Total synthesis of (+)-ambruticin S: Probing the pharmacophoric subunit

Article abstract of DOI:10.1021/jo100956v

An enantioselective synthesis of the antifungal natural product (+)-ambruticin S has been accomplished starting with the readily available methyl α-d-glucopyranoside, (R)-Roche ester, and (S)-glycidol as chirons, which encompassed seven of the 10 stereogenic centers of the target molecule. The remaining three centers were set by a highly diastereoselective, asymmetric cyclopropanation employing a chiral, nonracemic phosphonamide reagent. Our strategy for the construction of the dihydropyran subunit involved a highly syn-selective Lewis acid catalyzed 6-endo-trig cyclization. Other key steps in the synthesis featured an epoxide opening with a dithiane anion, two efficient phosphonamide-anion based olefinations, and a late-stage C-glycosylation.

Full text of DOI:10.1021/jo100956v

pubs.acs.org/joc
Total Synthesis of (þ)-Ambruticin S: Probing the
Pharmacophoric Subunit†
Stephen Hanessian,*,§ Thilo Focken,§ Xueling Mi,§ Rupal Oza,§ Bin Chen,§ Dougal Ritson,§
and Renaud Beaudegnies‡
§
ꢀ
ꢀ
ꢀ
Department of Chemistry, Universite de Montreal, C. P. 6128, Succ. Centre-Ville, Montreal, PQ,
Canada H3C 3J7, and ‡Syngenta Crop Protection AG, Crop Protection Research, Research Chemistry,
Schaffhauserstrasse 101, CH-4332 Stein, Switzerland
stephen.hanessian@umontreal.ca
Received May 14, 2010
An enantioselective synthesis of the antifungal natural product (þ)-ambruticin S has been accom-
plished starting with the readily available methyl R-D-glucopyranoside, (R)-Roche ester, and (S)-
glycidol as chirons, which encompassed seven of the 10 stereogenic centers of the target molecule. The
remaining three centers were set by a highly diastereoselective, asymmetric cyclopropanation
employing a chiral, nonracemic phosphonamide reagent. Our strategy for the construction of the
dihydropyran subunit involved a highly syn-selective Lewis acid catalyzed 6-endo-trig cyclization.
Other key steps in the synthesis featured an epoxide opening with a dithiane anion, two efficient
phosphonamide-anion based olefinations, and a late-stage C-glycosylation.
Introduction
0.03-1.6 μg/mL, and no observed toxicity in mice.2 Further
biological testing resulted in oral activity against histoplas-
mosis and coccidioidomycosis. The compounds inhibit fun-
gal growth presumably by interfering with the osmoregu-
latory system. It is suggested that the ambruticins induce the
high osmolarity glycerol (HOG) signaling pathway by tar-
geting hik1, a histidine kinase.6
The structure and absolute stereochemistry of (þ)-ambru-
ticin S was determined through a series of degradative
studies, aided by a single crystal X-ray of the triformate ester
of the alcohol obtained from reduction of the natural pro-
duct.1,7 The unique structural features of ambruticin S (1a)
include 10 stereocenters, three E-double bonds, a tetrasubstituted
(þ)-Ambruticin S (1a) is an antifungal natural polyketide
isolated in 1977 from myxobacterium Polyangium cellulo-
sum1,2 and belongs to a family that now consists of eight
naturally occurring members (Figure 1).3-5 The amino ana-
logues in the VS-series 1c-h were later isolated from a closely
related myxobacterium strain, Sorangium cellulosum So
ce10.4
The ambruticins show potent antifungal activity against a
broad range of pathogens, such as Aspergillus flavus, Blas-
tomyces dermatitidis, Coccidioides immitis, and Hansenula
anomala, with MICs (minimal inhibition concentration) of
† Dedicated to Professor Eric Jacobsen on the occasion of his 50th birthday.
(1) Connor, D. T.; Greenough, R. C.; von Strandtmann, M. J. Org.
Chem. 1977, 42, 3664–3669.
(2) Ringel, S. M.; Greenough, R. C.; Roemer, S.; Connor, D.; Gutt, A. L.;
Blair, B.; Kanter, G.; von Strandmann, M. J. Antibiot. 1977, 371–375.
(3) Isolation and characterization of ambruticin F (1b): Connor, D. T.;
von Strandtmann, M. J. Org. Chem. 1978, 43, 4606–4607.
(6) (a) Wesolowski, J.; Hassan, R. Y. A.; Reinhardt, K.; Hodde, S.;
ꢀ
Bilitewski, U. J. Appl. Microbiol. 2010, 108, 462–471. (b) Dongo, A.; Bataille-
Simoneau, N.; Campion, C.; Guillemette, T.; Hamon, B.; Iacomi-Vasilescu,
B.; Katz, L.; Simoneau, P. Appl. Environ. Microbiol. 2009, 75, 127–134.
(c) Vetcher, L.; Menzella, H. G.; Kudo, T.; Motoyama, T.; Katz, L.
Antimicrob. Agents Chemother. 2007, 51, 3734–3736. (d) Knauth, P.;
Reichenbach, H. J. Antibiot. 2000, 53, 1182–1190.
€
(4) Hofle, G.; Steinmetz, H.; Gerth, K.; Reichenbach, H. Liebigs Ann.
Chem. 1991, 941–945.
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Rajcoomar, V. Tetrahedron Lett. 1981, 22, 1751–1754. (b) Just, G.; Poitvin,
P. Can. J. Chem. 1980, 58, 2173–2177.
^
(5) Review: Michelet, V.; Genet, J.-P. Curr. Org. Chem. 2005, 9, 405–418.
DOI: 10.1021/jo100956v Published on Web 07/20/2010
r
J. Org. Chem. 2010, 75, 5601–5618 5601
2010 American Chemical Society

