Progress toward the total synthesis of psymberin/irciniastatin A

Article abstract of DOI:10.1021/jo9009003

(Chemical Equation Presented) In this paper, we describe our synthesis of four key building blocks for the total synthesis of psymberin (1) and its C4 epimer (2). Despite early difficulties in processing material to the advanced intermediate stage, we hav

Full text of DOI:10.1021/jo9009003

pubs.acs.org/joc
Progress toward the Total Synthesis of Psymberin/Irciniastatin A
Lauren E. Brown,† Yakira R. Landaverry,† James R. Davies,‡ Kristin A. Milinkevich,§,^
Sandra Ast, Joseph S. Carlson,^ Allen G. Oliver,† and Joseph P. Konopelski*,†
†Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California
95064, ‡Selcia Ltd., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United
Kingdom, §Department of Chemistry, One Shields Avenue, University of California, Davis, California 95616,
and Universita€t Potsdam Mathematisch-Naturwissenschaftliche Fakulta€t, Institut fu€r Chemie, Komplex II,
Karl-Liebknecht-Strasse 24-25, 14476 Golm, Germany. ^NSF-REU Summer Undergraduate Research
Fellowship Program
joek@chemistry.ucsc.edu
Received April 30, 2009
In this paper, we describe our synthesis of four key building blocks for the total synthesis of
psymberin (1) and its C4 epimer (2). Despite early difficulties in processing material to the advanced
intermediate stage, we have been successful in developing high-yielding syntheses for the pyran core,
natural side chain, 4-epi side chain, and aryl fragments of the molecule. Our findings from the
optimization process are presented herein.
Introduction
psymberin and analogues have been developed, including
De Brabander’s elegant first total synthesis of 1 and 2 in
2006, which conclusively determined that psymberin is in
fact the 4S isomer 1.4,5 To embark on the total synthesis of
this remarkably active molecule, we endeavored to develop a
rapid and convergent approach to both 1 and 2 as well as
libraries of stereoisomer and structural analogues. Our
successful efforts to produce several key building blocks
are disclosed herein.
In late 2003, our colleagues in the research group of
Professor Philip Crews isolated a highly potent cytotoxic
marine natural product from “an undescribed and incon-
spicuous sponge, Psammocinia sp.1” The molecule, psymber-
in (assigned by Crews et al. as either 1 or 2), was later
determined to be identical to iriciniastatin A, a compound
isolated and reported by Pettit and co-workers from extracts
of Ircinia ramose.2 The dual isolation of this compound from
different sponges combined with the reported difficulty in
isolating the compound from many sponge extracts adds
evidence to the speculation that this molecule, along with
structurally similar compounds, may in fact take origin from
symbiotic bacteria.3 Over the past 6 years, a number of
publications relating to the synthesis and semisynthesis of
(4) For the total synthesis of 1, see: (a) Jiang, X.; Garcıa-Fortanet, J.; De
´
Brabander, J. K. J. Am. Chem. Soc. 2005, 127, 1124–11255. (b) Shangguan,
N.; Kiren, S.; Williams, L. J. Org. Lett. 2007, 9, 1093–1096. (c) Huang, X;
Shao, N.; Palani, A.; Aslanian, R.; Buevich, A. Org. Lett. 2007, 9, 2597–2600.
(d) Smith, A. B.; Jurica, J. A.; Walsh, S. P. Org. Lett. 2008, 10, 5625–5628.
(5) For other articles related to the synthesis and stereochemical analysis
of psymberin fragments and analogs, see: (a) Kiren, S.; Williams, L. J. Org.
Lett. 2005, 7, 2905–2908. (b) Green, M. E.; Rech, J. C.; Floreancig, P. E. Org.
Lett. 2005, 7, 4117–4120. (c) Reach, J. C.; Floreancig, P. E. Org. Lett. 2005, 7,
5175–5178. (d) Henssen, B.; Kasparyan, E.; Marten, G.; Pietruszka, J.
