulting mixture was stirred at 08C
for 1.5 h. The reaction mixture was concentrated in vacuo,
diluted with CH2Cl2 (180 mL), washed with 10% NaHSO3
(3£30 mL), and saturated NaHCO3 (50 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. Preparative
TLC [0.5 mm£20 cm£20 cm, CH2Cl2 (saturated with
NH3)–MeOH (9:1)] afforded a-epoxide (2)-32 (5.6 mg,
54% yield) as a colorless oil: Rf 0.27 (CH2Cl2–MeOH
10:1); [a]2D0¼2148 (c 0.62, CHCl3); IR (neat) 3340 (m, br),
2940 (s), 1620 (s), 1510 (s), 1460 (m), 1390 (w), 1350 (w),
1290 (w), 1240 (s), 1170 (m), 1080 (m), 103 (m), 880 (m),
4.2.23. Iodide (1)-39. To a solution of diol (2)-38 (1.40 g,
3.23 mmol) in acetone (80 mL) was added p-toluenesulfo-
nic acid monohydrate (896 mg, 1.46 equiv.) and the
resulting mixture was stirred at room temperature for 1 h.
The reaction mixture was concentrated in vacuo to remove
acetone and diluted with ether (300 mL), washed with
saturated NaHCO3 (2£50 mL), dried (MgSO4), filtered and
concentrated in vacuo. Flash chromatography (hexanes–
ether 50:1!30:1!10:1) gave 1.33 g (87% yield) of
acetonide as a white solid: mp 61–63 8C; Rf 0.33
(hexanes–EtOAc 10:1); [a]2D0¼þ4.888 (c 2.83, CHCl3);
IR (CHCl3) 3020 (s), 2940 (s), 2860 (m), 1430 (w), 1380
(w), 1200 (s), 1110 (s), 1040 (s), 930 (w), 880 (w) cm21; 1H
NMR (500 MHz, CDCl3) d 0.96 (s, 3H), 1.01 (d, J¼6.9 Hz,
3H), 1.46 (s, 3H), 1.54 (s, 3H), 1.85 (m, 1H), 3.49 (dd,
J¼6.4 10.0 Hz, 1H), 3.59 (dd, J¼7.4, 10.0 Hz, 1H), 4.10
(dd, J¼3.0, 8.8 Hz, 1H), 4.70 (d, J¼8.8 Hz, 1H), 7.29–7.40
(m, 11H), 7.51 (m, 2H), 7.58 (m, 2H); 13C NMR (125 MHz,
CDCl3) d 138.3, 135.6, 135.5, 133.8, 129.5, 128.5, 128.1,
127.5, 127.0, 108.5, 82.5, 80.4, 66.3, 35.8, 27.2, 26.8, 19.2,
10.7. Anal. calcd for C30H38O3Si: C, 75.90; H, 8.07. Found:
C, 75.55; H, 8.21.
820 (m) cm21 1H NMR (500 MHz, CDCl3) d 0.89 (d,
;
J¼6.7 Hz, 6H), 0.97 (d, J¼6.9 Hz, 3H), 1.62–1.84 (m, 4H),
1.89 (m, 1H), 1.98 (m, 1H), 2.29 (s, 3H), 2.48 (dd, J¼7.9,
12.6 Hz, 1H), 2.61 (m, 1H), 2.74 (dd, J¼6.1, 12.7 Hz, 1H),
2.88 (dd, J¼2.1, 6.5 Hz, 1H), 3.08 (m, 1H), 3.14 (dd, J¼6.3,
8.6 Hz, 1H), 3.22 (dd, J¼6.6, 8.5 Hz, 1H), 3.25 (m, 1H),
3.39 (dt, J¼2.9, 8.1 Hz, 1H), 3.54 (ddd, J¼2.6, 6.8, 10.0 Hz,
1H), 3.64 (m, 1H), 3.67 (d, J¼2.0 Hz, 1H), 3.78 (s, 3H),
4.35 (d, J¼5.3 Hz, 2H), 4.54 (t, J¼5.2 Hz, 1H), 6.85 (d,
J¼8.6 Hz, 2H), 7.22–7.33 (m, 7H); 13C NMR (125 MHz,
CDCl3) d 158.8, 157.5, 138.0, 131.7, 129.0, 128.3, 127.8,
125.5, 114.0, 79.9, 75.8, 68.6, 66.2, 59.1, 56.6, 55.2, 44.5,
42.3, 40.6, 37.8, 34.7, 30.8, 28.9, 28.6, 19.6, 14.2; HRMS
(ESI) m/z found 524.3479 [(MþH)þ; calcd for C31H46N3O4:
524.3488].