Hanessian et al.
JOCArticle
biological evaluation of several structural analogues of the
ambruticins have been published.3,12 These structure-
activity relationship studies were mainly limited to modi-
fications of the tetrahydropyran subunit, as all of the ana-
logues were actually derived from the ambruticins them-
selves through semisynthesis.
Herein we report our efforts leading to the total synthesis
of (þ)-ambruticin S and a crystal structure of the previously
reported triformate ester. On the basis of this data, we
designed and synthesized selected truncated analogues with
the intention to exploit the pharmacophore believed to be
associated with ring C and the trisubstituted olefin (Figure 2).
Results
In our synthetic strategy outlined in Figure 2, we envisaged
a convergent, late stage assembly of three advanced frag-
ments through a phosphonamide anion based olefination
reaction and a C-glycosylation, respectively. It was thought
that the ring A tetrahydropyran diol could be derived from
methyl R-D-glucopyranoside (2) through a C-4 deoxygena-
tion of the hydroxyl group and a one-carbon homologation
of the C-6 side chain. The synthesis of the middle fragment 3
containing the trisubstituted cyclopropane would arise from
our phosphonamide-anion methodologies for cyclopropa-
nation13,14 and olefination.15,16 Thus, phosphonamide 513
could provide enantioselective and diastereoselective access
to the cyclopropane ring of ambruticin S, while the second
phosphonamide anion based olefination in our synthetic
plan would be carried out using a reagent prepared from
(R)-Roche ester (6). The construction of the ring C syn-
dihydropyran would employ a highly diastereoselective Lewis
acid catalyzed 6-endo-trig cyclization recently developed in our
laboratories.17 The requisite diol 4 was anticipated to come
from a dithiane anion addition to (R)-glycidol benzyl ether (7).
As shown in Scheme 1, our initial approach to build
subunit A started from methyl R-D-glucopyranoside (2)
and took advantage of an efficient, regioselective chlorination-
reductive dechlorination sequence to remove the superfluous
C-4 hydroxyl group.18 Thus, treatment of 2 with sulfuryl
chloride in the presence of pyridine, followed by hydrolysis
with sodium iodide in aqueous methanol, delivered 8 in 86%
yield.19 Selective removal of the secondary chloride was achie-
ved by hydrogenation in the presence of Raney nickel to yield
diol 9,20 which was converted to the dibenzyl ether 10 (67%
FIGURE 1. The ambruticin family.
FIGURE 2. Retrosynthetic analysis and bond construction strate-
gies of (þ)-ambruticin S.
tetrahydropyran, a trisubstituted dihydropyran, and a tri-
substituted cyclopropane, all encompassed in a linear array.
The intriguing structure of ambruticin S has led to four total
syntheses to date and some methodology studies.5 The first
total synthesis was achieved by Kende and co-workers in
1990.8 Since then, total syntheses have been reported by
the Martin,9 Lee,10 and Jacobsen11 groups. Syntheses and
(13) (a) Hanessian, S.; Cantin, L.-D.; Roy, S.; Andreotti, D.; Gomtsyan,
A. Tetrahedron Lett. 1997, 38, 1103–1106. (b) Hanessian, S.; Andreotti, D.;
Gomtsyan, A. J. Am. Chem. Soc. 1995, 117, 10393–10394.
(14) (a) For a review on asymmetric cyclopropanation, see: Lebel, H.;
Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977–
1050. (b) For a review on trans-1,2-diamino-cyclohexane derivatives in
asymmetric synthesis, see: Bennani, Y. L.; Hanessian, S. Chem. Rev. 1997,
97, 3161–3195.
(8) (a) Kende, A. S.; Mendoza, J. S.; Fujii, Y. Tetrahedron 1993, 49, 8015–
8038. (b) Kende, A. S.; Fujii, Y.; Mendoza, J. S. J. Am. Chem. Soc. 1990, 112,
9645–9646.
(9) (a) Berberich, S. M.; Cherney, R. J.; Colucci, J.; Courillon, C.; Geraci,
L. S.; Kirkland, T. A.; Marx, M. A.; Schneider, M. F.; Martin, S. F.
Tetrahedron 2003, 59, 6819–6832. (b) Kirkland, T. A.; Colucci, J.; Geraci,
L. S.; Marx, M. A.; Schneider, M.; Kaelin, D. E., Jr.; Martin, S. F. J. Am.
Chem. Soc. 2001, 123, 12432–12433.
(10) Lee, E.; Choi, S. J.; Kim, H.; Han, H. O.; Kim, Y. K.; Min, S. J.; Son,
S. H.; Lim, S. M.; Jang, W. S. Angew. Chem., Int. Ed. 2002, 41, 176–178.
(11) Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772–10773.
(12) (a) Tian, Z.-Q.; Wang, Z.; Xu, Y.; Tran, C. Q.; Myles, D. C.; Zhong,
Z.; Simmons, J.; Vetcher, L.; Katz, L.; Li, Y.; Shaw, S. J. ChemMedChem
2008, 3, 963–969. (b) Xu, Y.; Wang, Z.; Tian, Z.-Q.; Li, Y.; Shaw, S. J.
ChemMedChem 2006, 1, 1063–1065. (c) Connor, D. T.; Klutchko, S.; von
Strandtmann, M. J. Antibiot. 1979, 368–370. (d) Connor, D. T.; von
Strandtmann, M. J. Med. Chem. 1979, 22, 1144–1147. (e) Connor, D. T.;
von Strandtmann, M. J. Med. Chem. 1979, 22, 1055–1059.
(15) Hanessian, S.; Bennani, Y. L.; Leblanc, Y. Heterocycles 1993, 35,
1411–1424.
(16) Asymmetric olefination with cyclic phosphonamides: (a) Hanessian,
S.; Beaudoin, S. Tetrahedron Lett. 1992, 33, 7655–7658. (b) Hanessian, S.;
Beaudoin, S. Tetrahedron Lett. 1992, 33, 7659–7662. (c) Hanessian, S.;
Delorme, D.; Beaudoin, S.; Leblanc, Y. J. Am. Chem. Soc. 1984, 106,
5754–5756.
(17) Hanessian, S.; Focken, T.; Oza, R. Org. Lett. 2010, 12, 3172–3175.
(18) Jennings, H. J.; Jones, J. K. Can. J. Chem. 1962, 40, 1408–1414.
(19) (a) Chang, C.-W. T.; Liu, H.-W. Biorg. Med. Chem. Lett. 2002, 12,
1493–1496. (b) Lawton, B. T.; Szarek, W. A.; Jones, J. K. N. Carbohydr. Res.
1970, 14, 255–258.
(20) Lawton, B. T.; Szarek, W. A.; Jones, J. K. N. Carbohydr. Res. 1970,
15, 397–402.
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SCHEME 1. Synthesis of Ring A from Methyl R-D-Glucopyranoside (2)
SCHEME 2. Alternative Approaches to Intermediate 13
yield, two steps). After some experimentation, we found that
selective substitution of the C-6 chloride could be achieved
under free-radical conditions.21 Thus, treatment of 10 with
allyltriphenylstannane in the presence of ACCN (1,10-azobis-
(cyclohexanecarbonitrile) led to the C-allyl derivative 11 in
52% yield with recovery of starting material (43%). Isomer-
ization of 11 in the presence of Grubbs’ second generation
catalyst22 according to our recently reported method23 affor-
ded 12 in 84% yield, which was dihydroxylated with osmium
tetroxide followed by oxidation and subsequent reduction to
give alcohol 13 in 65% yield (last two steps). After protection
of the free hydroxyl group with benzyl bromide, hydrolysis of
the methyl glycoside under acidic conditions, and PCC oxida-
tion, the desired lactone 15 was obtained in 58% yield (three
steps).24 The entire sequence was realized in 10 steps from
commercially available and inexpensive 2 in 10% overall yield
(seven steps to intermediate 13, 16% overall yield).
Two alternative syntheses of intermediate 13 were also
explored (Scheme 2A). Displacement of the chloride 10 with
NaCN was notoriously slow, leading to the homologated
nitrile 16 in 37% yield with recovery of starting material
(41%).25 Nevertheless, reduction with DIBAL-H to the
aldehyde, followed by treatment with NaBH4 furnished 13
in 67% yield (two steps). A third approach to alcohol 13 is
shown in Scheme 2B. Starting from the known inter-
mediate 18, available from 17 in six steps and 55% overall
(21) Keck, G. E.; Yates, J. B. J. Am. Chem. Soc. 1982, 104, 5829–5831.
(22) (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29.
(b) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–
ꢀ
^
(24) Sanchez, M. E. L.; Michelet, V.; Besnier, I.; Genet, J. P. Synlett 1994,
956. (c) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron
Lett. 1999, 40, 2247–2250.
(23) Hanessian, S.; Giroux, S.; Larsson, A. Org. Lett. 2006, 8, 5481–5484.
705–708.
(25) For a related displacement, see: Barnes, N. J.; Davidson, A. H.;
Hughes, L. R.; Procter, G. J. Chem. Soc., Chem. Commun. 1985, 1292–1294.
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SCHEME 3. Synthesis of Ring C via 6-endo-trig Cyclization of Diol 4
yield,26 we proceeded with the reduction of the R,β-unsatu-
rated aldehyde using Pd/BaCO3 and subsequent epimerization
in the presence of DBU. Treatment of the saturated alde-
hyde thus obtained with the ylid generated from methyl-
triphenylphosphonium bromide gave vinyl tetrahydropyran
19. Hydroboration of the double bond under oxidative con-
ditions yielded primary alcohol 13 (59% yield, last three steps).
These two approaches afforded intermediate 13 in six steps
(14% overall yield) and nine steps (32% overall yield), respec-
tively, from commercially available and inexpensive starting
materials.
SCHEME 4. Synthesis of Ring B
The construction of ring C of ambruticin S started from
(R)-glycidol benzyl ether (7) and dithiane 20 and proceeded
as shown in Scheme 3. The required dithiane 20 was obtained
as a 9:1 mixture of E/Z isomers from treatment of 2-methyl-
mixture of diastereomers in 79% yield (over two steps.)
However, it was shown from preliminary studies that the
configuration of the newly formed stereocenter is irrelevant
for the subsequent 6-endo-trig cyclization forming dihydro-
pyran 23.17 Thus, conversion of diol 4 in the presence of
2-pentenal with 1,3-propanedithiol and BF3 OEt2.27 Inter-
3
estingly, only the anion derived from the E-isomer by depro-
tonation with butyllithium reacted with epoxide 7 to give
adduct 21 in 97% yield. Protection of the hydroxyl group
in 21 proved to be necessary in order to unmask the R,β-
unsaturated system. Thus, exposure of adduct 21 to TBSOTf
in the presence of 2,6-lutidine provided the corresponding
TBS-ether in 93% yield. After some optimization, we found
that the dithiane moiety could be removed conveniently from
the latter compound by treatment with benzeneseleninic acid
anhydride,28 giving the relatively unstable enone 22 in 79%
yield. Other methods screened for this conversion from 21
(Dess-Martin periodinane,29a HgO/HgCl2,29b HgCl2/CaCO3,29c
HgClO4,29d PhI(O2CCF3)2,29e and H5IO629f) either gave a
lower yield or led to decomposition. Luche reduction of
enone 22 and treatment with TBAF furnished diol 4 as a 3.6:1
catalytic amounts of BF3 OEt2 proceeded smoothly on a
3
multigram scale, furnishing the desired dihydropyran 23 in
81% yield. The benzyl group was then removed under Birch
conditions, giving rise to alcohol 24 in 93% yield.11 Oxida-
tion under Swern conditions and reaction of the resulting
aldehyde with MeMgBr, followed by a second Swern oxida-
tion, provided the desired ketone 25 in 72% yield for three
steps.9,30
With a facile access to ring C ketone 25, we turned our
attention to the synthesis of the cyclopropane unit, which
was accomplished through a highly stereoselective cyclopro-
panation of tert-butyl crotonate (26) using the trans-chloro-
allyl phosphonamide 5 (Scheme 4).13b Thus, deprotonation
of 5 with n-butyllithium at low temperature followed by
addition of tert-butyl crotonate gave the desired cyclopro-
pane adduct 27 as a single diastereomer in 89% yield. The
stereochemical outcome of the cyclopropanation was based
on our previous study13b and NMR analysis and ultimately
proven by single-crystal X-ray analysis. Removal of the
chiral auxiliary by ozonolysis of 27 afforded the crystalline
cyclopropyl aldehyde 28 in 70% yield.
(26) (a) Giuliano, R. M.; Buzby, J. H. J. Carbohydr. Chem. 1987, 6, 541–
552.
(27) For the preparation of an analogous dithiane, see: Ziegler, F. E.;
Fang, J. M.; Tam, C. C. J. Am. Chem. Soc. 1982, 104, 7174–7181.
(28) (a) Cussans, N. J.; Ley, S. V.; Barton, D. H. R. J. Chem. Soc., Perkin
Trans. 1 1980, 1654–1657. (b) Barton, D. H. R.; Cussans, N. J.; Ley, S. V.
J. Chem. Soc., Chem. Commun. 1977, 751–752.
(29) (a) Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2003, 5, 575–
578. (b) Corey, E. J.; Erickson, B. W. J. Org. Chem. 1971, 36, 3553–3560.
(c) Hanessian, S.; Ma, J.; Wang, W. J. Am. Chem. Soc. 2001, 123, 10200–
10206. (d) Fujita, E.; Nagao, Y.; Kaneko, K. Chem. Pharm. Bull. 1978, 26,
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(30) (a) Pospısil, J.; Marko, I. E. J. Am. Chem. Soc. 2007, 129, 3516–3517.
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(b) Pospısil, J.; Kumamoto, T.; Marko, I. Angew. Chem., Int. Ed. 2006, 45,
3357–3360. (c) Lukesh, J. M.; Donaldson, W. A. Tetrahedron Lett. 2005, 46,
5529–5531.
3743–3751. (e) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287–290.
(f) Shi, X. X.; Khanapure, S. P.; Rokach, J. Tetrahedron Lett. 1996, 37, 4331–
4334.
´
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SCHEME 5. Synthesis of Middle Segment, First Approach
SCHEME 6. Synthesis of Middle Segment, Second Approach
The synthesis of the middle segment containing the cyclo-
propane ring was first realized in a linear fashion commen-
cing from ketone 25 (Scheme 5). The latter was reacted with
phosphonamide 31, which is derived from alkylation of 1,3-
dimethyl-2-oxo-1,3,2-diazaphospholidine (30)31a,b with (R)-
3-tert-butyldimethylsilyloxy-2-methylpropyl iodide (29).32
Deprotonation of 31 at low temperature followed by addi-
tion of ketone 25 and quenching with AcOH furnished a
separable 6:1 mixture of E/Z isomers, with the desired
compound as the major one.17 Subsequent removal of the
TBS group with TBAF afforded the known alcohol 32 in
58% yield (two steps).9,10,30a The latter was then converted
into the corresponding iodide by treatment with iodine and
PPh3, followed by displacement of the iodide with the anion
of phosphorus acid diamide 30 to give phosphonamide 34
(76% yield, two steps). Olefination of cyclopropyl aldehyde
28 with the lithium anion of 34 proceeded with excellent
(31) (a) Pudovik, M. A.; Pudovik, A. N. Zh. Obshch. Khim. 1973, 43,
2147–2149. (b) For alkylation of phosphorous acid diamides, see: Koeller,
K. J.; Spilling, C. D. Tetrahedron Lett. 1991, 32, 6297–6300.
(32) Marshall, J. A.; Grote, J.; Audia, J. E. J. Am. Chem. Soc. 1987, 109,
1186–1194.
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SCHEME 7. Completion of Synthesis of (þ)-Ambruticin S (1a)
selectivity (E/Z > 25:1) to give diene 35 in 64% yield.
Reduction of the tert-butyl ester to alcohol 36, followed by
oxidation under Swern conditions to the corresponding
aldehyde, and treatment with the Ohira-Bestmann reagent33
provided alkyne 37 (79%, last three steps).
eomer with the desired syn-stereochemistry of the newly
formed tetrahydropyran. Next, we planned to perform a
stereoselective reduction of the triple bond with concomitant
removal of the three benzyl-protecting groups under dis-
solved metal conditions. Despite extensive experimentation,
all of our attempts remained unsuccessful when using either
lithium or sodium in liquid ammonia, leading to over-
reduced compounds. To circumvent this problem, we then
decided to employ a two-step sequence instead: (a) reduc-
tive cleavage of the three benzyl-protecting groups, and (b)
hydroxyl-directed trans-reduction of the triple bond. We
were pleased to find that the use of lithium 4,4-di-tert-
butylbiphenylide (LiDBB)35 led to selective removal of the
benzyl groups without adverse reactions to deliver alkyne 45
in 89% yield. Trans-reduction of the homopropargylic sys-
tem was then cleanly achieved with sodium bis(2-metho-
xyethoxy)aluminum hydride in diethyl ether to furnish the
known triol 46 (80% yield, E/Z > 10:1).11,36 For the final
oxidation of the primary hydroxyl group of triol 46 in the
presence of the two secondary ones we chose a method
already employed by Liu and Jacobsen in the same
context.11,37 Thus, platinum-catalyzed oxidation of 46 with
oxygen in aqueous solution at 50 °C provided (þ)-ambruti-
cin S (1a) in 91% yield. The spectral data (1H and 13C NMR)
of synthetic (þ)-ambruticin S (1a) thus obtained were iden-
tical with those reported for the natural product.38
An alternative, more convergent synthesis of advanced
alkyne 37 was also explored using a reversed sequence of
steps (Scheme 6). Thus, reaction of the crystalline aldehyde
28 with the anion prepared from phosphonamide epi-31
afforded 38 with excellent E/Z selectivity (>25:1). Conver-
sion into alkyne 40 was achieved through a three-step
sequence consisting of a DIBAL-H reduction to the alcohol,
Swern oxidation to 39, and homologation with the Ohira-
Bestmann reagent (71% overall yield). The alkyne moiety in
40 was then converted to its TIPS derivative 41, followed by
selective cleavage of the TBS-ether using CSA in MeOH and
CH2Cl2 at 0 °C. Treatment of the resulting alcohol with
iodine and PPh3 gave iodide 42 (64% yield for three steps).
Conversion to 3 was achieved in 79% yield by treatment with
the lithium anion of 1,3-dimethyl-2-oxo-1,3,2-diazaphos-
pholidine (30) at low temperature. Phosphonamide 3 was
then transformed into the corresponding lithium anion, and
coupled with ketone 25 to give triene 43 as a separable 6:1
mixture of E/Z isomers in 45% yield (92% based on recov-
ered starting material), with the desired E-olefin as major
isomer. Finally, deprotection of 43 with TBAF furnished
alkyne 37 in 88% yield.
Little is known regarding the 3-dimensional nature of
ambruticin S in the solid state despite an X-ray crystal
structure of the triformate ester 47 prepared from triol 46,
as the pertinent data are no longer accessible.1 Still, an
appreciation of the 3-dimensional topology of ambruticin
S was needed before truncated and simplified analogues
With alkyne 37 in hand, we could now commence the final
assembly of (þ)-ambruticin S (1a), as shown in Scheme 7.
Deprotonation of 37 with n-butyllithium, followed by addi-
tion of lactone 15, led to a 1:1 diastereomeric mixture of the
desired adduct. The removal of the anomeric hydroxyl group
was subsequently achieved by treatment with triethylsilane
and BF3 OEt2 at low temperature.24,34 Gratifyingly, the
3
(35) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924–
1930.
C-glycoside 44 was obtained in 66% yield as a single diaster-
(36) For other examples of sodium bis(2-methoxyethoxy)aluminum hy-
dride reductions of homopropargylic systems in natural product synthesis,
see: (a) Sasaki, M.; Matsumori, N.; Murata, M.; Tachibana, K. Tetrahedron
Lett. 1995, 36, 9011–9014. (b) Goekjian, P. G.; Wu, T.-C.; Kang, H.-Y.;
Kishi, Y. J. Org. Chem. 1991, 56, 6422–6434.
€
(33) (a) Muller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996,
521–522. (b) Ohira, S. Synth. Commun. 1989, 19, 561–564. (c) Procedure for
preparation: William, R. F.; Goundry, W. R. F.; Baldwin, J. E.; Lee, V.
Tetrahedron 2003, 59, 1719–1729.
(34) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976–4978.
(37) (a) Fried, J.; Sih, J. C. Tetrahedron Lett. 1973, 14, 3899–3902. (b) See
also: Heyns, K.; Paulsen, H. Chem. Ber. 1955, 88, 188–195.
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components with simple aromatic surrogates as shown in
Scheme 8.38 Oxidation of alcohol 32 to the corresponding
aldehyde with Dess-Martin periodinane (DMP),39 followed
by Pinnick oxidation,40 provided the carboxylic acid 48 in
excellent yield with no detectable epimerization of the sensi-
tive allylic stereocenter. Coupling with aniline derivatives
using 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-
one (DEPBT)41 provided crystalline amides 49a-c in mod-
erate yields. Reaction of 32 with phenols under Mitsunobu
conditions gave rise to aromatic ethers 50a,b. However, pre-
liminary testing of compounds 49a-c and 50a,b38 showed no
activity using ambruticin S as a control. Further studies on a
larger panel of amides and ethers are in progress and will be
reported in due course.
FIGURE 3. ORTEP drawing of X-ray crystal structure of trifor-
mate 47.
SCHEME 8. Synthesis of Truncated Analogues of Ambruticin S
Discussion
As previously mentioned, there are four published total
syntheses of ambruticin S, each involving a number of
distinctive features. Key disconnections and methods emplo-
yed in bond constructions are shown in Figure 4. For the
elaboration of ring A of ambruticin S, Kende,8 Martin,9 and
Lee10 started with carbohydrate precursors, which possessed
the required diol unit, and then proceeded to manipulate
existing functionality to effect deoxygenation and chain ex-
tension. Jacobsen, however, relied on a catalytic asymmetric
hetero-Diels-Alder cyclization between a suitably functio-
nalized diene and an aldehyde.11 While Kende and Lee
utilized a Yamamoto dianion-mediated formation of the tri-
substituted cyclopropane (ring B),42 Martin relied on meth-
odology developed with Doyle,43 and Jacobsen applied the
Charette cyclopropanation14a,44 protocol to achieve the
same. Access to ring C of ambruticin S was realized in a
variety of ways including ring-closing metathesis (Martin,
ꢀ30a,b
Lee, Marko
) and catalytic (Jacobsen) or noncatalytic
(Kende, Donaldson30c) hetero-Diels-Alder cyclization. The
three trans-configured olefinic appendages were introduced
by a combination of well-established methods.5 Of the four
total syntheses of ambruticin S, arguably that of Liu and
Jacobsen is most innovative in terms of conceptual design.
Other approaches to various subunits have been reviewed by
5
^
Michelet and Genet.
Inherent in our design strategy toward the total synthesis
of ambruticin S was the desire to introduce flexibility in the
nature of the components to be assembled with the intention
to probe structure activity relationships of analogues. Having
chosen a lactone branching strategy to create the C-glycoside
corresponding to ring A, we found it practical to take
advantage of the two-step synthesis of the 4-deoxy glycoside
9 from readily available methyl R-D-glucopyranoside (2)
could be designed. Therefore, we decided to generate new
crystals of triformate ester 47 to perform another X-ray anal-
ysis. Thus, treatment of triol 46 with N-formyl benzotriazole
((N-CHO)Bt) gave 47 in 85% yield. Recrystallization from
ethanol provided single crystals suitable for X-ray analysis
(Figure 3).38
(40) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37,
2091–2096.
(41) Li, H.; Jiang, X.; Ye, Y.-h.; Fan, C.; Romoff, T.; Goodman, M. Org.
Lett. 1999, 1, 91–93.
(42) Misumi, A.; Iwanaga, K.; Furuta, K.; Yamamoto, H. J. Am. Chem.
Soc. 1985, 107, 3343–3345.
(43) (a) Doyle, M. P.; Austin, R. E.; Bailey, S. A.; Dwyer, M. P.; Dyatkin,
A. B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras, S.; Oalmann, C. J.; Pieters,
R. J.; Protopopova, M. N.; Raab, C. E.; Roos, G. H. P.; Zhou, Q.-L.; Martin,
S. F. J. Am. Chem. Soc. 1995, 117, 5763–5775. (b) Doyle, M. P.; Pieters, R. J.;
While analogues of ambruticin S with variations in sub-
stituents on ring A still exhibit antifungal activity,12 little is
known regarding the functional requirements of the other
subunits. We therefore prepared a series of truncated analo-
gues of ambruticin S based on the ring C subunit, as a
common scaffold, replacing the cyclopropane and ring A
€
Martin, S. F.; Austin, R. E.; Oalmann, C. J.; Muller, P. J. Am. Chem. Soc.
1991, 113, 1423–1424.
(44) (a) Charette, A. B.; Lemay, J. Angew. Chem., Int. Ed. Engl. 1997, 36,
1090–1092. (b) Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am.
Chem. Soc. 1998, 120, 11943–11952.
(38) See Supporting Information.
(39) (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523–2584.
(b) Speicher, A.; Bomm, V.; Eicher, T. J. Prakt. Chem. 1996, 338, 588–590.
(c) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
(d) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
J. Org. Chem. Vol. 75, No. 16, 2010 5607

Hanessian et al.
JOCArticle
FIGURE 4. Overview of the four previous syntheses of ambruticin S and key bond construction strategies.
FIGURE 5. Formation of syn-dihydropyran 23 from diols 4.
(Scheme 1).45 Intermediates 11 and 12 were viewed as pot-
ential precursors to ring A-modified analogues. Likewise,
the 6-endo-trig Lewis acid mediated cycloetherification ap-
proach to ring C would allow the synthesis of a variety of
substituted analogues (Scheme 3).17 The diol precursor to
ring C was conveniently prepared from the commercially
available glycidol 7. Remarkably, the stereochemistry of the
allylic alcohol was of no consequence in the cyclization
reaction, strongly suggesting a cationic mechanism. Indeed,
subjecting the individual diastereomers of 4 to the conditions
the observed syn-isomer 23 is formed in high yields even
though it is subject to A1,2 strain (Figure 5). The results can
be rationalized considering a transition state model A lead-
ing to the preponderant formation of the syn-isomer 23,
despite the inherent A1,2 strain effect experienced by the jux-
taposition of the vicinal methyl and ethyl groups. Although
A
1,2 strain can be avoided in transition state model B, there
may be a more significant energetic penalty associated with
a 1,3-diaxial interaction, hence the prevalence of the syn-
isomer 23.
of cycloetherification (BF3 OEt2 in CH2Cl2) afforded the
3
Our elaboration of the trisubstituted cyclopropane ring B
was admirably suited to test a methodology relying on the
highly stereocontrolled conjugate addition of a chiral phos-
phonamide lithium anion to an R,β-unsaturated ester fol-
lowed by an intramolecular attack of the resulting enolate
upon the intermediate allylic chloride.13 Remarkably, the
reaction furnished a single diastereomer 27, which was
same product 23 in excellent yields.46 It should be noted that
(45) For a related approach, see: Hanessian, S.; Mi, X. Synlett 2010,
761–764.
(46) For a recent Lewis acid mediated synthesis of 2,6-disubstituted
ꢀ
pyrans, see: Guerinot, A.; Serra-Muns, A.; Gnamm, C.; Bensoussan, C.;
Reymond, S.; Cossy, J. Org. Lett. 2010, 12, 1808–1811.
5608 J. Org. Chem. Vol. 75, No. 16, 2010