Heterocycles 2007, 74, 245–249. (e) Huang, X.; Shao, N.; Palani, A.;
Aslanian, R.; Buevich, A.; Siedel-Dugan, C.; Huryk, R. Tetrahedron Lett.
2008, 49, 3592–3595. (f) Jiang, X.; Williams, N.; De Brabander, J. K. Org.
Lett. 2007, 9, 227–230. (g) lachance, H.; Marion, O.; Hall, D. G. Tetrahedron
Lett. 2008, 49, 6061–6064. (h) Huang, X.; Shao, N.; Huryk, R.; Palani, A.;
Aslanian, R.; Siedel-Dugan, C. Org. Lett. 2009, 11, 867–870.
(1) Cichewicz, R. H.; Valeriote, F. A.; Crews, P. Org. Lett. 2004, 6, 1951–
1954.
(2) Pettit, G. R.; Xu, J.-P.; Chapuis, J.-C.; Pettit, R. K.; Tackett, L. P.;
Doubek, D. L.; Hooper, J. N. A.; Schmidt, J. M. J. Med. Chem. 2004, 47,
1149–1152.
(3) See: Piel, J. Nat. Prod. Rep. 2009, 26, 338–362 and references therein.
DOI: 10.1021/jo9009003
r
Published on Web 07/02/2009
J. Org. Chem. 2009, 74, 5405–5410 5405
2009 American Chemical Society

Brown et al.
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SCHEME 1. Retrosynthetic Analysis for 1 and 2
FIGURE 1. Kocienski’s synthesis of compound 8 served as our
template for rapid assembly of pyran core fragments 9 and 10.
SCHEME 2. Valine-Mediated Asymmetric Aldol Reaction Is
More Successful with Aldehyde 12 than with 11
Results and Discussion
Our retrosynthetic analysis for 1 is depicted in Scheme 1.
We envisioned a coupling of aryl fragment 3, through a
suitable organometallic agent, to an epoxide (not shown)
to be built onto the lower portion of target fragment 6, in
which the C8 functionality is suitably protected. Subsequent
manipulation of the C8 functionality to a variety of groups
was deemed necessary to explore the often challenging
formation of the stereochemically defined aminal function-
ality6 through coupling with fragments such as 4 or 5. Thus,
our strategy involved disconnecting the molecule into three
main fragments, the aryl fragment 3, the side chain fragment
as 4 or 5, and the pyran core fragment 6, which can be further
deconstructed to 7. In addition to allowing for a highly
convergent assembly of 1, the modularity of our approach
would allow for alteration of stereochemistry and function-
ality on each of the three subunits so as to rapidly amass a
library of analogues.
SCHEME 3. Further Advancement of the Pyran Core Fragments
Excited to evaluate the potential for C8 diastereoinduc-
tion through several envisioned synthetic approaches, our
initial goal was to obtain the advanced intermediate 7 as
swiftly as possible. To this end, we relied heavily on the
pioneering work of Kocienski and co-workers to synthesize
the pyran core. Kocienski’s synthesis of pederin, theopeder-
in, and the mycalamides all share the common pyran inter-
mediate 8 (Figure 1).7 We envisioned that the analogous
protected alcohol 9 (and later 10) would dovetail nicely into
our synthesis of 1.
Our approach to compounds 9 (first generation) and 10
(second generation) based on Kocienski’s template are
depicted in Schemes 2 and 3. The hopes of hastily moving
multigram quantities of material through Kocienski’s pro-
cess were dashed on the discovery that our first-generation
substrate 9 suffered from a frustrating instability through
(6) For a recent exmple of succesful entry into this challenging function-
ality via asymmetric catalysis, see: Li, G.; Fronczek, F. R.; ntilla, J. C. J. Am.
Chem. Soc. 2008, 130, 12216–12217.
(7) (a) Kocienski, P. J.; Narquizian, R.; Raubo, P.; Smith, C.; Boyle, F. T.