4.2.22. Diol (2)-38. trans–cis¼10:1. Via the procedure
described above for the preparation of 22, reaction of
benzyltriphenylphosphonium chloride (11.4 g, 1.05 equiv.)
in benzene (200 mL) at 08C with n-BuLi (20.2 mL,
1.01 equiv.) in hexanes (1.4 M), addition of aldehyde (þ)-
A solution of acetonide (1.33 g, 2.81 mmol) in THF
(20 mL) was treated with TBAF (3.0 mL, 1.1 equiv.) in
THF (1.0 M) and the resultant mixture was stirred at room
temperature for 2 h. The reaction mixture was quenched by

A. B. Smith, III et al. / Tetrahedron 59 (2003) 6991–7009
7005
addition of saturated NH4Cl (70 mL) and extracted with
ether (3£100 mL). Combined extracts were washed with
saturated NaHCO3 (70 mL), dried (MgSO4), filtered,
concentrated, and purified by flash chromatography (hex-
anes–ether 5:1!3:1!1:1) to give alcohol as a colorless oil
(658 mg, 99% yield): Rf 0.23 (hexanes–EtOAc 3:1);
[a]2D0¼210.08 (c 1.23, CHCl3); IR (CHCl3) 3520 (w, br),
2980 (s), 2940 (s), 2880 (s), 1450 (m), 1360 (m), 1220 (s),
in toluene (1.0 M) slowly and the resulting mixture was
stirred for 5 h at 2788C. Saturated NH4Cl (60 mL) was
added and the reaction mixture was stirred at room
temperature for 1 h and the aqueous phase was extracted
with EtOAc (4£80 mL). Combined extracts were washed
with saturated NaHCO3 (80 mL), dried (MgSO4), filtered,
and concentrated in vacuo. The residue was then dissolved
in MeOH (20 mL) and treated with NaBH4 (825 mg,
8.91 equiv.) portionwise at room temperature. After
30 min, the reaction mixture was quenched by addition of
water (50 mL), extracted with EtOAc (4£80 mL). Com-
bined extracts were dried over MgSO4, filtered and
concentrated. Flash chromatography (hexanes–ether
4:1!2:1!1:1) gave alcohol as a colorless oil (546 mg,
89% yield): Rf 0.27 (hexanes–EtOAc 3:1); [a]2D0¼2128
(c 0.73, CHCl3); IR (neat) 3420 (m, br), 2980 (m), 2900 (m),
2880 (m), 1490 (m), 1450 (s), 1370 (s), 1230 (s), 1170 (s),
1050 (s), 880 (m) cm21; 1H NMR (500 MHz, CDCl3) d 1.02
(d, J¼6.9 Hz, 3H), 1.47 (s, 3H), 1.48–1.52 (m, 1H), 1.54 (s,
3H), 1.64–1.70 (m, 1H), 1.83 (m, 1H), 1.89 (m, 1H), 3.58
(m, 1H), 3.67 (m, 1H), 3.81 (dd, J¼3.1, 8.8 Hz, 1H), 4.73
(d, J¼8.7 Hz, 1H), 7.27–7.37 (m, 5H); 13C NMR
(125 MHz, CDCl3) d 138.2, 128.6, 128.3, 127.0, 108.5,
86.2, 80.4, 60.0, 37.3, 29.7, 27.2, 27.1, 13.5. Anal. calcd for
C15H22O3: C, 71.97; H, 8.86. Found: C, 71.98; H, 8.90.