Hanessian et al.
JOCArticle
converted to the crystalline aldehyde 28. The formation of
trans-olefins linking rings C and B was achieved by relying on
phosphonamide anion methodology, which provided a prac-
tical solution in delivering the trans-olefins 32 as a prepon-
derant isomer and 38 quasi-exclusively. Extension to the
acetylene 40 was achieved uneventfully, following which the
iodide 42 was converted to phosphonamide 3. Conversion to
its lithium anion and condensation with the methyl ketone 25
gave a 6:1 E/Z ratio of chromatographically separable
olefins albeit in modest yields with recovery of starting
materials. In our hands, a corresponding Julia-Kocienski
olefination47 employing a phenyltetrazole sulfone gave, at
best, a 3:1 ratio of olefins. Employing the classical Julia-
Lythgoe conditions48 reportedly gave an E/Z ratio of 95:1.30a
The fully elaborated acetylene 37 was then used as the C-
glycosylation component to access the coupled product 44.
Further functional group manipulations led to ambruticin S
(1a) in excellent yields.
90 psi for 24 h. Raney-nickel was filtered off, and the filtrate was
concentrated in vacuo. Brine was added to the residue and the
aqueous layer was extracted with warm ethyl acetate. The
combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo. The residue thus obtained was purified by col-
umn chromatography (hexanes/EtOAc, 1:1) to give 9 as a white
solid (596 mg, 70%): mp 106-107 °C;20 1H NMR (400 MHz,
CDCl3) δ 4.85 (d, J = 4.0 Hz, 1H), 3.99 (ddt, J = 17.2, 5.6,
2.0 Hz, 1H), 3.89 (ddd, J = 11.4, 9.2, 4.8 Hz, 1H), 3.58 (d, J =
5.2 Hz, 2H), 3.47 (s, 3H), 3.43 (dd, J = 9.2, 3.6 Hz, 1H), 2.10
(ddd, J = 12.4, 4.8, 2.0 Hz, 1H), 1.53 (q, J = 12.0 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 99.3, 73.9, 68.3, 67.6, 55.1, 46.2,
35.1; IR (film, NaCl) 3306, 2955, 2920, 1645, 1468, 1451, 1382,
1355, 1339, 1190, 1130, 1081, 1047, 906, 775, 729 cm-1;[R]D þ159.0°
(c 0.50, CH3OH); LRMS (ESI) calcd for C7H14ClO4 (M þ H)þ
196.1, 198.0, found 196.2, 198.1.
Methyl 6-Chloro-4,6-dideoxy-2,3-di-O-benzyl-r-D-glucopyra-
noside (10). Sodium hydride (500 mg of a 60% dispersion in
mineral oil, 12.5 mmol) was added portionwise to a solution of
diol 9(980 mg, 5.0 mmol) and benzyl bromide (1.50 mL, 12.5 mmol)
in DMF (12.5 mL) at 0 °C. The resulting suspension was allowed
to warm up to room temperature and stirred overnight. The
reaction mixture was then diluted with ether, and saturated
NH4Cl solution was added carefully. The organic layer was
separated and washed with saturated NH4Cl solution, brine
(10 mL), and dried (Na2SO4). Concentration in vacuo gave a
yellowish oil, which was purified by column chromatography
(hexanes/EtOAc, 4:1) to yield 1.80 g (96%) of dibenzyl ether 10
as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.41-7.30 (m,
10H), 4.87 (d, J = 12.0 Hz, 1H), 4.79 (d, J = 11.6 Hz, 1H),
4.73-4.69 (m, 3H), 4.00-3.94 (m, 2H), 3.53 (d, J = 5.2 Hz, 2H),
3.50 (dd, J = 9.2, 3.6 Hz, 1H), 3.42 (s, 3H), 2.16 (ddd, J = 12.8,
4.8, 2.0 Hz, 1H), 1.52 (q, J = 12.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 138.4, 138.1, 128.0, 128.0, 127.7, 127.4, 127.3, 127.2,
98.7, 79.9, 74.5, 73.0, 72.3, 67.0, 54.9, 46.3, 34.5; IR (film, NaCl)
3030, 2919, 1496, 1454, 1372, 1354, 1199, 1182, 1111, 1047, 999,
914, 737, 697 cm-1; [R]D þ47.4° (c 2.00, CHCl3); HRMS (ESI)
calcd for C21H25ClNaO4 (M þ Na)þ 399.1334, found 399.1330.
Methyl 6-C-(1-Propenyl)-4,6-dideoxy-2,3-di-O-benzyl-r-D-
glucopyranoside (11). To a solution of dibenzyl ether 10 (1.00 g,
2.7 mmol) in toluene (15 mL) was added allyltriphenyltin
(8.34 g, 21.3 mmol) and 1,10-azobis(cyclohexanecarbonitrile)
(714 mg, 2.9 mmol). The reaction mixture was heated in a sealed
tube to 150 °C for 1 h. Evaporation of all volatiles gave a residue,
which was redissolved in ethyl acetate and filtered from any
insoluble material. The syrup obtained after concentration
in vacuo was purified by flash chromatography (hexanes/ethyl
acetate, 95:5) to provide 427 mg (43%) of starting material 10
In summary, we have accomplished an enantioselective,
highly convergent total synthesis of ambruticin S (1a) in 17
steps and 5% yield (15% based on recovered starting
material) in the longest linear sequence starting from glycidol
7. With an emphasis on late stage couplings of highly
advanced fragments, our approach provides a flexible and
convenient access to a variety of ambruticin derivatives.
Experimental Section
Methyl 4,6-Dichloro-4,6-dideoxy-r-D-glucopyranoside (8). To
a suspension of methyl R-D-glucopyranoside (2) (1.0 g, 5.15
mmol) in pyridine (4.4 mL, 54.4 mmol) and chloroform (10 mL)
was added dropwise under vigorous stirring sulfuryl chlo-
ride (2.6 mL, 32.4 mmol) at -40 °C. The reaction mixture was
stirred for 3 h at that temperature, after which it was allowed to
warm to room temperature and stirred overnight. The mixture
was diluted with chloroform and washed with 10% aqueous
H2SO4 solution, followed by saturated NaHCO3 solution,
water, and brine. The organic phase was dried (Na2SO4) and
concentrated in vacuo to yield an oily residue, which was
dissolved in methanol (15 mL). To this mixture was added a
solution of sodium iodide (1.12 g, 7.5 mmol) in MeOH/water
(2 mL, 1:1). The resulting solution was left to stand for 8 h and
then neutralized with NaHCO3. Evaporation of all volatiles
gave a residue, which was extracted with hot chloroform and hot
ethyl acetate. The combined organic layers were dried (MgSO4)
and recrystallized (ethyl acetate/hexanes) to give dichloride 8 as
colorless needles (1.02 g, 86%): mp 156-157 °C;19 1H NMR
(400 MHz, CDCl3) δ 4.73 (d, J = 5.2 Hz, 1H), 4.45 (d, J = 4.8
Hz, 1H), 4.15 (t, J = 4.86 Hz, 1H), 3.99 (dd, J = 13.2, 4.8 Hz,
1H), 3.78 (dd, J = 13.2, 5.2 Hz, 1H), 3.68 (dd, J = 7.6, 2.8 Hz,
2H), 3.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 101.6, 71.0,
70.0, 69.7, 65.0, 55.9, 44.5; IR (film, NaCl) 3429, 2067, 1641,
1
and 528 mg (52%) of alkene 11 as a colorless oil: H NMR
(400 MHz, CDCl3) δ 7.42-7.30 (m, 10H), 5.89-5.79 (m, 1H),
5.06 (d, J = 16.8 Hz, 1H), 5.00 (d, J = 10.4 Hz, 1H), 4.87 (d, J =
12.0 Hz, 1H), 4.80 (d, J = 11.6 Hz, 1H), 4.73 (d, J = 12.0 Hz,
1H), 4.71 (d, J = 11.6 Hz, 1H), 4.68 (d, J = 3.6 Hz, 1H), 3.94
(ddd, J = 11.2, 9.6, 4.8 Hz, 1H), 3.78-3.72 (m, 1H), 3.49 (dd,
J = 9.2, 3.6 Hz, 1H), 3.39 (s, 3H), 2.28-2.19 (m, 1H), 2.15-2.06
(m, 2H), 1.65-1.53 (m, 2H), 1.60 (q, J = 11.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 138.6, 138.3, 137.8, 128.0, 127.7,
127.3, 127.3, 127.1, 114.4, 98.6, 80.4, 75.0, 72.9, 72.1, 66.2, 54.7,
37.2, 34.2, 29.5; IR (film, NaCl) 3390, 2928, 2855, 1721, 1496,
1454, 1381, 1355, 1273, 1195, 1114, 1048, 930, 913, 738, 698
cm-1; [R]D þ41.7° (c 2.26, CHCl3); HRMS (ESI) calcd for
C24H30NaO4 (M þ Na)þ 405.2036, found 405.2037.
1363, 1261, 1196, 1135, 1076, 1045, 1032, 986 cm-1; [R]D
þ
187.8° (c 2.00, H2O); LRMS (ESI) calcd for C7H13Cl2O4 (M þ
H)þ 231.0, 233.0, found 231.1, 233.1.
Methyl 6-Chloro-4,6-dideoxy-r-D-glucopyranoside (9). A so-
lution of dichloride 8 (1.00 g, 4.35 mmol) in MeOH (30 mL)
containing triethylamine (1.3 mL, 9.3 mmol) and Raney-nickel
(Raney2800, 2.00 g) was subjected to a hydrogen pressure of
Methyl 6-C-(2E-Propenyl)-4,6-dideoxy-2,3-di-O-benzyl-r-D-
glucopyranoside (12). To a solution of alkene 11 (833 mg,
2.18 mmol) and triethylamine (0.43 mL, 3.05 mmol) in methanol
(75 mL) was added Grubbs second generation catalyst (187 mg,
0.22 mmol), and the reaction mixture was heated to 60 °C for
18 h. After removal of all volatiles in vacuo, the residue thus
(47) (a) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563–2585.
(b) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998,
26–28.
(48) (a) Kocienski, P. J.; Lythgoe, B.; Ruston, S. J. Chem. Soc., Perkin
Trans. 1 1978, 829–834. (b) Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 14,
4833–4836.
J. Org. Chem. Vol. 75, No. 16, 2010 5609

Hanessian et al.
JOCArticle
obtained was purified by flash chromatography (hexanes/
EtOAc, 95:5) to yield 700 mg (84%) of alkene 12 as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 7.42-7.29 (m, 10H), 5.57-
5.41 (m, 2H), 4.85 (d, J = 12.4 Hz, 1H), 4.75 (d, J = 11.6 Hz,
1H), 4.74-4.67 (m, 3H), 3.98-3.92 (m, 1H), 3.78-3.72 (m, 1H),
3.50 (dd, J = 11.2, 3.6 Hz, 1H), 3.40 (s, 3H), 2.28-2.21 (m, 1H),
2.17-2.08 (m, 2H), 1.74-1.64 (m, 3H), 1.39 (q, J = 11.6 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 138.7, 138.3, 128.0, 127.7,
127.4, 127.3, 127.2, 127.1, 126.4, 98.6, 80.4, 75.1, 72.9, 72.1, 66.9,
54.6, 38.1, 36.6, 17.6; IR (film, NaCl) 3499, 2926, 2872, 1722,
(m, 10H), 4.86 (d, J = 12.0 Hz, 1H), 4.78 (d, J = 11.6 Hz, 1H),
4.72 (d, J = 11.6 Hz, 1H), 4.70 (d, J = 12.0 Hz, 1H), 4.66 (d, J =
2.4 Hz, 1H), 4.00-3.91 (m, 2H), 3.79-3.76 (m, 2H), 3.48 (dd,
J = 9.6, 3.2 Hz, 1H), 3.38 (s, 3H), 2.07 (ddd, J = 12.8, 4.8,
2.0 Hz, 1H), 1.78-1.72 (m, 2H), 1.48 (q, J = 12.0 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 138.5, 138.1, 128.0, 128.0, 127.6,
127.4, 127.3, 127.1, 98.6, 80.1, 74.8, 73.0, 72.2, 66.7, 60.5, 54.8,
37.7, 36.9; IR (film, NaCl) 3435, 3062, 3030, 2923, 1604, 1496,
1454, 1356, 1200, 1186, 1099, 1048, 996, 911, 736, 698 cm-1; [R]D
39.1° (c 3.00, CHCl3); HRMS (ESI) calcd for C22H28NaO5
(M þ Na)þ 395.1829, found 395.1820.
þ
1496, 1454, 1372, 1358, 1276, 1190, 1106, 1048, 733, 698 cm-1
;
[R]D þ35.1° (c 1.66, CHCl3); HRMS (ESI) calcd for C24H30-
Methyl 6-C-(Benzyloxymethyl)-4,6-dideoxy-2,3-di-O-benzyl-
r-D-glucopyranoside (14). To a 0 °C solution of alcohol 13
(320 mg, 0.86 mmol) and benzyl bromide (0.52 mL, 4.3 mmol)
in DMF (7 mL) was added sodium hydride (86 mg of a 60%
dispersion in mineral oil, 2.15 mmol). The reaction mixture was
allowed to warm to room temperature and stirred overnight.
After diluting the mixture with diethyl ether, it was quenched by
careful addition of saturated NH4Cl solution. The organic layer
was separated, washed with saturated NH4Cl solution and
brine, and dried (Na2SO4). Concentration in vacuo gave a
residue that was purified by flash chromatography (hexanes/
EtOAc, 4:1) to yield 364 mg (92%) of tribenzyl ether 14 as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.45-7.28 (m,
15H), 4.89 (d, J = 12.2 Hz, 1H), 4.80 (d, J = 11.7 Hz, 1H),
4.74-4.68 (m, 2H), 4.68 (d, J = 3.6 Hz, 1H), 4.53 (br s, 2H),
3.97-3.91 (m, 2H), 3.66-3.57 (m, 2H), 3.51 (dd, J = 9.4, 3.6 Hz,
1H), 3.38 (s, 3H), 2.11 (ddd, J = 12.8, 5.0, 2.1 Hz, 1H),
1.84-1.78 (m, 2H), 1.43 (q, J = 12.1 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 138.6, 138.3, 138.0, 128.0, 127.97, 127.6, 127.3,
127.29, 127.3, 127.2, 127.1, 98.5, 80.3, 75.1, 72.9, 72.7, 72.1, 66.3,
63.8, 54.5, 37.3, 35.1; IR (film, NaCl) 3062, 3030, 2922, 2861,
1604, 1586, 1496, 1454, 1357, 1245, 1204, 1188, 1099, 1048, 913,
783, 735, 698 cm-1; [R]D þ40.0° (c 1.00, CHCl3); HRMS (ESI)
calcd for C29H34O5Na (M þ Na)þ 485.2299, found 485.2275.
(3R,4S,6R)-3,4-Bis(benzyloxy)-6-(2-(benzyloxy)ethyl)-tetra-
hydropyran-2-one (15). A solution of tribenzylether 14 (600 mg,
1.3 mmol) in a mixture of acetic acid (130 mL) and diluted
sulfuric acid (2 M, 34 mL) was heated for 18 h to 80 °C. After
removal of all volatiles in vacuo, the residue was dissolved in
dichloromethane (150 mL). The organic phase was washed with
saturated NaHCO3 and brine, dried (MgSO4), and concentrated
in vacuo. The residue thus obtained was purified by flash chro-
matography (hexanes/EtOAc, 7:3) to give the hemiacetal as a
NaO4 (M þ Na)þ 405.2036, found 405.2041.
Methyl 6-C-(Hydroxymethyl)-4,6-dideoxy-2,3-di-O-benzyl-
r-D-glucopyranoside (13). Method A (from 12): To a stirred
solution of OsO4 (0.35 mL of a 2.5 wt % solution in t-BuOH,
0.0276 mmol) and N-methylmorpholine-N-oxide (485 mg, 4.14
mmol) in THF and water (15 mL, 9:1) was added a solution of
alkene 12 (527 mg, 1.38 mmol) in THF (8 mL). The reaction
mixture was stirred overnight and then cooled to 0 °C.
A solution of NaIO4 (886 mg, 4.14 mmol) in THF (4 mL) and
water (4 mL) was added dropwise to the mixture. After stirring
for 30 min at 0 °C, ethyl acetate was added, and the solution was
filtered through a pad of Celite. The filtrate was washed with
saturated Na2S2O3 solution, water, and brine, dried (MgSO4),
and concentrated in vacuo. The crude aldehyde thus obtained
was then dissolved in ethanol (16 mL) and water (4 mL), to
which NaBH4 (131 mg, 3.45 mmol) was added in one portion at
0 °C. The reaction mixture was allowed to warm to room tem-
perature and stirred for 1 h. After addition of ice-cold water, the
aqueous layer was extracted with ethyl acetate. The organic
phase was dried (MgSO4) and concentrated in vacuo. Purifica-
tion of the crude alcohol by flash chromatography (hexanes/
EtOAc, 3:2) afforded 335 mg (65%) of 13 as a colorless oil. In
addition, 128 mg (24%) of starting material 12 was recovered.
Method B (from 16): To a 0 °C solution of nitrile 16 (184 mg,
0.5 mmol) in toluene (5 mL) was added DIBAL-H (0.6 mL of a
1 M in hexanes, 0.6 mmol). After stirring for 30 min at that
temperature, the reaction mixture was quenched by addition of
methanol. Aqueous HCl solution (2 N, 1.0 mL) was then added,
and the mixture stirred for 45 min and filtered. After phase
separation of the filtrate, the aqueous layer was extracted with
diethyl ether. The combined organic phase was washed with 2 N
HCl solution, saturated NaHCO3 solution, and water, dried
(Na2SO4), and concentrated in vacuo to afford a colorless syrup.
This residue was dissolved in methanol (5 mL), and sodium
borohydride (38 mg, 1.0 mmol) was added to it. The mixture was
stirred at room temperature for 30 min, before excess sodium
borohydride was destroyed by the addition of acetone. Evapora-
tion in vacuo gave a residue, which was coevaporated three times
with methanol to remove boron byproduct. The residue was
dissolved in ethyl acetate, washed with 2 N HCl solution,
saturated NaHCO3 solution, and water, dried (Na2SO4), and
concentrated in vacuo. Purification by flash chromatography
(hexanes/EtOAc, 1:1) afforded 125 mg (67%) of alcohol 13 as a
colorless oil.
1
colorless oil (524 mg, 90%): H NMR (400 MHz, CDCl3) δ
7.38-7.30 (m, 15H), 5.23 (d, J = 3.6 Hz, 1H), 4.95-4.85 (m,
2H), 4.76-4.69 (m, 2H), 4.61-4.58 (m, 1H), 4.52-4.50 (m, 2H),
3.66-3.56 (m, 3H), 3.52-3.47 (m, 1H), 2.16-2.06 (m, 1H),
1.89-1.77 (m, 2H), 1.49-1.38 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 138.4, 138.3, 138.2, 138.1, 138.09, 137.9, 128.1, 128.0,
127.7, 127.6, 127.44, 127.4, 127.36, 127.3, 127.24, 127.2, 127.17,
97.0, 91.7, 83.6, 80.2, 78.2, 74.9, 74.5, 72.9, 72.6, 71.7, 71.7, 68.4,
66.2, 65.8, 64.6, 53.0, 36.6, 35.0; IR (film, NaCl) 3392, 3062,
3030, 2921, 2862, 1496, 1454, 1362, 1207, 1096, 911, 736, 697
cm-1; [R]D þ23.1° (c 2.00, CHCl3); LRMS (ESI) calcd for
C28H32NaO5 (M þ Na)þ 471.2, found 471.2.
Method C (from 19): To a solution of 19 (545 mg, 1.54 mmol)
in THF (10 mL) was added a 9-BBN (24.6 mL of a 0.5 M
solution in THF, 12.3 mmol), and the reaction mixture was
stirred overnight at room temperature. Hydrogen peroxide (3.2
mL of a 30% aqueous solution, 30.8 mmol) and 3 M NaOH
solution (5.1 mL, 15.4 mmol) were then added, and the resulting
mixture was heated for 2 h at 55 °C. After phase separation, the
aqueous phase was extracted with EtOAc. The combined or-
ganic phase was washed with water and brine, dried (MgSO4),
and concentrated in vacuo. The residue was purified by flash
chromatography (hexanes/EtOAc, 2:1) to give 516 mg (90%) of
13 as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.40-7.30
To a solution of the hemiacetal (400 mg, 0.89 mmol) in
CH2Cl2 (10 mL) was added 4 A molecular sieves (1.0 g), and
the resulting mixture was stirred for 15 min. It was then was
cooled to 0 °C, PCC (880 mg, 4.02 mmol) was added, and the
reaction mixture was stirred for 2 h at 0 °C. After dilution with
diethyl ether (10 mL) and pentane (10 mL), the mixture was
filtered over Celite. The filter cake was washed with Et2O/
pentane (1:1), and the combined filtrate was concentrated
in vacuo. Purification of the residue by flash chromatography
(hexanes/EtOAc, 4:1) yielded 280 mg (70%) of lactone 15 as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.45-7.31 (m,
15H), 50.7 (d, J = 11.6 Hz, 1H), 4.77 (d, J = 11.6 Hz, 1H),
5610 J. Org. Chem. Vol. 75, No. 16, 2010