Synlett 1998, 1432–1434. (b) Kocienski, P.; Narquizian, R.; Raubo, P.;
Smith, C.; Farrugia, L. J.; Muir, K.; Boyle, F. T. J. Chem. Soc., Perkin
Trans. 1 2000, 2357–2384.
many of the transformations. We attributed this decomposi-
tion to the loss of the primary tert-butyldimethylsilyl
(TBDMS) ether and thus repeated the synthesis of an
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analogous compound 10 that was truncated by one carbon
and bore the more robust tert-butyldiphenylsilyl (TBDPS)
protecting group at the primary alcohol.
SCHEME 4. Completion of the Synthesis of Aldehydes 29 and 7
for Use in Model Studies for the Coupling with 4/5 or Transfor-
med to 6for Further Functionalization of thePyran Core(Scheme1)
The synthesis began with an asymmetric aldol reaction
between silyl enol ether 13 and aldehyde 11 mediated by the
oxazaborolidine 14, generated in situ from N-tosylvaline and
BH3 THF.8 The enantiomeric ratio in this transformation
3
was estimated to be 97:3 by 1H NMR following conversion
to the Mosher ester.9 While our initial yields were far lower
than Kocienski’s, optimization of the oxazaborolidine for-
mation by increasing the reaction time increased the yield
from 20% to 60%. A major challenge in this transformation
was the isolation of two products from this transformation:
the desired alcohol 17 as well as TMS-ether 15. While
treatment of 15 with mild acid could invoke the desired
deprotection, it was at this step that we encountered what
would be a recurring theme throughout the first-generation
synthesis: the surprising lability of the TBDMS ether. None
of our attempts to remove the TMS ether were successful
without concomitant TBDMS loss, thus requiring a repro-
tection step to convert the diol to 17. Incorporation of the
more robust TBDPS protecting group eliminated the need
for reprotection and gave 18 in a much higher 88% overall
yield with comparable diastereoselectivity, determined to be
94:6 by chiral HPLC analysis.
With compounds 17 and 18 in hand, acetylation and
Dieckmann condensation proceeded uneventfully to give
β-keto lactones 21/22. Recrystallization of both lactones to
full enantioenrichment was possible at this stage and con-
firmed by optical rotation and chiral HPLC analysis. In
addition, X-ray crystallographic analysis of an enriched
sample of compound 22 gave a Flack parameter of 0.08,
indicative of the desired absolute configuration.10 The three
remaining steps involved methyl enol ether formation fol-
lowed by DIBALH reduction to give enones 25 and 26,
which then underwent conjugate addition to give β-vinyl
ketones 9 and 10, respectively. At this stage, the difference in
performance of the two compounds is quite striking: the
overall yield of our second-generation substrate 10 (41%) is
nearly double that of first-generation substrate 9 (23%) and
comparable to that for Kocienski’s β-vinyl ketone 8 (38%).
We attributed the lower comparative yields in the syntheses
of 17 and 25 to the inability to perform the requisite acidic
workup in each reaction without substantial loss of the
TBDMS ether. The TBDMS group can be considered more
vulnerable to deprotection under acidic conditions in part
because of its decreased size relative to the TBDPS group and
also perhaps due to the increased distance from the bulkier
region of the molecule that is imparted by the additional
methylene on the pendant chain. However, the cause for the
decreased yield in other transformations such as the conver-
sion of 19 to 21 and the remarkable instability of 23 was less
clear.
ketone reduction on 9 or 10 to give the desired chirality at C11.
We had hoped for substrate-induced diastereoselectivity in
this transformation, but unfortunately, wesaw little selectivity
with the use of common reducing agents such as LAH,
DIBALH, NaBH4, superhydride, and Luche conditions. For-
tunately, the first asymmetric reducing agent we employed,
TarB-NO2 in tandem with NaBH4,11 gave us the desired
stereochemistry (confirmed by 1,3 diaxial NOE interactions
among the pendant vinyl protons and those at C11 and C13
for compound 28) at C11 with a 19:1 diastereomeric ratio for
both the first- and second-generation substrates. This trans-
formation was not as high yielding as desired, however, due to
a competing hydroboration reaction between the pendant
alkene and the borane generated in the course of the reaction.