1
1170 (m), 1110 (m), 1080 (m), 1040 (s), 910 (s) cm21; H
NMR (500 MHz, CDCl3) d 1.05 (d, J¼7.0 Hz, 3H), 1.47
(s, 3H), 1.54 (s, 3H), 1.85 (m, 1H), 1.92 (br s, 1H), 3.56
(d, J¼5.3 Hz, 2H), 3.93 (dd, J¼3.0, 8.9 Hz, 1H), 4.76
(d, J¼8.9 Hz, 1H), 7.27–7.37 (m, 5H); 13C NMR
(125 MHz, CDCl3) d 137.8, 128.6, 128.3, 126.8, 108.7,
84.5, 80.0, 66.6, 34.7, 27.2, 27.0, 10.7. Anal. calcd for
C14H20O3: C, 71.16; H, 8.53. Found: C, 71.12; H, 8.60.
To a solution of alcohol (822 mg, 3.48 mmol) in benzene
(40 mL)–CH3CN (10 mL) were added imidazole (1.23 g,
4.34 equiv.), PPh3 (2.00 g, 2.19 equiv.), and I2 (1.59 g,
1.86 equiv.) and the resulting mixture was stirred at room
temperature for 20 min. The reaction mixture was poured
into saturated NaHCO3–20% Na2S2O3 (1:1, 160 mL) and
extracted with ether (3£160 mL). The combined extracts
were dried over MgSO4, filtered, concentrated, and purified
by flash chromatography (hexanes–ether 50:1) to give
alcohol iodide (þ)-39 as a colorless oil (942 mg, 79%
yield): Rf 0.30 (hexanes–EtOAc 10:1); [a]2D0¼þ20.18 (c
2.15, CHCl3); IR (neat) 3040 (m), 3010 (m), 2970 (s), 2910
(s), 2880 (s), 1480 (w), 1450 (m), 1370 (s), 1230 (s), 1160
Via the procedure described above for the preparation of
iodide (þ)-39, the reaction of alcohol (212 mg,
0.847 mmol) in benzene (10 mL)–CH3CN (2.5 mL) with
imidazole (215 mg, 3.74 equiv.), PPh3 (220 mg,
1.00 equiv.), I2 (204 mg, 1.02 equiv.), workup, and flash
chromatography (hexanes–ether 50:1) gave iodide (2)-35
as a colorless oil (241 mg, 79% yield): Rf 0.30 (hexanes–
EtOAc 10:1); [a]2D0¼23.18 (c 1.4, CHCl3); IR (neat) 2982
(s), 2932 (m), 2883 (m), 2359 (w), 1494 (w), 1454 (m), 1378
(s), 1369 (s), 1238 (s), 1164 (m), 1054 (s), 1027 (m), 887
1
(m), 1050 (s), 1020 (m), 980 (m), 880 (m) cm21; H NMR
(500 MHz, CDCl3) d 1.15 (d, J¼6.8 Hz, 3H), 1.46 (s, 3H),
1.53 (s, 3H), 1.89 (m, 1H), 3.01 (dd, J¼8.0, 9.8 Hz, 1H),
3.22 (dd, J¼5.7, 9.8 Hz, 1H), 3.90 (dd, J¼3.6, 8.6 Hz, 1H),
4.69 (d, J¼8.6 Hz, 1H), 7.29–7.36 (m, 5H); 13C NMR
(125 MHz, CDCl3) d 137.6, 128.7, 128.5, 127.0, 108.8,
84.8, 80.7, 36.4, 27.2, 27.0, 15.1, 11.5. Anal. calcd for
C14H19O2I: C, 48.57; H, 5.53. Found: C, 48.29; H, 5.45.