Hanessian et al.
JOCArticle
was dried (Na2SO4) and concentrated in vacuo. Purification
4.69-4.60 (m, 3H), 4.56 (d J = 11.8 Hz, 1H), 4.51 (d, J = 11.8
Hz, 1H), 4.07 (d, J = 6.8 Hz, 1H), 3.96-3.90 (m, 1H), 3.74-3.67
(m, 1H), 3.65-3.60 (m, 1H), 2.33 (ddd, J = 14.0, 5.6, 3.2 Hz,
1H), 2.06-1.89 (m, 2H), 1.77 (q, J = 12.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 169.9, 137.8, 137.4, 136.9, 128.1, 128.07,
128.0, 127.6, 127.4, 127.3, 127.28, 79.0, 75.3, 73.7, 73.3, 72.8,
71.6, 65.3, 35.5, 34.6; IR (film, NaCl) 3063, 3030, 2924, 2865,
1745, 1496, 1454, 1392, 1212, 1179, 1101, 1028, 911, 737, 698
cm-1; [R]D þ69.4° (c 2.00, CHCl3); HRMS (ESI) calcd for
C28H31O5 (M þ H)þ 447.2166, found 447.2155.
of the residue by flash chromatography (hexanes/EtOAc, 10:1
to 8:1) yielded 1.51 g (76%) of 19 as a colorless oil: H NMR
1
(400 MHz, CDCl3) δ 7.40-7.26 (m, 10H), 5.82 (ddd, J = 17.6,
9.6, 6.0 Hz, 1H), 5.76 (dt, J = 17.2, 1.6 Hz, 1H), 5.14 (dt, J =
10.4, 1.2 Hz, 1H), 4.86 (d, J = 12.0 Hz, 1H), 4.78 (d, J =
12.4 Hz, 1H), 4.72 (d, J = 11.6 Hz, 1H), 4.70 (d, J = 11.4 Hz,
1H), 4.69 (d, J = 3.6 Hz, 1H), 4.21 (dd, J = 11.6, 5.6 Hz, 1H),
3.97 (ddd, J = 11.2, 9.2, 4.8 Hz, 1H), 3.49 (dd, J = 5.6, 3.6 Hz,
1H), 3.39 (s, 3H), 2.14 (ddd, J = 12.8, 4.8, 2.0 Hz, 1H), 1.49 (q,
J = 12.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 138.7, 138.4,
138.3, 128.2, 127.9, 127.6, 128.5, 127.4, 115.7, 99.0, 80.3, 75.1,
73.2, 72.4, 67.6, 55.1, 37.1; [R]D þ34.1° (c 0.50, CHCl3); IR (film,
NaCl) 3063, 3030, 2922, 2854, 1683, 1650, 1604, 1496, 1454,
1358, 1259, 1192, 1099, 1044, 924, 813, 733, 696 cm-1; HRMS
(ESI) calcd for C22H26NaO4 (M þ Na)þ 377.1723, found
377.1722.
Methyl 6-Cyano-4,6-dideoxy-2,3-di-O-benzyl-r-D-glucopyra-
noside (16). To a solution of chloride 10 (376 mg, 1.0 mmol) in
N-methylpyrrolidone (10 mL) were added NaCN (490 mg,
10.0 mmol) and n-Bu4NI (3.70 g, 10.0 mmol). The reaction mix-
ture was heated to 60 °C for 48 h, after which it was diluted with
ether and saturated NaHCO3 solution was added. The organic
layer was separated, washed with brine, dried (Na2SO4), and
concentrated in vacuo. Purification of the residue by flash
chromatography (hexanes/EtOAc, 4:1) gave as the first fraction
154 mg (41%) of chloride 10 and as the second fraction 136 mg
2-((E)-Pent-2-en-2-yl)-1,3-dithiane (20). A mixture of 1,3-pro-
panedithiol (7.50 mL, 75.0 mmol), boron trifluoride etherate
(9.5 mL, 75.0 mmol), and glacial acetic acid (18.0 mL, 0.32 mol)
in dichloromethane (125 mL) was cooled to -20 °C. To the
vigorously stirred mixture was added slowly a solution of
2-methyl-2-pentenal (8.55 mL, 75.0 mmol) in CH2Cl2 (50 mL)
while maintaining the temperature between -20 to -15 °C. The
reaction mixture was stirred for 1 h at -20 °C and then siphoned
into ice-cold 10% aqueous KOH solution. The temperature
should be maintained below 5 °C during the quench. After
dilution with diethyl ether, the organic phase was separated,
washed with 10% KOH, water (3ꢀ), brine, and dried (Na2SO4).
Concentration in vacuo yielded 13.9 g (99%) of the crude dithiane
20 as a 10:1 mixture of E/Z isomers. The dithiane was used with-
1
(37%) of 16 as a colorless oil: H NMR (400 MHz, CDCl3) δ
7.38-7.26 (m, 10H), 4.85 (d, J= 12.4 Hz, 1H), 4.77 (d, J= 11.6 Hz,
1H), 4.69 (d, J = 12.4 Hz, 1H), 4.68 (d, J = 11.6 Hz, 1H), 4.66
(d, J = 3.6 Hz, 1H), 4.03-3.90 (m, 2H), 3.48 (dd, J = 9.6,
3.6 Hz, 1H), 3.40 (s, 3H), 2.52-2.50 (m, 2H), 2.16 (ddd, J =
12.8, 5.2, 2.4 Hz, 1H), 1.50 (q, J = 12.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 138.4, 138.1, 128.3, 128.28, 127.9, 127.7,
127.5, 116.7, 99.0, 79.8, 74.3, 73.3, 72.6, 63.1, 55.4, 36.5, 23.7; IR
(film, NaCl) 3063, 3031, 2925, 2252, 1722, 1602, 1496, 1454,
1356, 1275, 1190, 1107, 1044, 919, 804, 739, 714, 699 cm-1; [R]D
þ
23.2° (c 1.75, CHCl3); HRMS (ESI) calcd for C22H26NO4 (M þ
H)þ 368.1856, found 368.1838.
1
out further purification in the next step: H NMR (400 MHz,
(2S,3R,4S,6S)-3,4-Bis(benzyloxy)-2-methoxy-6-vinyl-tetrahydro-
2H-pyran (19). A mixture of methyl 2,3-di-O-benzyl-4-dexoy-β-
L-threo-hex-4-endodialdopyranoside (18) (500 mg, 1.41 mmol)
and 5% palladium on barium carbonate (540 mg) in methanol
(16 mL) was stirred under an atmosphere of hydrogen (14.5 psi)
for 12 h. Palladium was then removed by filteration through a
pad of Celite, the filtrate was concentrated in vacuo to a vol-
ume of approximately 8 mL, and 1,8-diazabicycloundec-7-ene
(1.2 mL, 8.5 mmol) was added to it. The reaction mixture was
stirred for additional 12 h, before it was concentrated to dryness
in vacuo. The residue was dissolved in dichloromethane, washed
with 2 M aqueous HCl solution, saturated NaHCO3 solution,
and brine, dried (Na2SO4), and concentrated in vacuo. Purifica-
tion of the residue by flash chromatography (hexanes/EtOAc,
4:1 to 3:1) gave 432 mg (86%) of methyl 2,3-di-O-benzyl-4-
deoxy-R-D-xylo-hexodialdopyranoside as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 9.62 (s, 1H), 7.34-7.29 (m, 10 H),
4.87 (d, J = 12.4 Hz, 1H), 4.77-4.74 (m, 3H), 4.69 (d, J = 2.0
Hz, 1H), 4.18 (dd, J = 12.4, 2.8 Hz, 1H), 3.98 (ddd, J = 10.8,
9.2, 5.2 Hz, 1H), 3.48 (dd, J = 9.2, 3.2 Hz, 1H), 3.41 (s, 3H), 2.36
(ddd, J = 13.2, 5.2, 2.8 Hz, 1H), 1.48 (q, J = 12.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 199.5, 138.3, 138.1, 128.3, 128.2,
127.9, 127.7, 127.5, 99.3, 79.7, 74.5, 73.5, 72.4, 72.2, 55.6, 31.6;
[R]D þ35.0° (c 1.05, CHCl3); LRMS (ESI) calcd for C21H25O5
(M þ H)þ 357.2, found 357.1.
CDCl3, major isomer) δ 5.65-5.61 (m, 1H), 4.56 (s, 1H),
2.98-2.90 (m, 3H), 2.87-2.81 (m, 2H), 2.08-2.01 (m, 2H),
1.78 (d, J = 3.1 Hz, 4H), 0.97 (t, J = 7.5 Hz, 3H); 13C NMR (100
MHz, CDCl3, major isomer) δ 132.3, 131.6, 55.3, 31.6, 25.5,
21.3, 14.9, 13.7; IR (film, NaCl) 2957, 2935, 2891, 1457, 1424,
1422, 1378, 1275, 1172, 745, 679 cm-1; LRMS (ESI) calcd for
C9H17S2 (M þ H)þ 189.1, found 189.1.
(R,E)-1-(Benzyloxy)-3-(2-(pent-2-en-2-yl)-1,3-dithian-2-yl)-
propan-2-ol (21). To a -78 °C solution of dithiane 20 (11.5 g,
61.0 mmol) in THF (60 mL) was added n-BuLi (33.3 mL of a
1.6 M solution in hexanes, 53.3 mmol) dropwise. The reaction
mixture was stirred for 5 min at that temperature, warmed to
0 °C, and stirred for 30 min, before it was recooled to -78 °C.
A solution of (R)-benzyl glycidol (7) (5.0 g, 30.5 mmol) in THF
(40 mL) was then added slowly. The reaction mixture was stirred
for 30 min and quenched by addition of saturated NH4Cl
solution. The aqueous layer was extracted with EtOAc, and
the combined organic phase was dried (Na2SO4) and concen-
trated. The residue was purified by flash chromatography
(hexanes/EtOAc, 10:1 to 4:1) to give 10.5 g (97%) of dithiane
1
adduct 21 as a colorless oil: H NMR (400 MHz, CDCl3) δ
7.39-7.25 (m, 5H), 6.05 (tq, J = 7.1, 1.2 Hz, 1H), 4.55 (s, 2H),
4.07-3.98 (m, 1H), 3.44 (dd, J = 9.6, 4.8 Hz, 1H), 3.39 (dd, J =
9.6, 6.3 Hz, 1H), 2.88-2.65 (m, 5H), 2.25-2.04 (m, 4H),
2.00-1.88 (m, 2H), 1.77 (d, J = 0.6 Hz, 3H), 1.04 (t, J = 7.5
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 138.0, 133.8, 132.5,
128.3, 127.6, 127.6, 74.1, 73.2, 67.5, 58.3, 42.8, 27.3, 27.2, 25.0,
22.1, 14.0, 13.5; IR (film, NaCl) 2957, 2935, 2909, 2870, 1453,
1422, 1100, 1089, 736, 699 cm-1; [R]D -6.3° (c 1.58, CHCl3);
HRMS (ESI) calcd for C19H28NaO2S2 (M þ Na)þ 375.1423,
found 375.1434.
(R,E)-1-(Benzyloxy)-2-((tert-butyldimethylsilyl)oxy)-5-methyloct-
5-en-4-one (22). A cold (0 °C) solution of dithiane adduct 21
(10.4 g, 29.5 mmol) and 2,6-lutidine (8.6 mL, 74.1 mmol) in
CH2Cl2 (380 mL) was treated withTBSOTf (13.6mL, 59.2 mmol)
for 1 h. The reaction mixture was quenched with saturated
To a suspension of methyltriphenylphosphonium bromide
(6.0 g, 16.9 mmol) in THF (60 mL) was added slowly n-BuLi
(10.5 mL of a 1.6 M solution in hexanes, 16.9 mmol) at -78 °C.
After 10 min of stirring at that temperature, the resulting
solution was warmed to 0 °C and stirred for 1 h. A solution of
methyl 2,3-di-O-benzyl-4-deoxy-R-D-xylo-hexodialdopyrano-
side (2.0 g, 5.6 mmol) in THF (60 mL) was then added slowly
to the ylide at 0 °C. The reaction mixture was allowed to warm to
temperature, stirred overnight, and subsequently quenched by
addition of saturated NH4Cl solution. After extraction of the
aqueous layer with diethyl ether, the combined organic phase
J. Org. Chem. Vol. 75, No. 16, 2010 5611