Nonetheless, optimization of the dismal 10-33% yields to
55% on the second-generation substrate was eventually
achieved. Silyl protection gave compounds 27 and 28.
In anticipation of the impending coupling studies at the C8
center, the substrate was subjected to oxidative cleavage of
the vinyl group to give aldehydes 29 and 7 (Scheme 4). The
optimal yield for the second-generation product 7 was
obtained by a two-stage, one-pot treatment with OsO4/
NMO followed by NaIO4, in contrast to the lower yielding
first-generation procedure converting 27 to 29, in which the
intermediate 1,2-diol was isolated by chromatography prior
to periodate cleavage. The relatively unstable aldehyde 7
could be easily protected as the dimethoxy acetal 6 for
further manipulations at the lower portion of the molecule.
However, installation of C16-C18 was deferred at this stage
in favor of first performing model studies on the aminal
formation reaction with the side-chain C1-N7 fragments.
In the early planning stages of our psymberin synthesis,
the assembly of side-chain fragments, in both the natural and
C4-epimer forms, were also synthetic sequences for which we
had anticipated speedy completion. Our synthesis of the
4-epi side chain 5 is depicted in Scheme 5. Beginning from
known PMB ether 30 (obtained from (S)-glycidol) copper-
catalyzed epoxide opening with isopropylidene Grignard
reagent was followed by methylation to give methyl ether
32. Deprotection and oxidation gave aldehyde 33. Com-
pound 33 was then subjected to syn-selective cyanide induc-
tion using the method of Ward et al. to afford cyanohydrin
From this point on, our synthesis diverges from Kocienski’s
template. The first desired transformation was an asymmetric
(8) (a) Kiyooka, S.-i.; Kaneko, Y.; Kume, K.-i. Tetrahedron Lett. 1992,
33, 4927–4930. (b) Kiyooka, S.-i.; Kira, H.; Hena, M. A. Tetrahedron Lett.
1996, 37, 2597–2600. (c) Kiyooka, S.-i.; Kaneko, Y.; Komura, M.; Matsuo,
H.; Nakano, M. J. Org. Chem. 1991, 56, 2276–2278.
(9) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519.
(10) Flack, H. D.; Bernardinelli, G. Acta Crystallogr., Sect. A: Found.
Crystallogr. 1999, 55, 908–915.
(11) (a) Suri, J. T.; Vu, T.; Hernandez, A.; Congdon, J.; Singaram, B.
Tetrahedron Lett. 2002, 43, 3649–3652. (b) Cordes, D. B.; Nguyen, T. M.;
Kwong, T. J.; Suri, J. T.; Luibrand, R. T.; Singaram, B. Eur. J. Org. Chem.
2005, 5289–5285. (c) Kim, J.; Suri, J. T.; Cordes, D. B.; Singaram, B. Org.
Process Res. Dev. 2006, 10, 949–958.
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SCHEME 5. Synthesis of the 4-epi Side Chain in Amide Form (5)
SCHEME 6. Attempts To Synthesize the Natural Side Chain
from MacMillan’s Aldehyde 36
stereochemistry at C4-C5, we turned to MacMillan’s elegant
proline-catalyzed aldol reaction17 that has been shown to give
bis-TBDPS ether 36(Scheme 6)witha 9:1 diastereomeric ratio
and a 93% ee.18 Immediate protection of this aldehyde gave
alcohol 37, which was fully resistant to methylation, pre-
sumably due to steric bulk about the secondary hydroxyl.
Instead, selective deprotection of the primary silyl ether using
HF-pyridine gave diol 38.