1
(m), 813 (w) cm21; H NMR (500 MHz, CDCl3) d 1.00
(d, J¼6.8 Hz, 3H), 1.46 (s, 3H), 1.53 (s, 3H), 1.68–1.75
(m, 1H), 1.82 (m, 1H), 1.83–1.95 (m, 1H), 3.07–3.19
(m, 2H), 3.75 (dd, J¼3.6, 8.6 Hz, 1H), 4.71 (d, J¼8.6 Hz,
1H), 7.28–7.36 (m, 5H); 13C NMR (125 MHz, CDCl3) d
138.2, 128.6, 128.3, 126.9, 108.6, 85.4, 80.4, 38.0, 34.1,
27.2, 27.1, 13.2, 4.3. Anal. calcd for C15H21O2I: C, 50.01; H,
5.88. Found: C, 50.00; H, 5.79.
4.2.24. Iodide (2)-35. A solution of iodide (þ)-39 (841 mg,
2.43 mmol) in DMSO (3 mL) was treated with NaCN
(191 mg, 1.61 equiv.) and the resultant mixture was stirred
at room temperature for 24 h. The reaction mixture was
poured into water (50 mL) and extracted with EtOAc
(3£70 mL). Combined extracts were washed with brine
(50 mL), dried over Na2SO4, filtered and concentrated in
vacuo. Flash chromatography (hexanes–ether 16:1!5:1)
afforded cyanide as a colorless oil (545 mg, 91% yield): Rf
0.20 (hexanes–EtOAc 10:1); [a]2D0¼21.88 (c 1.1, CHCl3);
IR (neat) 3080 (w), 3040 (m), 3020 (m), 2980 (s), 2920 (s),
2880 (s), 2240 (m), 1490 (m), 1450 (s), 1420 (m), 1370 (s),
4.2.25. Alcohol (2)-36. Jacobsen catalyst (S,S)-15 (273 mg,
0.28 equiv.) was added to a solution of epoxide 10 (394 mg,
1.53 mmol) in iso-butanol (0.42 mL) at room temperature.
After 5 days, the reaction mixture was filtered through a
silica gel plug, concentrated in vacuo, and purified by flash
chromatography, using hexanes–ether (3:1!1:1) as eluant,
to give 316 mg (63% yield) of (2)-36 as a pale yellow oil:
Rf 0.17 (hexanes–EtOAc 3:1); [a]2D0¼26.88 (c 1.1, CHCl3);
IR (neat) 3450 (m, br), 2953 (s), 1674 (s), 1471 (m), 1421
(s), 1350 (w), 1250 (s), 1087 (s), 1002 (w), 859 (s), 837
(s) cm21; 1H NMR (500 MHz, CDCl3) d 0.01 (s, 9H), 0.88
(d, J¼6.6 Hz, 3H), 0.89 (d, J¼6.6 Hz, 3H), 0.97 (m, 2H),
1.50–1.65 (m, 2H), 1.82 (m, 1H), 2.05 (m, 2H), 2.95
(d, J¼46.7 Hz, 1H), 3.04–3.11 (m, 2H), 3.19 (m, 1H), 3.29
(m, 1H), 3.35 (dd, J¼6.5, 8.8 Hz, 1H), 3.49–3.63 (m, 3H),
4.14 (m, 2H); 13C NMR (125 MHz, CDCl3) d 156.3, 83.9,
83.5, 76.2, 76.0, 74.2, 73.9, 63.5, 41.2, 41.0, 31.9, 31.5,
30.3, 29.7, 29.0, 28.7, 28.6, 19.4, 17.9, 21.5; HRMS (ESI)
1
1230 (s), 1160 (s), 1050 (s), 990 (m), 880 (m) cm21; H
NMR (500 MHz, CDCl3) d 1.18 (d, J¼6.8 Hz, 3H), 1.46
(s, 3H), 1.53 (s, 3H), 2.07 (m, 1H), 2.27 (dd, J¼8.3, 16.8 Hz,
1H), 2.38 (dd, J¼6.1, 16.8 Hz, 1H), 3.81 (dd, J¼3.5, 8.7 Hz,
1H), 4.70 (d, J¼8.7 Hz, 1H), 7.30–7.37 (m, 5H); 13C NMR
(125 MHz, CDCl3) d 137.2, 128.8, 128.7, 126.9, 118.4,
109.0, 84.3, 80.2, 30.9, 27.1, 27.0, 22.3, 13.8. Anal. calcd
for C15H19 NO2: C, 73.44; H, 7.81; N, 5.71. Found: C,
73.54; H, 7.89; N, 5.65.