Hanessian et al.
JOCArticle
NH4Cl solution, the aqueous layer was extracted with CH2Cl2,
and the combined organic phase was dried (Na2SO4) and con-
centrated. The residue was purified by flash chromatography
(hexanes/EtOAc, 20:1 to 9:1) to yield 12.8 g (93%) of the TBS-
ether as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.38-7.32
(m, 4H), 7.32-7.26 (m, 1H), 6.05-6.00 (m, 1H), 4.53 (s, J = 12.2
Hz, 1H), 4.51 (d, J = 12.4 Hz, 1H), 3.99-3.93 (m, 1H), 3.42 (dd,
J = 9.9, 4.1 Hz, 1H), 3.36 (dd, J = 9.9, 5.6 Hz, 1H), 2.86-2.71
(m, 2H), 2.70-2.60 (m, 2H), 2.33 (dd, J = 14.9, 6.4 Hz, 1H),
2.18-2.09 (m, 2H), 2.06 (dd, J = 14.9, 3.9 Hz, 1H), 2.02-1.84
(m, 2H), 1.74 (s, 3H), 1.06 (t, J = 7.5 Hz, 3H), 0.89 (s, 9H), 0.10
(s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.5,
134.1, 131.7, 128.2, 127.5, 127.3, 74.9, 73.1, 68.6, 58.6, 44.1, 27.5,
27.3, 26.0, 25.2, 22.2, 18.1, 14.2, 13.7, -4.0, -4.5; IR (film,
NaCl) 2957, 2928, 2855, 1478, 1456, 1454, 1251, 1097, 1004, 836,
776, 733, 697 cm-1; [R]D -6.4° (c 0.94, CHCl3); LRMS (ESI)
calcd for C25H43O2S2Si (M þ H)þ 467.3, found 467.3.
(2R,6R)-2-(Benzyloxymethyl)-6-ethyl-5-methyl-3,6-dihydro-
2H-pyran (23). To a solution of diol 4 (4.53 g, 17.1 mmol, dr
3.6:1) in CH2Cl2 (220 mL) was added BF3 OEt2 (0.22 mL,
3
1.7 mmol) in one portion. The reaction mixture was stirred for
18 h at room temperature. After evaporation of all volatiles in
vacuo, the residue was purified by flash chromatography
(hexanes/EtOAc, 20:1 to 10:1) to give 3.40 g (81%) of diastereo-
1
merically pure syn-pyran 23 as a colorless oil: H NMR (400
MHz, CDCl3) δ 7.42-7.34 (m, 4H), 7.34-7.27 (m, 1H), 5.60-
5.56 (m, 1H), 4.68 (d, J = 12.3 Hz, 1H), 4.61 (d, J = 12.3 Hz,
1H), 4.12 (br s, 1H), 3.78 (dddd, J = 10.2, 6.4, 3.8, 3.8 Hz, 1H),
3.60 (dd, J = 10.3, 6.4 Hz, 1H), 3.50 (dd, J = 10.3, 4.2 Hz, 1H),
2.10-1.88 (m, 2H), 1.83 (ddq, J = 14.7, 7.4, 3.6 Hz, 1H), 1.63 (br
s, 3H), 1.54 (ddq, J = 14.2, 7.2, 7.2 Hz, 1H), 0.95 (t, J = 7.3 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 138.5, 135.4, 128.3, 127.6,
127.4, 120.1, 77.9, 73.3, 73.2, 72.8, 28.1, 25.5, 19.0, 8.4; IR (film,
NaCl) 2964, 2934, 2858, 1454, 1368, 1118, 1062, 1028, 1005
cm-1; [R]D þ74.7° (c 1.96, CHCl3); HRMS (ESI) calcd for
C16H22NaO2 (M þ Na)þ 269.1512, found 269.1514.
To a solution of the TBS-ether (5.0 g, 10.7 mmol) in CH2Cl2
(140 mL) was added benzeneseleninic acid anhydride (70%, 5.51 g,
10.7 mmol) and propylene oxide (1 mL). The reaction mixture
was stirred for 16 h at room temperature, and solid NaHCO3
(5.0 g) was added. The solvent was removed, and the residue was
purified by flash chromatography (hexane/EtOAc, 10:1 to 4:1)
to give enone 22 (3.20 g, 79%) as a colorless to light yellowish oil:
1H NMR (400 MHz, CDCl3) δ 7.39-7.27 (m, 5H), 6.67 (dt, J =
7.0, 0.9 Hz, 1H), 4.56 (s, 2H), 4.43 (dddd, J = 7.4, 5.2, 5.2,
5.2 Hz, 1H), 3.49 (dd, J = 9.8, 5.1 Hz, 1H), 3.42 (dd, J = 9.7,
5.4 Hz, 1H), 2.95 (dd, J = 15.3, 7.4 Hz, 1H), 2.82 (dd, J = 15.3,
4.9 Hz, 1H), 2.27 (dq, J = 7.4, 7.4 Hz, 2H), 1.78 (s, 3H), 1.10 (t,
J = 7.6 Hz, 3H), 0.86 (s, 9H), 0.07 (s, 3H), 0.02 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 200.3, 145.0, 138.3, 137.4, 128.3,
127.5, 127.47, 74.4, 73.2, 69.0, 42.0, 25.8, 22.4, 18.0, 13.0, 11.1,
-4.6, -5.0; IR (film, NaCl) 2957, 2930, 2857, 1668, 1252, 1112,
836 cm-1; [R]D þ28.5° (c 2.0, CHCl3); HRMS (ESI) calcd for
C22H37O3Si (M þ H)þ 377.2506, found 377.2526.
((2R,6R)-6-Ethyl-5-methyl-3,6-dihydro-2H-pyran-2-yl)methanol
(24). To a -78 °C solution of sodium (0.70 g, 30.4 mmol) in
liquid ammonia (50 mL) was added a solution of benzyloxy-
methyl pyran 23 (1.50 g, 6.1 mmol) in THF (10 mL). The
reaction was warmed to -33 °C and stirred for 1 h. Subse-
quently, the mixture was recooled to -78 °C and quenched by
addition of solid NH4Cl. The resulting mixture was allowed to
warm to room temperature and evaporated to dryness. Remain-
ing traces of ammonia were removed in vacuo. The residue was
dissolved in the minimum amount of water, adjusted to pH 7
with 1 N HCl, and extracted with dichloromethane. The com-
bined organic phase was dried over sodium sulfate, and all
volatiles were removed in vacuo. Purification of the residue by
flash chromatography (hexanes/EtOAc, 4:1 to 2:1) yielded
1
hydroxymethyl pyran 24 as a colorless oil (0.887 g, 93%): H
NMR (400 MHz, CDCl3) δ 5.54 (ddd, J = 5.7, 3.1, 1.6 Hz, 1H),
4.07 (br s, 1H), 3.66-3.58 (m, 2H), 3.57-3.51 (m, 1H), 2.46 (s,
OH), 2.07-1.90 (m, 1H), 1.84-1.80 (m, 1H), 1.75 (ddq, J =
14.7, 7.3, 3.5 Hz, 1H), 1.59 (dd, J = 2.2, 1.1 Hz, 3H), 1.54 (ddq,
J = 14.2, 7.3, 7.3 Hz, 1H), 0.89 (t, J = 7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 135.2, 120.0, 77.8, 73.7, 65.7, 26.9, 25.4,
18.9, 8.3; IR (film, NaCl) 3415, 2965, 2936, 2880, 1455, 1438,
1374, 1117, 1056, 1023, 1002 cm-1; [R]D þ108.2° (c 2.5, CHCl3).
HRMS (ESI) calcd for C9H16NaO2 (M þ Na)þ 179.1043, found
179.1043.
(2R,4S,E)-1-(Benzyloxy)-5-methyloct-5-ene-2,4-diol (4). To a
stirred solution of 22 (13.27 g, 35.2 mmol) and cerium chloride
heptahydrate (15.74 g, 42.2 mmol) in 300 mL of methanol was
added sodium borohydride (1.6 g, 42.2 mmol) portionwise at
0 °C. The reaction mixture was stirred for 1 h at 0 °C, after which
acetone was added to destroy residual sodium borohydride. All
volatiles were evaporated in vacuo, and the residue was parti-
tioned between water and CH2Cl2. The aqueous phase was
extracted with CH2Cl2, and the combined organic phase was
washed with saturated NaCl solution, dried (Na2SO4), and
concentrated in vacuo to give crude mono-TBS diol (13.3 g,
100%, dr = 3.6:1 by 1H NMR), which was used in the next step
without further purification. To a solution of crude mono-TBS
diol (12.3 g, 32.5 mmol) in THF (300 mL) was added TBAF
(42.2 mL of a 1 M solution in THF, 42.2 mmol). The reaction
mixture was stirred for 2 h, and subsequently quenched by
addition of saturated NH4Cl solution. After evaporation of all
volatiles and extraction of the remaining aqueous layer with
EtOAc, the combined organic phase was dried (Na2SO4) and
concentrated. Purification of the residue by flash chromato-
graphy (hexanes/EtOAc, 4:1 to 1:1) gave 7.30 g (79% over
2 steps) of diol 4 as a colorless oil (dr 3.6:1 by 1H NMR). Major
isomer: 1H NMR (400 MHz, CDCl3) δ 7.38-7.27 (m, 5H), 5.42
(bt, J = 7.0 Hz, 1H), 4.55 (s, 2H), 4.25 (dd, J = 9.2, 3.6 Hz, 1H),
4.06-3.99 (m, 1H), 3.45 (dd, J = 9.5, 4.1 Hz, 1H), 3.40 (dd,
J = 9.5, 6.9 Hz, 1H), 3.29 (br s, OH), 2.99 (br s, OH), 2.08-1.95
(m, 2H), 1.73-1.58 (m, 2H), 1.60 (dt, J = 1.4, 0.8 Hz, 3H), 0.95
(t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 137.8, 136.1,
128.4, 128.2, 127.8, 127.7, 77.5, 74.4, 73.3, 70.9, 37.9, 20.7, 14.0,
11.4; IR (film, NaCl) 3391, 2960, 2930, 2917, 2871, 1454, 1364,
1306, 1091, 1074, 1028, 999, 860 cm-1; [R]D -11.0° (c 1.7, CHCl3);
HRMS (ESI) calcd for C16H24NaO3 (M þ Na)þ 287.1618, found
287.1611.
1-((2R,6R)-6-Ethyl-5-methyl-3,6-dihydro-2H-pyran-2-yl)ethanone
(25). To a -78 °C solution of DMSO (1.0 mL, 14.1 mmol) in
CH2Cl2 (40 mL) was added dropwise oxalyl chloride (4.65 mL of
a 2 M solution in CH2Cl2, 9.3 mmol). After 15 min, a solution of
hydroxymethyl pyran 24 (1.11 g, 7.16 mmol) in CH2Cl2 (10 mL)
was added, and the mixture was stirred for 1 h -78 °C. Tri-
ethylamine (4.0 mL, 28.7 mmol) was then added, and the mix-
ture maintained for 15 min at -78 °C before it was warmed to
0 °C. After another 15 min at 0 °C, the reaction mixture was dilu-
ted with Et2O, water was added, and the layers were separated.
The organic layer was washed with water and brine and dried
(MgSO4). Concentration in vacuo yielded crude (2R,6R)-6-
ethyl-5-methyl-3,6-dihydro-2H-pyran-2-carbaldehyde as a yel-
lowish oil (1.10 g, 100%), which was used in the next step
1
without further purification: H NMR (400 MHz, CD2Cl2) δ
9.72 (s, 1H), 5.64 (s, 1H), 4.20 (s, 1H), 3.99 (dd, J = 8.7, 6.1 Hz,
1H), 2.17-2.11 (m, 2H), 1.86 (ddq, J = 14.7, 7.4, 3.4 Hz, 1H),
1.66 (s, 3H), 1.65-1.55 (m, 1H), 0.97 (t, J = 7.4 Hz, 3H); 13C
NMR (100 MHz, CD2Cl2) δ 202.0, 136.0, 119.1, 78.2, 77.6, 25.8,
25.5, 18.8, 8.1; IR (film, NaCl) 2965, 2934, 2877, 1738, 1455,
1435, 1116, 1057, 1025 cm-1; HRMS (ESI) calcd for C9H15O2
(M þ H)þ 155.1067, found 155.1062.
To a solution of the crude aldehyde (1.10 g, 7.16 mmol)
in THF (60 mL) was added slowly methylmagnesium bromide
5612 J. Org. Chem. Vol. 75, No. 16, 2010

Hanessian et al.
JOCArticle
(7.2 mL of a 3 M solution in Et2O, 21.6 mmol) at 0 °C. The
reaction mixture was stirred for 2 h at 0 °C before it was quenc-
hed by addition of wet acetone followed by saturated NH4Cl
solution. After evaporation of all volatiles, the remaining aqu-
eous phase was extracted with EtOAc. The combined organic
phase was washed with brine, dried (Na2SO4), and concen-
trated. The residue thus obtained (1.22 g, 100%) was pure eno-
ugh to be used in the next step without further purification (1:1
mixture of diastereomers by H NMR): H NMR (400 MHz,
CDCl3, mixture of diastereomers) δ 5.60-5.54 (m, 1H), 5.54-
5.49 (m, 1H), 4.07 (br s, 1H), 4.03 (br s, 1H), 3.94-3.86 (m, 1H),
3.66-3.58 (m, 1H), 3.41 (ddd, J = 10.8, 3.4, 3.4 Hz, 1H), 3.26-
3.19 (m, 1H), 2.94 (d, J = 1.5 Hz, OH), 2.35 (d, J = 3.8 Hz, OH),
2.21-2.09 (m, 1 H), 1.94-1.68 (m, 5H), 1.63-1.57 (m, 6H),
1.56-1.43 (m, 2H), 1.14 (d, J = 7.0 Hz, 6H), 0.91 (t, J = 7.4 Hz,
3H), 0.88 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3,
mixture of diastereomers) δ 135.4, 134.9, 120.4, 119.8, 78.03,
78.0, 76.0, 70.4, 69.1, 27.2, 25.5, 24.3, 18.83, 18.8, 17.8, 17.4, 8.6,
8.4; LRMS (ESI) calcd for C10H19O2 (M þ H)þ:171.1, found
171.2
To a -78 °C solution of DMSO (1.0 mL, 14.1 mmol) in
CH2Cl2 (40 mL) was added dropwise oxalyl chloride (4.6 mL of
a 2 M solution in CH2Cl2, 9.2 mmol). After 15 min, a solution of
crude 1-[(2R,6R)-6-ethyl-5-methyl-3,6-dihydro-2H-2-pyranyl]ethan-
1-ol (1.22 g, 7.16 mmol) in CH2Cl2 (10 mL) was added, and
the mixture was stirred for 1 h -78 °C. Triethylamine (4.0 mL,
28.7 mmol) was then added, and the mixture was maintained for
15 min at -78 °C before it was warmed to 0 °C. After another
15 min at 0 °C, the reaction mixture was diluted with Et2O, water
was added, and the layers were separated. The organic layer was
washed with water and brine and dried (MgSO4). After careful
concentration in vacuo, the residue was purified by flash chro-
matography (pentane/Et2O, 1:0 to 10:1) to yield ketone 25 as a
volatile, light yellow liquid (0.87 g, 72% over three steps from
hydroxymethyl pyran 21): 1H NMR (400 MHz, CDCl3) δ 5.61-
5.54 (m, 1H), 4.15-4.07 (m, 1H), 3.93 (dd, J = 10.5, 4.2 Hz, 1H),
2.26 (s, 3H), 2.22-2.01 (m, 2H), 1.83 (ddq, J = 14.6, 7.4, 3.4 Hz,
1H), 1.61 (br s, 3H), 1.54 (ddq, J = 14.3, 7.15, 7.15 Hz, 1H), 0.96
(t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 210.0, 135.6,
119.5, 78.7, 78.3, 27.3, 25.7, 25.6, 18.9, 8.6; IR (film, NaCl) 2968,
2937, 1722, 1435, 1354, 1117, 1058 cm-1; [R]D þ191.7° (c 1.97,
CHCl3); HRMS (ESI) calcd for C10H17O2 (M þ H)þ 169.1223,
found 169.1222.
(1S,2S,3R)-tert-Butyl 2-((E)-2-((3aS,7aS)-1,3-Dimethyl-2-oxi-
dohexahydro-1H-benzo[d][1,3,2]diazaphosphol-2(3H)-yl)vinyl)-
3-methylcyclopropanecarboxylate (27). To a -78 °C solution of
chloroallylphosphonamide 5 (0.788 g, 3.0 mmol) in THF (25 mL)
was added n-butyl lithium (2.44 mL of a 1.6 M solution in
hexanes, 3.90 mmol). Subsequently, a -78 °C solution of tert-
butyl crotonate (0.597 g, 4.20 mmol) in THF (5 mL) was added
slowly via cannula. The reaction mixture was stirred for 2 h at
-78 °C and then quenched by addition of a saturated ammo-
nium chloride solution. The layers were separated, and the
aqueous phase was extracted with ethyl acetate. The combined
organic phase was washed with brine, dried over Na2SO4 and
concentrated in vacuo. Purification of the residue by flash
chromatography (short plug of silica gel, EtOAc/EtOH, 1:0 to
4:1) provided adduct 27 (0.98 g, 89%) as a light yellow solid: mp
111-113 °C; 1H NMR (400 MHz, CDCl3) δ 6.34 (ddd, J = 19.8,
16.5, 9.6 Hz, 1H), 5.56 (dd, J = 20.9, 16.5 Hz, 1H), 2.75-2.67
(m, 1H), 2.45 (d, J = 11.1 Hz, 3H), 2.44 (d, J = 11.1 Hz, 3H),
2.42-2.34 (m, 1H), 2.13 (ddd, J = 9.5, 4.3 Hz, 1H), 2.02-1.89
(m, 2H), 1.73-1.70 (m, 2H), 1.68-1.58 (m, 1H), 1.52 (t, J = 4.7
Hz, 1H), 1.40 (s, 9H), 1.33-1.16 (m, 3H), 1.12 (d, J = 6.4 Hz,
3H), 1.08-0.94 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 171.8,
149.5 (d, J = 4.9 Hz), 120.7 (d, JP-C = 153.7 Hz), 80.5, 64.5 (d,
J = 7.4 Hz), 63.5 (d, J = 5.4 Hz), 30.9, 30.6 (d, J = 24.8 Hz),
28.6 (d, J = 5.0 Hz), 28.5 (d, J = 7.9 Hz), 28.5, 28.0, 27.9, 24.1,
24.0, 23.2, 12.6. 31P NMR (162 MHz, CDCl3) δ 32.4; IR (film,
NaCl) 2936, 2865, 1717, 1448, 1367, 1322, 1251, 1215, 1157,
1010, 818, 759 cm-1; [R]D þ114.1° (c 1.49, CHCl3); HRMS (ESI)
calcd for C19H34N2O3P (M þ H)þ 369.2302, found 369.2297.
(1S,2S,3R)-tert-Butyl 2-Formyl-3-methylcyclopropanecarboxy-
late (28). A -78 °C solution of phosphonamide 27 (477 mg,
1.29 mmol) in CH2Cl2 (20 mL) was treated with a stream of
ozone for 1-2 h until a light blue color persisted and starting
material could no longer be detected by TLC. The reaction
mixture was flushed with argon to remove excess ozone, di-
methyl sulfide was added at -78 °C, and the mixture was allowed
to warm to room temperature. After dilution with dichloro-
methane, the organic phase was washed with saturated ammonium
chloride solution and brine and dried over Na2SO4. Concentra-
tion in vacuo gave a residue, which was purified by column chro-
matography (hexanes/Et2O, 4:1). The product (166 mg, 70%)
was obtained as a colorless oil, which slowly crystallized upon
standing in the cold to give thick, colorless needles: mp 31-
32 °C; 1H NMR (400 MHz, CDCl3) δ 9.56 (d, J = 4.0 Hz, 1H),
2.42 (ddd, J = 9.3, 4.2, 4.2 Hz, 1H), 2.22 (dd, J = 5.9, 4.6 Hz,
1H), 1.96 (ddq, J = 9.4, 6.4, 6.3 Hz, 1H), 1.44 (s, 9H), 1.26 (d,
J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 198.4, 170.3,
81.3, 35.8, 30.2, 28.0, 25.5, 11.6; IR (film, NaCl) 2979, 1721,
1369, 1311, 1292, 1215, 1158 cm-1; [R]D þ155.8° (c 0.95, CHCl3);
HRMS (ESI) calcd for C10H16NaO3 (M þ Na)þ 207.0992, found
207.1000.
1
1
1,3-Dimethyl-1,3,2-diazaphospholidine 2-Oxide (30). To a
cold (0 °C) solution of N,N0-dimethylethylenediamine (2.69 mL,
25 mmol) and NEt3 (13.9 mL, 100 mmol) in a mixture of benzene
(30 mL) and THF (30 mL) was added dropwise phosphorus
trichloride (2.18 mL, 25 mmol) under vigorous stirring. The
suspension was allowed to warm to room temperature and stir-
red for 1 h, after which it was recooled to 0 °C. Water (0.45 mL,
25 mmol) was then added slowly under vigorous stirring, and the
reaction mixture was stirred for 16 h at room temperature.
Filtration through a small pad of MgSO4 and concentration
gave an oily residue, which was redissolved in benzene/THF and
filtered again (Celite). After concentration in vacuo, the crude
phosphorus acid diamide 30 (2.18 g, 65%) was obtained as an
yellowish oil, which was used without further purification:31 1
H
NMR (400 MHz, CDCl3) δ 7.21 (d, JP-H = 603.4 Hz, 1H),
3.33-3.26 (m, 2H), 3.19-3.12 (m, 2H), 2.73 (dd, J = 10.6, 0.6
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 47.9 (d, J = 9.3 Hz),
31.8 (d, J = 3.2 Hz); 31P NMR (162 MHz, CDCl3) δ 19.9; IR
(film, NaCl) 2917, 2826, 2329, 2228, 1472, 1352, 1269, 1224,
1166, 1033, 934, 927, 890, 730, 692 cm-1; LRMS (ESI) calcd for
C5H16N2O2P (M þ H þ MeOH)þ 167.1, found 167.1.
(R)-2-(3-((tert-Butyldimethylsilyl)oxy)-2-methylpropyl)-1,3-
dimethyl-1,3,2-diazaphospholidine 2-Oxide (31). To a cold (0 °C)
solution of phosphorus acid diamide 30 (3.07 g, 22.9 mmol) and
(R)-3-tert-butyldimethylsilyloxy-2-methylpropyl iodide (29)
(3.14 g, 10.0 mmol) in a mixture of THF (40 mL) and DMF
(10 mL) was added portionwise NaH (0.8 g of a 60% dispersion
in mineral oil, 20.0 mmol). The reaction mixture was allowed to
warm to room temperature and stirred overnight. After careful
addition of saturated NH4Cl solution, the aqueous layer was
extracted with EtOAc. The combined organic phase was washed
with water and brine, dried (Na2SO4), and concentrated in
vacuo. After purification of the residue by flash chromatography
(EtOAc, then EtOAc/EtOH, 9:1), 3.05 g (95%) of phosphon-
amide 31 was obtained as a light yellow oil: 1H NMR (400 MHz,
CDCl3) δ 3.42 (ddd, J = 9.4, 5.7, 2.2 Hz, 1H), 3.34 (dd, J = 9.6,
6.7 Hz, 1H), 3.23-3.15 (m, 2H), 3.12-3.02 (m, 2H), 2.64 (d,
J = 9.5 Hz, 3H), 2.63 (d, J = 9.4 Hz, 3H), 2.10 (ddd, J = 17.1,
16.0, 3.7 Hz, 1H), 1.85-1.70 (m, 1H), 1.53 (ddd, J = 15.7, 15.7,
8.7 Hz, 1H), 0.96 (d, J = 6.7 Hz, 3H), 0.87 (s, 9H), 0.02 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 68.4 (d, J = 14.7 Hz), 48.2 (d,
J = 7.9 Hz), 48.0 (d, J = 7.7 Hz), 31.9 (d, J = 5.2 Hz), 31.7 (d,
J. Org. Chem. Vol. 75, No. 16, 2010 5613