From diol 38, we first opted to convert the compound to
the 1,2 cyclic sulfate ester 40, which has been shown by
Sharpless to readily accept various nucleophiles.19 Unfortu-
nately, this compound reacted sluggishly in the presence of
isopropylidene Grignard, and we struggled to ascertain
appropriate conditions for the cleavage of the resultant
sulfate ester to the desired free alcohol.20
Fortunately, conversion of 38 to epoxide 42 using the
method of Martinelli et al. proved far more fruitful
(Scheme 7).21 Compound 42 was then opened and methy-
lated to give 43 in good yield with the conditions we had
employed in the synthesis of fragment 5. Deprotection of the
hemiacetal gives the aldehyde, which is ready for oxidation
to either the acid 4 or other functionalities suitable for
coupling with the pyran core.
While we were encountering unanticipated difficulties in
the synthesis of the side chain and pyran core fragments, our
synthesis of our envisioned aryl fragment proceeded rapidly
and in excellent yield. The construction of the desired
compound 3 is depicted in Scheme 8 and began from known
aldehyde 44.22 Our initial attempts to perform the synthesis
on the bis-silylated diphenol (not shown) were met with
protection group loss and complex mixtures in the oxidation
step. We thus opted for more robust acetate protecting
groups, which were then converted to silyl ethers at the
34 in a 6:1 syn/anti diastereomeric ratio.12 The unstable
cyanohydrin was immediately protected and subjected to
nitrile hydrolysis using Parkins and Ghaffar’s catalyst13
giving separable amides 5 and 35, which is enantiomeric to
the desired “natural” side chain.
With the 4-epi side chain in hand, our initial inclination
was to perform a similar route from (R)-glycidol to obtain
the natural side chain fragment ent-35, with an additional
Mitsunobu-like inversion performed on the cyanohydrin
formed from ent-33 to afford the desired anti stereochemistry
as seen in the natural product. This inversion is somewhat
challenging due to the known tendency of aliphatic cyano-
hydrins to racemize under traditional Mitsunobu condi-
tions.14 Unpublished experiments performed on similar
compounds in our laboratory indicated this racemization
can be avoided by employing a method similar to Effenber-
ger and Stelzel,15 in which the cyanohydrin hydroxyl is first
converted to a sulfonate leaving group and then displaced by
an acetate to give the desired inversion of stereochemistry.
While our studies indicated good success in this transforma-
tion using Shimizu’s chlorinated mesylate as a leaving
group,16 we ultimately determined that this approach to
the natural side chain was too lengthy and decided to focus
our efforts on developing of a more efficient route to the
completion of this small fragment.
Our more rapid pathway into the natural side chain
fragment focused on synthesizing the compound as the
carboxylic acid 4. In order to established the requisite anti
(12) (a) Ward, D. E.; Hrapchak, M. J.; Sales, M. Org. Lett. 2000, 2, 57–
60. (b) Ward, D. E.; Sales, M.; Hrapchak, M. J. Can. J. Chem. 2001, 79, 1775–
1785.
(13) Ghaffar, T.; Parkins, A. W. Tetrahedron Lett. 1995, 36, 8657–8660.
(14) Warmerdam, E. G. J. C.; Brussee, J.; Kruse, C. G.; van der Gen, A.
Tetrahedron 1993, 49, 1063–1070.
(15) Effenberger, F.; Stelzer, U. Angew. Chem., Int. Ed. Engl. 1991, 30,
873–874.
(16) Shimizu, T.; Hiranuma, S.; Nakata, T. Tetrahedron Lett. 1996, 37,
6145–6148.
(17) (a) Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W.
C. Angew. Chem., Int. Ed. 2004, 43, 2152–2154. (b) Northrup, A. B.;
MacMillan, D. W. C. Science 2004, 305, 1752–1755.
(18) In our hands, the diastereomeric ratio for this transformation ranged
from 6:1 to 8:1.
(19) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538–7539.
(20) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 655–658.
(21) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.;
Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447–450.