To a solution of cyanide (600 mg, 2.45 mmol) in CH2Cl2
(6 mL) at 2788C was added DIBAL-H (5.0 mL, 2.0 equiv.)

7006
A. B. Smith, III et al. / Tetrahedron 59 (2003) 6991–7009
m/z 354.2069 [(MþNa)þ; calcd for C16H33NO4NaSi:
wise. The resulting white suspension was stirred for 20 min
and concentrated in vacuo. The residue was diluted in
glacial AcOH (30 mL) and sulfuryl chloride (2.6 mL,
2.0 equiv.) was added dropwise. The reaction mixture was
heated to 708C with a gas outlet for 5 h and stirred at room
temperature for 12 h. To the white slurry was added ether
(70 mL) and the mixture was stirred for 90 min. Filtration
and air-drying gave amine salt 41 as a white solid (1.37 g,
44% yield): mp 231–234 8C; IR (KBr) 2998 (m, br), 1609
(m), 1507 (s), 1460 (s), 1385 (m), 1299 (s), 1267 (s), 1221
(w), 1110 (w), 1093 (w), 1068 (s), 1024 (s), 973 (m), 909
(m), 886 (s), 806 (s) cm21; 1H NMR (500 MHz, CD3OD) d
3.90 (s, 3H), 4.04 (s, 2H), 7.12 (d, J¼8.5 Hz, 1H), 7.37 (dd,
J¼2.2, 8.5 Hz, 1H), 7.50 (d, J¼2.2 Hz, 1H); 13C NMR
(125 MHz, CD3OD) d 157.2, 131.9, 130.2, 127.3, 124.0,
113.8, 56.8, 43.4; HRMS (CI, methane) m/z 155.0267
[(M2NH3Cl)þ; calcd for C8H8OCl: 155.0264].
354.2077].
Determination of stereochemistry of (2)-36. (S)-MTPA
1
ester of (2)-36. H NMR (500 MHz, CD3OD) d 0.035 (s,
9H), 0.85 (d, J¼6.9 Hz, 3H), 0.87 (d, J¼6.7 Hz, 3H), 0.97
(t, J¼8.3 Hz, 2H), 1.73 (m, 2H), 1.83 (m, 1H), 1.95 (m, 1H),
2.20 (m, 1H), 3.17 (m, 1H), 3.23 (m, 1H), 3.33 (m, 2H), 3.46
(t, J¼5.5 Hz, 2H), 3.52 (s, 3H), 3.59 (m, 1H), 4.12 (m, 2H),
5.30 (m, 1H), 7.42–7.52 (m, 5H).
(R)-MTPA ester of (2)-36. 1H NMR (500 MHz, CD3OD) d
0.032 (s, 9H), 0.88 (d, J¼6.9 Hz, 3H), 0.90 (d, J¼6.8 Hz,
3H), 0.97 (m, 2H), 1.70–1.84 (m, 2H), 1.92 (m, 2H), 2.11
(m, 2H), 3.23–3.64 (m, 7H), 3.52 (s, 3H), 4.13 (m, 2H), 5.26
(m, 1H), 7.41–7.52 (m, 5H).
4.2.28. Urea (2)-42. Under argon, TBAF (3 equiv.) in THF
(0.11 mL, 1.0 M) was added to a solution of (2)-40
(20.4 mg, 0.0362 mmol) in THF (0.5 mL) at room tempera-
ture. The reaction mixture was stirred for 24 h at room
temperature and concentrated in vacuo to give a secondary
amine, which was used for the next reaction without
purification. To a solution of triphosgene (39.8 mg,
3.7 equiv.) in CH2Cl2 (0.5 mL) was added a mixture of 41
(24.3 mg, 3.5 equiv.) and i-Pr2NEt (0.10 mL, 16 equiv.)