Hanessian et al.
JOCArticle
J = 5.3 Hz), 31.5 (d, J = 4.0 Hz), 29.8 (d, J = 117 Hz), 25.8,
18.1, 17.7 (d, J = 4.9 Hz), -5.4, -5.5. 31P NMR (162 MHz,
CDCl3) δ 42.0; IR (film, NaCl) 2954, 2929, 2856, 1472, 1251,
1225, 1157, 1087, 1035, 942, 836, 806, 776 cm-1; [R]D -6.3° (c
3.6, CHCl3); LRMS (ESI) calcd for C14H34N2O2PSi (M þ H)þ
321.2, found 321.2.
compound 33 was obtained as a colorless oil (505 mg, 97%): 1H
NMR (400 MHz, CDCl3) δ 5.59 (d, J = 4.9 Hz, 1H), 5.24 (d,
J = 9.1 Hz, 1H), 4.12 (s, 1H), 3.88 (dd, J = 10.8, 1.9 Hz, 1H),
3.18-3.11 (m, 1H), 3.11-3.05 (m, 1H), 2.71-2.62 (m, 1H),
2.19-2.08 (m, 1H), 1.96-1.87 (m, 1H), 1.85-1.73 (m, 1H), 1.70
(s, 3H), 1.61 (s, 3H), 1.60-1.49 (m, 1H), 1.12 (d, J = 6.6 Hz,
3H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
137.3, 135.1, 128.5, 120.7, 77.8, 77.6, 34.3, 30.1, 25.6, 21.2, 18.9,
15.2, 12.6, 8.2; IR (film, NaCl) 2962, 2929, 2972, 2868, 1453,
1373, 1192, 1115, 1050 cm-1; [R]D -6.3° (c 1.43, CHCl3); HRMS
(ESI) calcd for C14H23INaO (M þ Na)þ 357.0686, found
357.0683.
2-((S,E)-4-((2R,6R)-6-Ethyl-5-methyl-3,6-dihydro-2H-pyran-
2-yl)-2-methylpent-3-en-1-yl)-1,3-dimethyl-1,3,2-diazaphospho-
lidine 2-Oxide (34). Toa mixture ofiodide 33 (505 mg, 1.51 mmol)
and phosphorus acid diamide 30 (1.22 g, 9.1 mmol) in THF
(5.0 mL) was added LiHMDS (6.0 mL of a 1 M solution in THF,
6.0 mmol) at -78 °C. The reaction mixture was stirred for 15 min
at that temperature, after which it was slowly warmed to room
temperature. Purification by flash chromatography (EtOAc, then
EtOAc/EtOH, 9:1) gave 391 mg (76%) of 34 as a light yellow oil:
1H NMR (400 MHz, CDCl3) δ 5.47 (d, J = 4.9 Hz, 1H), 5.19 (d,
J = 9.3 Hz, 1H), 3.98 (br s, 1H), 3.70 (dd, J = 10.5, 2.3 Hz, 1H),
3.18-3.02 (m, 2H), 3.02-2.90 (m, 2H), 2.62-2.50 (m, 7H),
2.06-1.90 (m, 1H), 1.90-1.72 (m, 3H), 1.71-1.61 (m, 1H),
1.57 (s, 3H), 1.50 (s, 3H), 1.48-1.36 (m, 1H), 0.96 (d, J = 6.7
Hz, 3H), 0.80 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
135.0, 134.0, 130.2 (d, J = 7.5 Hz), 120.5, 77.9, 76.9, 47.8 (d, J =
7.8 Hz), 47.4 (d, J = 8.6 Hz), 34.2 (d, J = 115.2 Hz), 31.8 (d, J =
5.3 Hz), 31.3 (d, J = 5.9 Hz), 29.8, 27.5 (d, J = 3.9 Hz), 25.4, 22.5
(d, J = 13.1 Hz), 18.7, 12.7, 8.2; 31P NMR (162 MHz, CDCl3) δ
40.5; IR (film, NaCl) 2961, 2918, 1450, 1376, 1349, 1263, 1226,
1210, 1163, 1115, 1036, 942, 798 cm-1; [R]D þ31.0° (c 0.97,
CHCl3); LRMS (ESI) calcd for C18H34N2O2P (M þ H)þ 341.2,
found 341.2.
(S,E)-4-((2R,6R)-6-Ethyl-5-methyl-3,6-dihydro-2H-pyran-2-
yl)-2-methylpent-3-en-1-ol (32). To a solution of phosphon-
amide 31 (3.4 g, 10.6 mmol) in THF (30 mL) was added n-BuLi
(5.6 mL of a 1.6 M solution in hexanes, 8.96 mmol) at -78 °C.
The mixture was stirred for 2 h at -78 °C, and then ketone 25
(800 mg, 4.76 mmol) was added to it. The reaction mixture was
stirred for 1 h at -78 °C, after which it was allowed to warm to
room temperature, AcOH (3.0 mL) was added, and stirring was
continued for 20 min. After addition of saturated NaHCO3
solution and extraction with CH2Cl2, the combined organic
phase was dried and concentrated. The residue was purified
by flash chromatography (hexanes/Et2O, 10:1 to 4:1) to give a
1.01 g (62%) of a E/Z-mixture of TBS-olefins as a colorless oil
(E/Z = 6:1 by 1H NMR). As second fraction, 220 mg of ketone
25 (28%) was recovered. An analytical pure sample of the E-
TBS-olefin was obtained by flash chromatography (hexanes/
Et2O, 100:1 to 20:1): 1H NMR (400 MHz, CDCl3) δ 5.61-5.57
(m, 1H), 5.23 (d, J = 9.3 Hz, 1H), 4.12 (br s, 1H), 3.85 (dd, J =
10.7, 2.8 Hz, 1H), 3.47 (dd, J = 9.7, 6.0 Hz, 1H), 3.37 (dd, J =
9.7, 7.4 Hz, 1H), 2.66-2.54 (m, 1H), 2.19-2.08 (m, 1H),
1.93-1.84 (m, 1H), 1.84-1.72 (m, 1H), 1.62-1.60 (m, 3H),
1.70 (d, J = 1.17 Hz, 3H), 1.60-1.50 (m, 1H), 0.99 (d, J = 6.7
Hz, 3H), 0.92 (t, J = 7.3 Hz, 3H), 0.91 (s, 9H), 0.053 (s, 3H), 0.05
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 136.3, 135.1, 128.0,
121.0, 77.94, 77.9, 67.8, 35.0, 30.1, 25.9, 25.6, 19.0, 18.3, 17.2,
12.6, 8.2, -5.3, -5.4; IR (film, NaCl) 2958, 2929, 2895, 2856,
1471, 1462, 1255, 1118, 1091, 1051, 1030, 836, 774, 665 cm-1
;
[R]D þ47.7° (c 1.37, CHCl3); LRMS (ESI) calcd for C20H39O2Si
(M þ H)þ 339.3, found 339.2.
Toa cold(0 °C) solutionofthe E-TBS-olefin (1.76 g, 5.2 mmol)
in THF (50 mL) was added TBAF (7.8 mL of a 1 M solution in
THF, 7.8 mmol). The mixture was stirred for 3 h at room
temperature, and then saturated NH4Cl solution was added.
After evaporation of all volatiles in vacuo, the remaining aqu-
eous layer was extracted with EtOAc. The combined organic
phase was dried (Na2SO4) and concentrated. Purification of the
residue by flash chromatography (hexanes/EtOAc, 10:1 to 4:1)
gave 1.09 g (93%) of alcohol 32 as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 5.61-5.57 (m, 1H), 5.24 (d, J = 9.5 Hz, 1H),
4.11 (br s, 1H), 3.87 (dd, J = 10.7, 3.0 Hz, 1H), 3.54-3.46 (m,
1H), 3.39 (dd, J = 10.4, 7.8 Hz, 1H), 2.74-2.62 (m, 1H),
2.19-2.07 (m, 1H), 2.00-1.88 (m, 1H), 1.85-1.75 (m, 1H),
1.73 (d, J = 1.4 Hz, 3H), 1.62 (ddd, J = 2.4, 2.4, 1.2 Hz, 3H),
1.60-1.48 (m, 2H), 0.99 (d, J = 6.7 Hz, 3H), 0.93 (t, J = 7.3 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 138.3, 135.1, 127.1, 120.7,
78.0, 77.5, 67.7, 35.0, 30.3, 25.6, 18.9, 16.9, 13.1, 8.3; IR (film,
NaCl) 3392, 2963, 2932, 2872, 1454, 1378, 1337, 1116, 1054,
1031, 847 cm-1; [R]D: þ57.1° (c 1.52, CHCl3); LRMS (ESI) calcd
for C14H25O2 (M þ H)þ 225.2, found 225.1.
(1S,2S,3R)-tert-Butyl 2-((R,1E,4E)-5-((2R,6R)-6-Ethyl-5-methyl-
3,6-dihydro-2H-pyran-2-yl)-3-methylhexa-1,4-dien-1-yl)-3-methy-
lcyclopropanecarboxylate (35). To a solution of phosphonamide
34 (107 mg, 0.31 mmol) in THF (2 mL) was added t-BuLi (0.24
mL of a 1.7 M solution in hexanes, 8.96 mmol) at -78 °C. The
mixture was stirred for 2 h at -78 °C, and then aldehyde 28
(91 mg, 0.49 mmol) was added to it. The reaction mixture was
stirred for 1 h at -78 °C, AcOH (0.3 mL) was then added, and
the reaction mixture was allowed to warm to room temperature.
After addition of saturated NaHCO3 solution and extraction
with CH2Cl2, the combined organic phase was dried and con-
centrated. The residue was purified by flash chromatography
(hexanes/Et2O, 20:1 to 10:1) to give 74 mg (64%) of triene 35 as a
1
1
colorless oil (E/Z>20:1 by H NMR): H NMR (400 MHz,
CDCl3) δ 5.62-5.54 (m, 2H), 5.28 (d, J = 8.9 Hz, 1H), 5.09 (dd,
J = 15.3, 8.8 Hz, 1H), 4.11 (br s, 1H), 3.86 (dd, J = 10.5, 2.3 Hz,
1H), 3.16-3.05 (m, 1H), 2.19-2.07 (m, 1H), 2.00 (ddd, J = 9.0,
9.0, 4.3 Hz, 1H), 1.93-1.84 (m, 1H), 1.83-1.73 (m, 1H), 1.66 (s,
3H), 1.61 (s, 3H), 1.59-1.48 (m, 2H), 1.46 (s, 9H), 1.27 (dd, J =
4.4, 4.4 Hz, 1H), 1.09 (d, J = 6.4 Hz, 3H), 1.07 (d, J = 6.8 Hz,
3H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
173.0, 137.0, 135.3, 135.1, 129.0, 123.8, 120.8, 80.1, 77.8, 77.77,
35.0, 30.2, 29.8, 29.6, 28.2, 25.6, 22.1, 21.0, 18.9, 12.5, 12.4, 8.2;
IR (film, NaCl) 2963, 2917, 1718, 1366, 1154, 1117, 1062, 1049
cm-1; [R]D þ154.5° (c 0.49, CHCl3); LRMS (ESI) calcd for
C24H38NaO3 (M þ Na)þ 397.3, found 397.2.
(2R,6R)-6-Ethyl-2-((S,E)-5-iodo-4-methylpent-2-en-2-yl)-5-
methyl-3,6-dihydro-2H-pyran (33). A solution of triphenylpho-
sphine (1.23 g, 4.69 mmol) and imidazole (0.53 g, 7.78 mmol) in
CH2Cl2 (10 mL) was treated with iodine (1.19 g, 4.69 mmol) at
0 °C under exclusion of light. To this mixture was then added
slowly a solution of alcohol 32 (0.35 g, 1.56 mmol) in Et2O
(10 mL). The reaction mixture was allowed to warm to room
temperature, stirred for 2 h, diluted with Et2O, and subsequently
quenched by addition of a 1:1 mixture of saturated Na2S2O3 and
saturated NaHCO3 solutions. The organic phase was separated,
washed with water and brine, and dried over MgSO4. Concen-
tration gave a residue that was purified by flash chromato-
graphy (short plug of silica gel, hexanes/Et2O, 20:1). The title
((1S,2S,3R)-2-((R,1E,4E)-5-((2R,6R)-6-Ethyl-5-methyl-3,6-
dihydro-2H-pyran-2-yl)-3-methyl-hexa-1,4-dien-1-yl)-3-methyl-
cyclopropyl)methanol (36). To a solution of tert-butyl ester 35
(47 mg, 0.126 mmol) in CH2Cl2 (2 mL) was added DIBAL-H
(0.38 mL of a 1 M solution in CH2Cl2, 0.38 mmol) at 0 °C. The
reaction mixture was stirred for 2 h at that temperature and
subsequently quenched with saturated NaK tartrate solution.
5614 J. Org. Chem. Vol. 75, No. 16, 2010