(22) Xie, L.; Takeuchi, Y.; Cosentino, L. M.; Lee, K.-H. J. Med. Chem.
1999, 42, 2662–2672.
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SCHEME 7. Completion of the Natural Side Chain from Diol 38
This chemistry, as well as further elaboration of the pyran
core and the preliminary results for our envisioned N7-C8
coupling scenarios, are currently under investigation in our
laboratory. These findings, combined with the eventual
completion of the total synthesis of 1, will be reported in
due course.
Experimental Section
(2S,4R,6R)-4-(tert-Butyldimethylsilanyloxy)-6-[2-(tert-butyldiphe-
nylsilanyloxy)ethyl]-5,5-dimethyltetrahydropyran-2-carbaldehyde (7).
Compound 28 (60 mg, 0.11 mmol, 1.0 equiv) was dissolved in a
mixture of 5 mL of t-BuOH, 1 mL of THF, and 0.5 mL of water.
N-Methylmorpholine N-oxide (28 mg, 0.24 mmol, 2.2 equiv) was
added, followed by one drop of a 4% solution of OsO4 in t-BuOH.
The mixture was stirred overnight. The following day, pH 7.0
phosphate buffered saline (10 mL) was added followed by sodium
periodate (128 mg, 0.6 mmol, 5.5 equiv). The mixture was stirred at
room temperature for 2 h and quenched with the addition of 500 mg
of solid Na2S2O3. After being stirred for 30 min, the solution was
diluted with water and extracted with ethyl acetate. The combined
organics were washed with saturated aqueous Na2S2O3 followed by
brine and dried over Na2SO4. Flash column chromatography (5%
ethyl acetate in hexanes) gave 57 mg (95%) of aldehyde 7 as a
colorless oil: [R]25D=þ36.8 (c 1.0, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ=9.73 (d, J=1.5 Hz, 1H), 7.70-7.65 (m, 4H), 7.45-7.37
(m, 6H), 4.12 (dd, J=2.0, 6.5 Hz, 1H), 3.92 (dt, J=5.0, 10.0 Hz, 1H),
3.83 (ddd, J=3.5, 6.5, 10.0 Hz, 1H), 3.35 (dd, J=1.5, 10.0 Hz, 1H),
3.22 (dd, J=4.5, 11.0 Hz, 1H), 2.10 (ddd, J=2.0, 4.5, 13.5 Hz, 1H),
1.81-1.72 (m, 2H), 1.63 (dddd, J=5.0, 5.0, 10.0, 14.0 Hz, 1H), 1.05
(s, 9H), 0.90 (s, 9H), 0.84 (s, 3H), 0.81 (s, 3H), 0.09 (s, 3H), 0.05
(s, 3H); 13C NMR (125 MHz, CDCl3) δ=205.8, 135.6, 133.9, 129.7,
127.7, 78.1, 72.7, 60.8, 38.7, 32.2, 29.3, 26.8, 25.7, 23.0, 19.1, 17.9,
12.7, -4.2, -5.2; IR (thin film)=2958, 1735, 1472, 1258, 1112, 959,
837, 702 cm-1; HRMS [MþHþ] for C32H51O4Si2 calcd 555.3320,
found 555.3337.
SCHEME 8. Rapid Assembly of Aryl Fragment 3
(2R,4R,6S)-4-(tert-Butyldimethylsilanyloxy)-2-[2-(tert-butyl-
diphenylsilanyloxy)ethyl]-6-dimethoxymethyl-3,3-dimethyltetra-
hydropyran (6). Aldehyde 7 (44 mg, 0.08 mmol, 1.0 equiv) was
dissolved in 2 mL of trimethylorthoformate in an oven-dried
flask under an atmosphere of nitrogen. Catalytic PTSA (1 mg)
was added, and the mixture was stirred at room temperature for
45 min. The reaction was quenched with the addition of 1 mL
of saturated aqueous sodium bicarbonate. The mixture was
extracted with ethyl acetate, and the combined organics were
washed with brine, dried over Na2SO4, and filtered to give a
crude oil that was subjected to flash column chromatography.