in CH2Cl2 (0.5 mL) dropwise. After 5 min, a solution of
the secondary amine in CH2Cl2 (0.5 mL) was added in
one portion. Preparative TLC [0.5 mm£20 cm£20 cm,
CH2Cl2–MeOH (20:1)] afforded 11.9 mg (52% yield) of
(2)-42 as a colorless oil: Rf 0.37 (CH2Cl2–MeOH 10:1);
[a]2D0¼221.48 (c 0.238, CHCl3); IR (neat) 3338 (w, br),
2931 (s), 2871 (s), 1626 (s), 1532 (s), 1502 (s), 1462 (m),
1379 (m), 1257 (s), 1169 (w), 1098 (s), 1064 (s), 1027 (m),
(S)-MTPA ester (R)-MTPA ester
(S)–(R)
b1/b2 2.20/1.95
2.11/1.83
5.26
1.92
þ0.09/þ0.12
þ0.04
c
e
g
k
l
5.30
1.83
20.09
20.01
4.12
1.73
4.13
1.80
20.07
20.04/20.03
0.85/0.87
0.89/0.90
4.2.26. Acetonide (2)-40. A solution of alcohol (2)-36
(24.6 mg, 0.0743 mmol) in DMF (0.3 mL) was treated with
NaH (95%, 5.0 mg, 2.8 equiv.) and the resulting mixture
was stirred at room temperature for 1 h. TBAI (1.2 mg,
0.080 equiv.) and a solution of iodide (2)-35 (25.4 mg,
0.0705 mmol) in DMF (0.3 mL) were added and the
reaction mixture was stirred at room temperature for 12 h.
the reaction mixture was diluted with EtOAc (50 mL),
washed with water (3£20 mL), dried (MgSO4), filtered and
concentrated. Flash chromatography (hexanes–ether
20:1!4:1!1:1) afforded 11.1 mg (26% yield) of acetonide
(2)-40 as a pale yellow oil: Rf 0.47 (hexanes–EtOAc 3:1);
[a]2D0¼2198 (c 0.58, CHCl3); IR (neat) 2954 (s), 1696 (s),
1455 (w), 1420 (m), 1368 (w), 1305 (w), 1237 (m), 1171
(w), 1095 (m), 1049 (m), 860 (m), 837 (m) cm21; 1H NMR
(500 MHz, CDCl3) d 0.01 (s, 9H), 0.846 (d, J¼6.7 Hz, 3H),
0.849 (d, J¼6.7 Hz, 3H), 0.96 (dd, J¼7.5, 9.3 Hz, 2H), 0.99
(dd, J¼1.7, 6.8 Hz, 3H), 1.46 (s, 3H), 1.52 (s, 3H), 1.60–
1.83 (m, 8H), 3.06–3.45 (m, 10H), 3.76 (m, 1H), 4.12 (m,
2H), 4.70 (d, J¼8.6 Hz, 1H), 7.26–7.36 (m, 5H); 13C NMR
(125 MHz, CDCl3) d 156.3, 138.6, 128.5, 128.2, 128.1,
127.0, 108.4, 86.0, 85.9, 80.4, 79.2, 79.1, 79.0, 78.8, 78.7,
78.6, 78.3, 76.5, 76.4, 76.3, 67.2, 67.1, 67.0, 63.1, 40.5,
40.4, 40.2, 34.4, 30.3, 30.0, 29.9, 29.7, 28.8, 28.4, 28.2,
28.1, 28.0, 27.7, 27.5, 27.2, 19.4, 17.9, 14.2, 14.1, 21.5;
HRMS (ESI) m/z 586.3527 [(MþNa)þ; calcd for
C31H53NO6 NaSi: 586.3540].