Hanessian et al.
JOCArticle
The resulting mixture was warmed to room temperature and
stirred vigorously until two clear layers were obtained. The
layers were separated, and the aqueous phase was extracted
with CH2Cl2. The combined organic phase was washed with
brine, dried (Na2SO4), and concentrated in vacuo. Purification
of the residue by flash chromatography (hexanes/EtOAc, 4:1)
yielded hydroxymethyl vinyl cyclopropane 36 (37 mg, 96%) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 5.60-5.57 (m, 1H),
5.49 (ddd, J = 15.4, 6.4, 0.5 Hz, 1H), 5.28 (dddd, J = 9.0, 2.4,
1.2, 1.2 Hz, 1H), 5.13 (ddd, J = 15.4, 8.6, 1.3 Hz, 1H), 3.86 (dd,
J = 10.7, 2.8 Hz, 1H), 4.12 (br s, 1H), 3.53-3.50 (m, 2H),
3.15-3.05 (m, 1H), 2.19-2.09 (m, 1H), 1.93-1.83 (m, 1H),
1.83-1.74 (m, 1H), 1.67 (d, J = 1.3 Hz, 3H), 1.62-1.60 (m, 3H),
1.60-1.50 (m, 1H), 1.36-1.29 (m, 1H), 1.07 (d, J = 6.8 Hz, 3H),
1.06 (d, J = 5.9 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H), 0.91-0.84 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 135.3, 135.1, 135.0, 129.5,
125.7, 120.9, 77.9, 77.8, 66.6, 34.9, 30.1, 29.7, 25.6, 24.3, 21.1,
19.0, 17.6, 13.1, 12.3, 8.2; IR (film, NaCl) 3368, 2962, 2929, 2871,
(1S,2S,3R)-tert-Butyl-2-((R,E)-4-((tert-butyldimethylsilyl)-
oxy)-3-methylbut-1-en-1-yl)-3-methyl-cyclopropanecarboxylate
(38). To a -78 °C solution of phosphonamide epi-31 (538 mg,
1.67 mmol) in THF (7 mL) was added n-BuLi (1.0 mL of a 1.6 M
solution in hexanes, 1.60 mmol), and the mixture was stirred for
2 h at that temperature. A solution of aldehyde 28 (155 mg,
0.84 mmol) in THF (3 mL) was then added, and the reaction
mixture was stirred for 1 h at -78 °C. After quench with acetic
acid (1.0 mL), the mixture was warmed to room temperature,
diluted with CH2Cl2, and neutralized by addition of satur-
ated NaHCO3 solution. The aqueous layer was extracted with
CH2Cl2, andthe combined organicphase was driedover Na2SO4.
After evaporation of all volatiles in vacuo, the residue was
purified by flash chromatography (hexanes/EtOAc, 20:1) to
give ester 38 (214 mg, 72%) as a colorless oil (E/Z ratio >20:1
by 1H NMR): 1H NMR (400 MHz, CDCl3) δ 5.55 (dd, J = 15.4,
7.4 Hz, 1H), 5.18 (dd, J = 15.4, 8.7 Hz, 1H), 3.47 (dd, J = 9.7,
6.5 Hz, 1H), 3.41 (dd, J = 9.7, 6.8 Hz, 1H), 2.38-2.26 (m, 1H),
2.00 (ddd, J = 9.0, 9.0, 4.3 Hz, 1H), 1.59-1.49 (m, 1H), 1.45 (s,
9H), 1.28 (dd, J = 4.5, 4.5 Hz, 1H), 1.11 (d, J = 6.4 Hz, 3H), 0.98
(d, J = 6.7 Hz, 3H), 0.90 (s, 9H), 0.05 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 172.6, 135.3, 125.4, 79.7, 67.7, 39.2, 29.6, 29.4,
27.8, 25.6, 25.4, 21.6, 18.0, 16.3, 12.2,-5.66, -5.7; IR (film,
NaCl) 2958, 2931, 2858, 2867, 1720, 1367, 1258, 1155, 1107,
1088, 837, 776 cm-1; [R]D þ83.2° (c 1.19, CHCl3); HRMS (ESI)
calcd for C20H38NaO3Si (M þ Na)þ 377.2482, found 377.2480.
(1S,2S,3R)-2-((R,E)-4-((tert-Butyldimethylsilyl)oxy)-3-meth-
ylbut-1-en-1-yl)-3-methyl-cyclopropanecarbaldehyde (39). To a
-78 °C solution of tert-butyl ester 38 (380 mg, 1.07 mmol) in
CH2Cl2 (10 mL) was added DIBAL-H (4.3 mL of a 1 M solu-
tion in CH2Cl2, 4.3 mmol). The reaction mixture was warmed to
-30 °C, stirred for 2 h at that temperature, and subsequently
quenched with saturated NaK tartrate solution. The resulting
mixture was warmed to room temperature and stirred vigo-
rously until two clear layers were obtained. The layers were
separated, and the aqueous phase was extracted with CH2Cl2.
The combined organic phase was washed with brine, dried over
Na2SO4, and concentrated in vacuo. Purification of the residue
by flash chromatography (hexanes/EtOAc, 4:1) yielded the
hydroxymethyl vinyl cyclopropane (254 mg, 83%) as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 5.46 (dd, J = 15.4, 7.3 Hz,
1H), 5.22 (ddd, J = 15.4, 8.5, 1.0 Hz, 1H), 3.49 (dd, J = 9.7, 6.2
Hz, 1H), 3.53-3.48 (m, 2H), 3.38 (dd, J = 9.7, 7.1 Hz, 1H),
2.36-2.25 (m, 1H), 1.59 (br s, OH), 1.33 (ddd, J = 8.5, 8.5, 5.1
Hz, 1H), 1.08 (d, J = 5.9 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H), 0.90
(s, 9H), 0.93-0.84 (m, 2H), 0.05 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 133.4, 127.4, 67.9, 66.2, 39.2, 29.6, 29.3, 25.6, 24.1,
18.0, 17.2, 16.5, 12.8, -5.64, -5.67; IR (film, NaCl) 3339, 2956,
2930, 2886, 2858, 1472, 1463, 1386, 1256, 1116, 1087, 1025, 964,
837, 775 cm-1; [R]D þ45.8° (c 1.62, CHCl3); LRMS (ESI) calcd
for C16H33O2Si (M þ H)þ 285.2, found 285.1.
1452, 1411, 1368, 1115, 1089, 1071, 1054, 1049, 1022 cm-1; [R]D
þ
95.6° (c 0.25, CHCl3); LRMS (ESI) calcd for C20H32NaO2 (M þ
Na)þ 327.2, found 327.2.
(2R,6R)-6-Ethyl-2-((R,2E,5E)-6-((1S,2S,3R)-2-ethynyl-3-met-
hylcyclopropyl)-4-methylhexa-2,5-dien-2-yl)-5-methyl-3,6-dihydro-
2H-pyran (37). Method A (from 36): To a -78 °C solution of
DMSO (25 μL, 0.356 mmol) in CH2Cl2 (1 mL) was added
dropwise oxalyl chloride (0.12 mL of a 2 M solution in CH2Cl2,
0.24 mmol). After 20 min, a solution of 36 (35 mg, 0.115 mmol)
in CH2Cl2 (1 mL) was added, and the resulting mixture was
stirred for 1 h at -78 °C. Triethylamine (64 μL, 0.46 mmol) was
then added, and the mixture maintained for 15 min at -78 °C
before it was allowed to warm to room temperature. The
reaction mixture was diluted with CH2Cl2, water was added,
and the layers were separated. The organic layer was washed
with water and brine and dried (Na2SO4). Concentration
in vacuo yielded the crude aldehyde as a light yellow oil (35 mg,
100%), which was used in the next step without further puri-
fication. To a suspension of the aldehyde (35 mg, 0.115 mmol)
and anhydrous K2CO3 (48 mg, 0.35 mmol) in methanol (1 mL)
was added dimethyl-1-diazo-2-oxypropylphosphonate (40 mg,
0.21 mmol), and the reaction mixture was stirred overnight at
room temperature. After dilution with diethyl ether, water was
added, and the layers were separated. The organic layer was
washed with brine, dried (MgSO4), and concentrated in vacuo.
Purification of the residue by flash chromatography (hexanes/
Et2O, 100:1 to 40:1) gave alkyne 37 (28 mg, 82% over two steps
from hydroxymethyl vinyl cyclopropane 36) as a colorless oil.
Method B (from 43): To a 0 °C solution of E,E-TIPS-alkyne
43 (101 mg, 0.22 mmol) in THF (4 mL) was added TBAF (0.33 mL
of a 1 M solution in THF, 0.33 mmol). The mixture was warmed
to room temperature and stirred for 1 h. After addition of
saturated NH4Cl solution and evaporation of all volatiles
in vacuo, the remaining aqueous layer was extracted with EtOAc.
The combinedorganic phase was washed(brine), dried(Na2SO4),
and concentrated. The residue thusobtained was purified byflash
chromatography (hexanes/Et2O, 100:1 to 50:1) to give alkyne 37
(58 mg, 88%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ
5.61-5.55 (m, 2H), 5.28 (d, J = 8.9 Hz, 1H), 5.05 (ddd, J = 15.3,
8.6, 1.2 Hz, 1H), 4.12 (br s, 1H), 3.86 (dd, J = 10.7, 2.9 Hz, 1H),
3.15-3.05 (m, 1H), 2.19-2.08 (m, 1H), 1.92-1.83 (m, 2H),
1.83-1.73 (m, 2H), 1.66 (d, J = 1.2 Hz, 3H), 1.63-1.60 (m,
3H), 1.60-1.50 (m, 1H), 1.38-1.27 (m, 1H), 1.08 (d, J = 6.3 Hz,
3H), 1.07 (d, J = 6.9 Hz, 3H), 0.97-0.94 (m, 1H), 0.92 (t, J = 7.3
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 137.1, 135.3, 135.1,
129.1, 123.8, 120.9, 86.6, 77.9, 77.8, 64.7, 35.0, 30.1, 29.7, 25.6,
22.6, 21.0, 19.0, 14.8, 12.8, 12.3, 8.2; IR (film, NaCl) 3315, 2963,
2930, 2872, 2119, 1454, 1368, 1115, 1050, 962 cm-1; [R]D þ187.7°
(c 1.0, CHCl3); HRMS (ESI) calcd for C21H31O (M þ H)þ
299.2369, found 299.2363.
To a -78 °C solution of DMSO (0.255 mL, 3.6 mmol) in
CH2Cl2 (15 mL) was added dropwise oxalyl chloride (1.2 mL of
a 2 M solution in CH2Cl2, 2.4 mmol). After 20 min, a solution of
the hydroxymethyl vinyl cyclopropane (340 mg, 1.2 mmol) in
CH2Cl2 (5 mL) was added, and the resulting mixture stirred for
1 h at -78 °C. Triethylamine (0.67 mL, 4.8 mmol) was added, and
the mixture was maintained for 15 min at -78 °C before it was
warmed to room temperature. The reaction mixture was diluted
with CH2Cl2, water was added, and the layers were separated.
The organic layer was washed with water, brine, and dried
(Na2SO4). Concentration in vacuo yielded the crude aldehyde
39 as a light yellow oil (340 mg, 100%), which was used in the
next step without further purification. Alternatively, the crude
product can be purified by flash chromatography (hexanes/
Et2O, 10:1) to give aldehyde 39 as a colorless oil: 1H NMR
(400 MHz, CDCl3) δ 9.22 (d, J=4.8 Hz, 1H), 5.62 (dd, J =
15.5, 7.4 Hz, 1H), 5.25 (ddd, J=15.4, 8.5, 0.6 Hz, 1H), 3.49
J. Org. Chem. Vol. 75, No. 16, 2010 5615

Hanessian et al.
JOCArticle
(dd, J = 9.7, 6.4 Hz, 1H), 3.42 (dd, J = 9.7, 6.7 Hz, 1H),
2.39-2.29 (m, 1H), 2.25 (ddd, J = 9.0, 9.0, 4.2 Hz, 1H),
1.84-1.75 (m, 1H), 1.68 (ddd, J = 4.5, 4.5, 4.5 Hz, 1H), 1.19
(d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 0.91 (s, 9H), 0.05
(s, 6H); 13C NMR (100 MHz, CDCl3) δ 200.1, 136.8, 124.2, 67.9,
39.5, 39.2, 31.1, 25.9, 22.7, 18.3, 16.6, 12.4, -5.3, -5.33; IR
(ddd, J = 15.4, 8.7, 0.7 Hz, 1H), 3.56-3.46 (m, 1H), 3.46-3.38
(m, 1H), 2.42-2.31 (m, 1H), 1.80 (dddd, J = 9.0, 9.0, 4.7, 0.5 Hz,
1H), 1.47 (br s, OH), 1.39-1.28 (m, 1H), 1.11 (d, J = 6.4 Hz,
3H), 1.09-1.03 (m, 22H), 1.02 (d, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 134.6, 128.3, 110.7, 76.7, 67.3, 39.9, 30.4,
23.5, 18.6, 16.65, 16.6, 13.0, 11.3; IR (film, NaCl) 3346, 2957,
(film, NaCl) 2957, 2930, 2857, 1712, 1255, 1088, 836, 775 cm-1
;
2942, 2891, 2865, 2146, 1462, 1034, 994, 882, 676 cm-1; [R]D
þ
LRMS (ESI) calcd for C16H31O2Si (M þ H)þ 283.2, found
171.8° (c 1.14, CHCl3); LRMS (ESI) calcd for C20H37OSi (M þ
283.1.
H)þ 321.3, found 321.2.
tert-Butyl(((R,E)-4-((1S,2S,3R)-2-ethynyl-3-methylcyclopropyl)-
2-methylbut-3-en-1-yl)oxy)dimethylsilane (40). To a suspension
of crude aldehyde 39 (340 mg, 1.2 mmol) and anhydrous K2CO3
(500 mg, 3.6 mmol) in methanol (6 mL) was added dimethyl-1-
diazo-2-oxypropylphosphonate (415 mg, 2.16 mmol), and the
reaction mixture was stirred overnight at room temperature.
After dilution with diethyl ether, water was added, and the
layers were separated. The organic layer was washed with brine,
dried (MgSO4), and concentrated in vacuo. Purification of the
residue by flash chromatography (hexanes/Et2O, 20:1 to 10:1)
gave alkyne 40 (286 mg, 85% over two steps from the hydro-
xymethyl vinyl cyclopropane) as a colorless oil: 1H NMR
(400 MHz, CDCl3) δ 5.57 (ddd, J = 15.4, 7.4, 0.6 Hz, 1H),
5.15 (ddd, J = 15.4, 8.5, 1.1 Hz, 1H), 3.50 (dd, J = 9.7, 6.2 Hz,
1H), 3.40 (dd, J = 9.7, 7.0 Hz, 1H), 2.38-2.26 (m, 1H), 1.89 (d,
J = 2.1 Hz, 1H), 1.80 (ddd, J = 8.8, 8.5, 4.8, 0.6 Hz, 1H),
1.38-1.29 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H), 0.99 (d, J = 6.8 Hz,
3H), 0.99-0.94 (m, 1H), 0.91 (s, 9H), 0.06 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 135.7, 125.8, 86.6, 68.1, 64.7, 39.6, 29.8,
25.9, 22.6, 18.4, 16.7, 14.8, 12.9, -5.3, -5.33; IR (film, NaCl)
3317, 2956, 2930, 2896, 2886, 2857, 1471, 1462, 1256, 1114, 1087,
1062, 962, 837, 775 cm-1; [R]D þ110.3° (c 1.94, CHCl3); LRMS
(ESI) calcd for C17H31OSi (M þ H)þ 279.2, found 279.1.
tert-Butyldimethyl(((R,E)-2-methyl-4-((1S,2R,3S)-2-methyl-3-
((triisopropylsilyl)ethynyl)cyclopropyl)but-3-en-1-yl)oxy)silane
(41). To a solution of alkyne 40 (81 mg, 0.29 mmol) in THF
(3 mL) was added n-BuLi (0.27 mL of a 1.6 M solution, 0.43
mmol) at -78 °C. The reaction mixture was stirred for 1 h at that
temperature, and then TIPSCl (140 mg, 0.73 mmol) was added.
The mixture was stirred for 30 min at -78 °C, warmed to room
temperature, and stirred for another 30 min. After quenching
the mixture with saturated NH4Cl solution, the layers were
separated, and the aqueous one was extracted with EtOAc. The
combined organic phase was washed with brine, dried (Na2SO4),
and concentrated. The residue thus obtained was purified by
flash chromatography (hexanes/EtOAc, 80:1 to 40:1) to yield
To a cold (0 °C) mixture of triphenylphosphine (120 mg,
0.46 mmol), imidazole (47 mg, 0.69 mmol), and iodine (116 mg,
0.46 mmol) in CH2Cl2 (4 mL) was added a solution of the
alcohol (73 mg, 0.23 mmol) in CH2Cl2 (1 mL). The resulting
mixture was allowed to slowly warm to room temperature and
stirred overnight. The mixture was the diluted with CH2Cl2, and
10% aqueous Na2S2O3 solution was added. After phase separa-
tion, the organic layer was washed with water and brine, dried
(Na2SO4), and concentrated. The residue was purified by flash
chromatography (hexanes/Et2O, 100:0 to 20:1) to yield 82 mg
(83%) of iodide 42 as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 5.53 (dd, J = 15.3, 7.3 Hz, 1H), 5.20 (ddd, J = 15.3,
8.5, 0.7 Hz, 1H), 3.21 (dd, J = 9.5, 5.6 Hz, 1H), 3.12 (dd, J = 9.5,
6.9 Hz, 1H), 2.44-2.33 (m, 1H), 1.79 (ddd, J = 8.8, 8.8, 4.8 Hz,
1H), 1.39-1.30 (m, 1H), 1.13 (d, J = 6.7 Hz, 3H), 1.11 (d, J =
6.4 Hz, 3H), 1.09-1.03 (m, 22H); 13C NMR (100 MHz, CDCl3)
δ 135.3, 127.4, 110.7, 76.7, 38.8, 30.2, 23.6, 20.8, 18.6, 16.5, 25.4,
13.1, 11.3; IR (film, NaCl) 2958, 2942, 2864, 2147, 1462, 1194,
1057, 995, 960, 882, 666 cm-1; [R]D þ167.8° (c 1.29, CHCl3);
HRMS (ESI) calcd for C20H36ISi (M þ H)þ 431.1626, found
431.1644.
1,3-Dimethyl-2-((R,E)-2-methyl-4-((1S,2R,3S)-2-methyl-3-
((triisopropylsilyl)ethynyl)cyclopropyl)but-3-en-1-yl)-1,3,2-dia-
zaphospholidine 2-Oxide (3). To a mixture of iodide 42 (117 mg,
0.27 mmol) and freshly prepared phosphorus acid diamide 30
(217 mg, 1.62 mmol) in THF (1 mL) was added LiHMDS
(1.08 mL of a 1 M solution in THF, 1.08 mmol) at -78 °C.
The reaction mixture was stirred for 10 min at that temperature,
subsequently allowed to warm to room temperature, and stirred
for another 30 min. After addition of saturated NH4Cl solution
and extraction with CH2Cl2, the combined organic phase was
washed (brine), dried (Na2SO4), and concentrated in vacuo. The
residue thus obtained was purified by flash chromatography
(EtOAc, then EtOAc/EtOH, 9:1) to give 93 mg (79%) of
1
phosphonamide 3 as a pale yellow oil: H NMR (400 MHz,
CDCl3) δ 5.49 (dd, J = 15.2, 8.1 Hz, 1H), 5.02 (dd, J = 15.2,
9.2 Hz, 1H), 3.18-3.10 (m, 2H), 3.10-3.00 (m, 2H), 2.61 (d, J =
9.6 Hz, 3H), 2.59 (d, J = 9.2 Hz, 3H), 2.44-2.31 (m, 1H),
1.93-1.74 (m, 2H), 1.68 (ddd, J = 9.1, 9.1, 4.7 Hz, 1H),
1.33-1.24 (m, 1H), 1.08-0.89 (m, 28H); 13C NMR (100 MHz,
CDCl3) δ 138.0 (d, J = 7.7 Hz), 125.0, 110.4, 76.5, 48.0 (d, J =
7.9 Hz), 47.5 (d, J = 8.7 Hz), 34.3 (d, J = 115.9 Hz), 32.6 (d, J =
4.0 Hz), 32.0 (d, J = 5.2 Hz), (d, J = 5.8 Hz), 31.5, 30.8, 23.2,
22.9 (d, J = 12.6 Hz), 18.4, 16.7, 12.9, 11.1. 31P NMR (162 MHz,
CDCl3) δ 39.9; IR (film, NaCl) 2942, 2892, 2865, 2144, 1463,
1263, 1225, 1162, 1035, 882, 665 cm-1; [R]D þ153.2° (c 1.1,
CHCl3); LRMS (ESI) calcd for C24H46N2OPSi (M þ H)þ 437.3,
found 437.3.
1
120 mg (95%) of TIPS-alkyne 41 as a colorless oil: H NMR
(400 MHz, CDCl3) δ 5.55 (dd, J = 15.4, 7.4 Hz, 1H), 5.15 (dd,
J = 15.4, 8.6 Hz, 1H), 3.50 (dd, J = 9.7, 6.3 Hz, 1H), 3.41 (dd,
J = 9.7, 6.9 Hz, 1H), 2.38-2.27 (m, 1H), 1.77 (ddd, J = 8.8, 8.8,
4.7 Hz, 1H), 1.37-1.26 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H),
1.08-1.01 (m, 22H), 1.00 (d, J = 6.7 Hz, 3H), 0.92 (br s, 9H),
0.06 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 135.4, 126.3, 111.1,
76.4, 68.2, 39.6, 30.7, 25.9, 23.4, 18.6, 18.4, 16.7, 16.4, 13.0,
11.4, -5.28, -5.3; IR (film, NaCl) 2957, 2978, 2935, 2892, 2864,
2148, 1463, 1255, 1114, 1087, 883, 836, 775 cm-1; [R]D þ120.6° (c
1.22, CHCl3); LRMS (ESI) calcd for C26H51OSi2 (M þ H)þ
435.3, found 435.3.
(((1S,2S,3R)-2-((R,E)-4-Iodo-3-methylbut-1-en-1-yl)-3-methyl-
cyclopropyl)ethynyl)triisopropylsilane (42). A solution of TIPS-
alkyne 41 (120 mg, 0.28 mmol) in a mixture of CH2Cl2 (2 mL)
and MeOH (2 mL) was treated at 0 °C with camphorsulfonic
acid (6 mg, 0.026 mmol) for 1 h. The reaction mixture was
quenched by addition of saturated NaHCO3 solution and
extracted with CH2Cl2. The combined organic phase was
washed (brine), dried (Na2SO4), and concentrated. The residue
was purified by flash chromatography (hexanes/EtOAc, 10:1 to
(((1S,2S,3R)-2-((R,1E,4E)-5-((2R,6R)-6-Ethyl-5-methyl-3,6-
dihydro-2H-pyran-2-yl)-3-methyl-hexa-1,4-dien-1-yl)-3-methyl-
cyclopropyl)ethynyl)triisopropylsilane (43). To a -78 °C solution
of phosphonamide 3 (210 mg, 0.44 mmol) in THF (3 mL) was
added n-BuLi (0.18 mL of a 2.5 M solution in THF, 0.45 mmol).
The mixture was stirred for 3 h at that temperature, after which
ketone 25 (110 mg, 0.65 mmol) was added. The reaction mixture
was stirred for 1 h at -78 °C, warmed to room temperature, and
subsequently quenched by addition of AcOH (0.4 mL). The
mixture was diluted with CH2Cl2, washed with saturated NaH-
CO3 solution and brine, and dried (Na2SO4). Concentration
1
4:1) to give 73 mg (81%) of the alcohol as a colorless oil: H
NMR (400 MHz, CDCl3) δ 5.52 (dd, J = 15.4, 7.9 Hz, 1H), 5.23
5616 J. Org. Chem. Vol. 75, No. 16, 2010