Following purification, compound 6 (43 mg, 93%) was isolated
as a clear, colorless oil: [R]26D=þ19.8 (c 1.2, CH2Cl2); 1H NMR
(500 MHz, CDCl3) δ=7.71-7.67 (dt, J=1.5, 8.0 Hz, 4H), 7.44-
7.36 (m, 6H), 4.40 (d, J=7.0 Hz, 1H), 3.84-3.75 (m, 3H), 3.54
(dd, J=4.0, 8.0 Hz, 1H), 3.45 (dd, J=2.0, 11.0 Hz, 1H), 3.36
(s, 3H), 3.22 (s, 3H), 1.95 (bs, 1H), 1.80-1.70 (m, 2H), 1.66 (ddd,
J=5.5, 8.5, 13.5 Hz, 1H), 1.06 (s, 9H), 0.92 (s, 3H), 0.91 (s, 9H),
0.84 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ=135.6, 134.4, 134.2, 129.5, 127.6, 103.3, 73.1, 62.0,
54.8, 52.6, 38.1, 32.0, 30.1, 26.8, 25.7, 24.6, 19.1, 17.9, -4.4,
penultimate step. The phenols were then protected with
acetyl chloride, giving 45 in 85% yield. Oxidation to the
desired amide was first performed by treatment with
N-hydroxysucccinimde followed by IBX to give activated
ester 46.23 Interestingly, the high yield in this transformation
was completely dependent on order of addition, requiring
premixing of the substrate with NHS prior to oxidation
(premixing of IBX with NHS prior to substrate addition
gave yields varying from 25 to 50%). This is indicative that
the actual mechanism of this transformation may differ from
that reported in the literature,24 which suggests that an
intermediate IBX-NHS complex is the active oxidant. The
activated ester was then treated with diethylamine to pro-
duce the desired aromatic amide with concomitant acyl
hydrolysis, affording compound 47 in a 56% yield. The
conversion to the desired TBDPS-protected product 3 could
be achieved by two routes, both of which proved to be
similarly successful (84%) on a small scale.
Our initial unpublished results as well as personal com-
munication with Professor De Brabander indicate the envi-
sioned disconnection of this aryl fragment may suffer from
the hydrolytic stability of the diethylamide, which has
thus far been entirely resistant to lactone closure outside of
highly acidic refluxing conditions. Thus, some retooling of
our dihydroisocoumarin synthesis is apparently necessary.
-5.1; IR (thin film)=2956, 1471, 1256, 1091, 975, 835, 701 cm-1
;
HRMS [M þ Hþ] for C34H57O5Si2 calcd 601.3739, found
601.37089.
Acknowledgment. We thank the NIH (CA98878) for sup-
port of this work. Y.R.L. thanks MBRS (GM58903-05) for
additional support. K.A.M. and J.S.C. thank NSF-REU
(CHE-0552641) for funding. We thank J. Kim and J. Loo for
technical assistance. Purchase of the 600 MHz NMR used in
these studies was supported by funds from the National
€
(23) Mazitschek, R.; Mulbaier, M.; Giannis, A. Angew. Chem., Int. Ed.
2002, 41, 4059–4061.
(24) Schulze, A.; Giannis, A. Adv. Synth. Catal. 2004, 346, 252–256.
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Institutes of Health (S10RR019918) and National Science
Foundation (CHE-0342912). The single-crystal X-ray dif-
fraction data for 22 were recorded on an instrument supported
by the National Science Foundation, Major Research Instru-
mentation (MRI) Program under Grant No. CHE-0521569.
Supporting Information Available: Synthetic procedures,
1
complete spectroscopic data, H and 13C NMR spectra for all
new compounds, chiral HPLC data for 18 and 24, and CIF file
for 22. This material is available free of charge via the Internet at
http://pubs.acs.org.
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