1
888 (w), 812 (w) cm21; H NMR (500 MHz, CDCl3) d
0.844 (d, J¼6.7 Hz, 3H), 0.845 (d, J¼6.7 Hz, 3H), 0.99
(d, J¼6.9 Hz, 3H), 1.42 (m, 1H), 1.46 (s, 3H), 1.52 (s, 3H),
1.60–1.88 (m, 7H), 3.08 (dd, J¼6.4, 8.8 Hz, 1H), 3.14 (dd,
J¼6.5, 8.8 Hz, 1H), 3.20 (m, 1H), 3.31–3.44 (m, 7H), 3.75
(dd, J¼3.4, 8.4 Hz, 1H), 3.86 (s, 3H), 4.30 (m, 2H), 4.69
(d, J¼8.6 Hz, 1H), 6.84 (d, J¼8.4 Hz, 1H), 7.14 (dd, J¼2.2,
8.4 Hz, 1H), 7.24–7.35 (m, 6H); 13C NMR (125 MHz,
CDCl3) d 157.5, 154.1, 138.6, 133.3, 129.5, 128.5, 128.1,
127.1, 126.9, 122.5, 112.1, 108.4, 86.0, 80.4, 78.2, 78.0,
77.8, 76.3, 67.0, 56.2, 44.0, 39.5, 39.2, 34.4, 29.9, 28.8,
28.0, 27.3, 27.2, 19.4, 19.3, 14.1; HRMS (ESI) m/z 639.3204
[(MþNa)þ; calcd for C34H49N2O6 NaCl: 639.3177].
4.2.29. b-Epoxide (1)-34. A solution of acetonide (2)-42
(11.1 mg, 0.0180 mmol) in MeOH (0.3 mL) was treated
with p-toluenesulfonic acid monohydrate (31.5 mg,
9.17 equiv.) and the resulting mixture was stirred at room
temperature for 12 h. The reaction mixture was concen-
trated to remove MeOH, diluted with EtOAc (40 mL),
washed with saturated NaHCO3 (10 mL), dried (MgSO4),
filtered and concentrated. Flash chromatopraphy (CH2Cl2–
MeOH 45:1) afforded 5.7 mg (55% yield) of diol as a
colorless oil: Rf 0.30 (CH2Cl2–MeOH 10:1); [a]2D0¼2258
(c 0.24, CHCl3); IR (neat) 3360 (m, br), 2955 (s), 1626 (s),
1532 (s), 1502 (s), 1462 (m), 1399 (m), 1257 (s), 1099 (s),
4.2.27. Amine salt 41. To a solution of 4-methoxybenzyl-
amine (2.10 mL, 16.1 mmol) in THF (4 mL) at 08C was
added HCl (16.1 mL, 1.00 equiv.) in ether (1.0 M) drop-
1
1064 (s), 1024 (m) cm21; H NMR (500 MHz, CDCl3) d
0.866 (d, J¼6.7 Hz, 3H), 0.869 (d, J¼6.7 Hz, 3H), 0.92 (d,

A. B. Smith, III et al. / Tetrahedron 59 (2003) 6991–7009
7007
J¼6.7 Hz, 3H), 1.49 (m, 1H), 1.55 (br s, 2H), 1.64 (m, 1H),
1.74–1.96 (m, 5H), 3.12–3.21 (m, 2H), 3.27–3.54 (m, 8H),
3.65 (br m, 1H), 3.86 (d, J¼0.9 Hz, 3H), 4.31 (m, 2H), 4.54
(dt, J¼5.5, 15.7 Hz, 1H), 4.59 (dd, J¼5.2, 7.5 Hz, 1H), 6.85
(dd, J¼2.4, 8.4 Hz, 1H), 7.15 (dd, J¼2.2, 8.4 Hz, 1H),
7.25–7.35 (m, 6H); 13C NMR (125 MHz, CDCl3) d 157.6,
157.5, 154.2, 141.4, 133.2, 129.6, 128.5, 127.9, 127.2,
127.0, 126.9, 122.5, 112.2, 78.5, 78.4, 78.2, 78.1, 78.0, 77.9,
77.8, 77.7, 77.6, 77.1, 76.4, 76.3, 75.3, 67.3, 67.2, 56.2,
44.1, 39.8, 39.7, 34.7, 34.6, 31.8, 31.7, 31.6, 28.9, 28.8,
27.8, 27.7, 27.4, 19.4, 13.4, 13.2; HRMS (ESI) m/z found
599.2881 [(MþNa)þ; calcd for C31H45N2O6NaCl:
599.2864].
Health (National Cancer Institute) through grant CA-19033.
We thank Drs Joseph Barbosa, Jian Liu, and Sergey Savinov
for assistance in molecular modeling. In addition, we thank
Drs George Furst and Rakesh Kohli, Directors of the
University of Pennsylvania Spectroscopic Facilities for
assistance in obtaining high-field NMR spectra and high-
resolution mass spectra, respectively.
References
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112 equiv.). After 5 min, TMSCl (50 mL, 113 equiv.) was
added and the resultant mixture was stirred at room
temperature for 3 h then concentrated in vacuo. The residue
was dissolved in MeOH (0.5 mL) and K2CO3 (1.6 mg,
3.3 equiv.) was added. The reaction mixture was stirred at
room temperature for 7 h, diluted with CH2Cl2 (10 mL),
washed with saturated NH4Cl (5 mL), dried (MgSO4),
filtered and concentrated. Preparative TLC [0.5 mm£20
cm£20 cm, benzene–CH2Cl2–MeOH (10:5:1)] afforded
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Rf 0.20 (PhH–CH2Cl2–MeOH 5:5:1); [a]2D0¼þ188 (c 0.25,
CHCl3); IR (neat) 3346 (w), 2955 (s), 1627 (s), 1530 (s),
1501 (s), 1462 (m), 1396 (w), 1257 (s), 1102 (s), 1064 (m),
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1
887 (w) cm21; H NMR (500 MHz, CDCl3) d 0.86p (dd,
J¼0.7, 6.7 Hz, 3H, rotamers), 0.87p (dd, J¼0.7, 6.7 Hz,
3H), 1.09 (d, J¼6.3 Hz, 3H), 1.55–1.69 (m, 3H), 1.74–1.85
(m, 3H), 1.94 (m, 2H), 2.73p (ddd, J¼2.1, 7.5, 7.5 Hz, 1H),
3.12–3.23 (m, 2H), 3.27–3.58 (m, 8H), 3.64p (dd, J¼2.1,
5.1 Hz, 1H), 3.85p (d, J¼1.4 Hz, 3H), 4.31 (m, 2H), 4.51
(dd, J¼5.5, 13.2 Hz, 1H), 6.84 (d, J¼8.1 Hz, 1H), 7.15 (dd,
J¼2.1, 8.4 Hz, 1H), 7.22–7.34 (m, 6H); 13C NMR
(125 MHz, CDCl3) d 157.5, 154.2, 137.9, 137.8, 133.3,
129.6, 128.5, 128.0, 127.2, 125.5, 122.5, 112.2, 78.4, 78.3,
78.1, 77.6, 76.9, 76.5, 76.4, 76.3, 67.4, 67.0, 58.3, 58.2,
56.2, 44.0, 39.6, 39.5, 39.3, 34.0, 33.9, 33.3, 28.9, 28.2,
27.8, 27.7, 27.5, 19.4, 17.2, 16.9; HRMS (ESI) m/z 581.2779
[(MþNa)þ; calcd for C31H43N2O5NaCl: 581.2758].
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(d, J¼6.3 Hz, 3H), 1.46–1.83 (m, 8H), 2.80p (ddd, J¼1.9,
6.5, 6.5 Hz, 1H), 3.10–3.51 (m, 10H), 3.72p (dd, J¼1.9,
6.3 Hz, 1H), 3.79 (s, 3H), 4.12 (d, J¼5.8 Hz, 2H), 6.67 (m,
1H), 7.02 (d, J¼8.5 Hz, 1H), 7.15 (dd, J¼2.1, 8.3 Hz, 1H),
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1.88 (m, 8H), 2.82p (ddd, J¼2.2, 3.7, 6.0 Hz, 1H), 3.15–
3.57 (m, 10H), 3.71p (dd, J¼2.2, 2.2 Hz, 1H), 3.81 (s, 3H),
4.17 (d, J¼5.8 Hz, 2H), 6.33 (m, 1H), 7.01 (d, J¼8.4 Hz,
1H), 7.17 (m, 1H), 7.25–7.34 (m, 6H).
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Acknowledgements
Financial support was provided by the National Institutes of

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