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gave a residue that was purified by flash chromatography
(hexanes/EtOAc, 20:1 to 10:1, then EtOAc/EtOH, 10:0 to 9:1).
Olefin 43 (88 mg, 44%) was isolated as the first fraction as a 6:1
mixture of E/Z isomers. The isomers can be separated by flash
chromatography (hexanes/EtOAc, 80:1). As second fraction,
ketone 25 (56 mg, 51%), and as third fraction, phosphonamide 3
(98 mg, 45%) were recovered. E,E-Alkene 43, colorless oil: 1H
NMR (400 MHz, CDCl3) δ 5.63-5.54 (m, 2H), 5.28 (d, J = 8.9
Hz, 1H), 5.05 (ddd, J = 15.3, 8.6, 0.8 Hz, 1H), 4.12 (br s, 1H),
3.87 (dd, J = 10.6, 2.7 Hz, 1H), 3.16-3.06 (m, 1H), 2.20-2.08
(m, 1H), 1.95-1.84 (m, 1H), 1.84-1.71 (m, 2H), 1.67 (d, J = 0.9
Hz, 3H), 1.61 (s, 3H), 1.60-1.50 (m, 1H), 1.36-1.25 (m, 1H),
1.11-0.97 (m, 28H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 136.7, 135.3, 135.1, 129.2, 124.3, 120.9, 111.1,
77.9, 77.8, 76.3, 35.0, 30.4, 30.2, 25.6, 23.4, 21.0, 19.0, 18.6, 16.4,
12.9, 12.3, 11.3, 8.2; IR (film, NaCl) 2960, 2941, 2865, 2146,
1462, 1115, 1050, 883, 976, 665 cm-1; [R]D þ176.3° (c 0.89,
CHCl3); LRMS (ESI) calcd for C30H51OSi (M þ H)þ 455.4,
0.95 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 138.5,
138.4, 138.3, 137.0, 135.3, 135.0, 129.2, 128.32, 128.3, 128.28,
128.2, 127.6, 127.57, 127.54, 127.5, 123.9, 120.8, 87.9, 83.0, 79.5,
77.9, 77.7, 75.5, 74.4, 72.9, 72.7, 71.9, 70.2, 66.4, 37.1, 35.6, 34.9,
30.1, 29.7, 25.6, 22.5, 21.0, 18.9, 15.3, 12.9, 12.2, 8.2; IR (film,
NaCl) 3063, 3029, 2960, 2920, 2866, 2239, 1496, 1454, 1361,
1293, 1207, 1177, 1099, 1028, 962, 735, 697 cm-1; [R]D þ73.2°
(c 1.0, CHCl3); HRMS (ESI) calcd for C49H60NaO5 (M þ Na)þ
751.4333, found 751.4342.
(2S,3R,4S,6R)-2-(((1S,2S,3R)-2-((R,1E,4E)-5-((2R,6R)-6-Eth-
yl-5-methyl-3,6-dihydro-2H-pyran-2-yl)-3-methylhexa-1,4-dien-
1-yl)-3-methylcyclopropyl)ethynyl)-6-(2-hydroxyethyl)tetrahydro-
2H-pyran-3,4-diol (45). To a -78 °C solution of alkyne 44
(52 mg, 0.071 mmol) in THF (5 mL) was added freshly prepared
LDBB (2.1 mL of a 0.5 M solution in THF, 1.05 mmol) until a
green color persisted. After stirring for 1 h at -78 °C, analysis by
TLC indicated complete conversion of tribenzyl alkyne 34, and
saturated NH4Cl solution was added. Removal of all volatiles
in vacuo gave an aqueous mixture, which was extracted by EtOAc.
The combined organic phase was washed with brine, dried
(Na2SO4), and concentrated. Purification of the residue by flash
chromatography (hexanes/EtOAc, 2:1, then EtOAc) yielded 29
1
found 455.3. E,Z-Alkene, colorless oil: H NMR (400 MHz,
CDCl3) δ 5.63-5.56 (m, 2H), 5.11-5.03 (m, 2H), 4.34 (dd, J =
10.7, 3.0 Hz, 1H), 4.10 (br s, 1H), 3.21-3.13 (m, 1H), 2.29-2.18
(m, 1H), 1.81-1.71 (m, 6H), 1.61 (br s, 3H), 1.59-1.50 (m, 1H),
1.34-1.26 (m, 1H), 1.10-0.97 (m, 28H), 0.89 (t, J = 7.3 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 137.0, 135.3, 135.2, 130.5,
124.6, 121.0, 111.1, 77.5, 76.3, 72.1, 34.8, 30.5, 29.6, 25.5, 23.4,
21.6, 19.0, 18.6, 18.58, 16.5, 13.0, 11.3, 8.1; IR (film, NaCl) 2960,
2942, 2865, 2146, 1462, 1053, 882 cm-1; LRMS (ESI) calcd for
C30H51OSi (M þ H)þ 455.4, found 455.4.
1
mg (89%) of triol 45 as a colorless oil: H NMR (400 MHz,
CD3OD) δ 5.64-5.53 (m, 2H), 5.28 (d, J = 9.0 Hz, 1H), 5.14
(ddd, J = 15.2, 8.6, 1.0 Hz, 1H), 4.11 (br s, 1H), 3.85 (dd, J =
10.7, 2.9 Hz, 1H), 3.80 (dd, J = 9.5, 1.7 Hz, 1H), 3.72-3.55 (m,
3H), 3.53-3.45 (m, 1H), 3.16-3.09 (m, 2H), 2.18-2.08 (m, 1H),
1.96 (ddd, J = 12.9, 5.0, 1.7 Hz, 1H), 1.93-1.84 (m, 1H),
1.82-1.67 (m, 3H), 1.66 (d, J = 1.2 Hz, 3H), 1.62 (dd, J =
2.3, 1.2 Hz, 3H), 1.60-1.50 (m, 1H), 1.39-1.27 (m, 3H), 1.08 (d,
J = 6.3 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H), 1.02 (ddd, J = 4.9,
4.9, 1.8 Hz, 1H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz,
CD3OD) δ 137.9, 136.4, 136.3, 130.6, 125.6, 122.1, 88.8, 79.5,
77.2, 75.1, 74.1, 73.1, 72.7, 59.4, 40.6, 39.4, 36.3, 31.2, 31.0, 26.6,
23.8, 21.6, 19.1, 16.2, 13.2, 12.7, 8.8; IR (film, NaCl) 3391, 2963,
2928, 2872, 2238, 1453, 1368, 1303, 1065, 962, 930 cm-1; [R]D
þ138.7° (c 0.53, CHCl3); HRMS (ESI) calcd for C28H42NaO5
(M þ Na)þ 481.2925, found 481.2929.
(2R,6R)-2-((R,2E,5E)-6-((1S,2S,3R)-2-(((2S,3R,4S,6R)-3,4-
Bis(benzyloxy)-6-(2-(benzyloxy)-ethyl)tetrahydro-2H-pyran-2-
yl)ethynyl)-3-methylcyclopropyl)-4-methylhexa-2,5-dien-2-yl)-6-
ethyl-5-methyl-3,6-dihydro-2H-pyran (44). To a -78 °C solution
of alkyne 37 (58 mg, 0.19 mmol) in THF (1 mL) was added
n-BuLi (0.14 mL of a 1.6 M solution in hexanes, 0.22 mmol).
After stirring for 2 h at that temperature, a solution of lactone 15
(100 mg, 0.22 mol) in THF (1 mL) was added to the solution of
the generated anion. Stirring was continued for 1.5 h at -78 °C,
and the reaction mixture subsequently quenched by addition of
saturated NH4Cl solution and then diluted with EtOAc. After
phase separation, the aqueous layer was extracted with EtOAc.
The combined organic phase was washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was partially
purified by flash chromatography (hexanes/EtOAc, 20:1 to 2:1)
to give unreacted alkyne 37 (19 mg, 33%) as the first fraction and
the alkyne lactone adduct (136 mg) as second fraction (dr 1:1 by
1H NMR). The alkyne lactone adduct was contaminated with
unreacted lactone and butyl lactone adduct. The impure adduct
was used in the next step without further purification.
(2S,3R,4S,6R)-2-((E)-2-((1S,2S,3R)-2-((R,1E,4E)-5-((2R,6R)-
6-Ethyl-5-methyl-3,6-dihydro-2H-pyran-2-yl)-3-methylhexa-1,4-
dien-1-yl)-3-methylcyclopropyl)vinyl)-6-(2-hydroxyethyl)tetrahydro-
2H-pyran-3,4-diol (46). To a solution of triol 45 (30 mg, 0.065
mmol) in diethyl ether (6 mL) was added sodium bis(2-metho-
xyethoxy)aluminum hydride (0.21 mL of a 65% solution in tol-
uene, 0.7 mmol) at 0 °C. The reaction mixture was allowed to
warm to room temperature and stirred for 4 h. The reaction
mixture was then cooled to 0 °C, carefully quenched by addition
of saturated Rochelle salt solution, and vigorously stirred at
room temperature until two clear layers were obtained. After
phase separation, the aqueous layer was extracted with EtOAc.
The combined organic phase was washed with brine, dried
(Na2SO4), and concentrated in vacuo. Purification of the residue
by flash chromatography (EtOAc) yielded 24 mg (80%) of triol
46 as a colorless oil: 1H NMR (700 MHz, CD3OD) δ 5.59 (ddd,
J = 5.8, 3.1, 1.7 Hz, 1H), 5.51 (dd, J = 15.4, 6.7 Hz, 1H), 5.46
(dd, J = 15.2, 6.5 Hz, 1H), 5.38 (ddd, J = 15.3, 9.0, 0.7 Hz, 1H),
5.26 (dddd, J = 9.1, 2.6, 1.4, 1.4 Hz, 1H), 5.16 (ddd, J = 15.3,
8.8, 1.1 Hz, 1H), 4.09 (br s, 1H), 3.84 (dd, J = 10.7, 2.8 Hz, 1H),
3.69-3.60 (m, 3H), 3.56-3.48 (m, 2H), 3.15-3.09 (m, 1H), 2.97
(dd, J = 9.0, 9.0 Hz, 1H), 2.17-2.10 (m, 1H), 1.96 (ddd, J =
12.6, 5.0, 1.6 Hz, 1H), 1.89-1.85 (m, 1H), 1.79-1.69 (m, 2H),
1.65 (d, J = 1.3 Hz, 3H), 1.67-1.62 (m, 1H), 1.60 (dt, J = 3.4,
1.2 Hz, 3H), 1.59-1.52 (m, 1H), 1.50-1.46 (m, 1H), 1.34 (q, J =
12.1 Hz, 1H), 1.15-1.12 (m, 1H), 1.06 (d, J = 1.3 Hz, 3H), 1.05
(d, J = 6.8 Hz, 3H), 1.06-1.02 (m, 1H), 0.89 (t, J = 7.3 Hz, 3H);
13C NMR (176 MHz, CD3OD) δ 138.3, 136.3, 136.2, 136.1,
131.0, 127.0, 126.4, 122.1, 81.8, 79.6, 79.5, 77.3, 73.7, 73.6, 59.7,
40.9, 39.5, 36.4, 31.8, 31.2, 29.9, 26.6, 22.4, 21.7, 19.2, 13.5, 12.7,
To a -50 °C solution of the alkyne lactone adduct thus pre-
pared in a mixture of CH2Cl2 (3 mL) and CH3CN (3 mL) was
added triethylsilane (0.12 mL, 0.75 mmol). After stirring for 1 h
at that temperature, BF3 OEt2 (50 μL, 0.40 mmol) was added.
3
The reaction mixture was stirred for an additional 1 h at -50 °C
and then quenched by addition of triethylamine (0.14 mL,
1.0 mmol). The mixture was diluted with dichloromethane, washed
with saturated NH4Cl solution and brine, dried (Na2SO4), and
concentrated in vacuo. Purification of the residue by flash
chromatography (hexanes/EtOAc, 10:1 to 4:1) yielded 91 mg
(66% over two steps) of pure tribenzyl alkyne 44 as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 7.49-7.43 (m, 2H),
7.42-7.29 (m, 13H), 5.62 (d, J = 4.9 Hz, 1H), 5.54 (dd, J =
15.3, 6.5 Hz, 1H), 5.30 (d, J = 8.8 Hz, 1H), 5.08 (dd, J = 15.3,
8.6 Hz, 1H), 4.96 (d, J = 10.6 Hz, 1H), 4.91 (d, J = 10.5 Hz, 1H),
4.71 (s, 2H), 4.54 (s, 2H), 4.16 (br s, 1H), 3.99 (dd, J = 9.5, 1.3
Hz, 1H), 3.90 (dd, J = 10.7, 2.7 Hz, 1H), 3.70-3.53 (m, 4H),
3.44 (t, J = 9.2 Hz, 1H), 3.16-3.07 (m, 1H), 2.23-2.08 (m, 2H),
1.99-1.75 (m, 5H), 1.69 (s, 3H), 1.64 (s, 3H), 1.62-1.52 (m, 1H),
1.51-1.32 (m, 2H), 1.11 (s, 3H), 1.09 (s, 3H), 1.07-1.02 (m, 1H),
J. Org. Chem. Vol. 75, No. 16, 2010 5617

Hanessian et al.
JOCArticle
8.7; IR (film, NaCl) 3368, 2960, 2920, 2872, 1668, 1451, 1368,
1062, 963 cm-1; [R]D þ83.0° (c 1.25, CHCl3); HRMS (ESI) calcd
for C28H44NaO5 (M þ Na)þ 483.3081, found 483.3097.
solution of triol 46 (6 mg, 0.013 mmol), DMAP (5 mg, 0.041
mmol), and i-Pr2NEt (47 μL, 0.27 mmol) in CH2Cl2 (2 mL) was
added N-formylbenzotriazole (33 mg, 0.22 mmol). The reaction
mixture was allowed to warm to room temperature and stirred
for 4 h. The residue obtained after concentration of the reaction
mixture in vacuo was purified by flash chromatography (hexane/
EtOAc, 4:1 to 2:1) to yield 6 mg (85%) of triformate 47 as an off-
white solid. Recrystallization from ethanol gave colorless crys-
tals: mp 93-94 °C; 1H NMR (700 MHz, CDCl3) δ 8.07 (s, 1H),
8.05 (s, 2H), 5.60 (d, J = 4.7 Hz, 1H), 5.49 (dd, J = 15.1, 6.4 Hz,
1H), 5.42 (dd, J = 15.3, 8.6 Hz, 1H), 5.35 (dd, J = 15.3, 7.4 Hz,
1H), 5.28 (d, J = 8.9 Hz, 1H), 5.18-5.14 (m, 1H), 5.08 (dd, J =
15.2, 8.9 Hz, 1H), 4.94 (t, J = 9.5 Hz, 1H), 4.35-4.27 (m, 2H), 4.13
(br s, 1H), 3.87 (dd, J = 10.8, 2.4 Hz, 1H), 3.70-3.65 (m, 1H), 3.76
(dd, J = 9.1, 7.8 Hz, 1H), 3.12-3.06 (m, 1H), 2.24 (dd, J = 11.9,
4.5 Hz, 1H), 2.17-2.11 (m, 1H), 1.98-1.92 (m, 1H), 1.90-1.84
(m, 2H), 1.83-1.77 (m, 1H), 1.67 (s, 3H), 1.62 (s, 3H), 1.61-1.53
(m, 2H), 1.50-1.44 (m, 1H), 1.15-1.09 (m, 1H), 1.10-1.03 (m,
7H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (176 MHz, CDCl3) δ
160.9, 160.1, 159.8, 140.0, 135.6, 135.08, 135.03, 129.5, 125.0,
122.2, 120.9, 79.0, 78.0, 77.8, 71.8, 71.6, 71.5, 60.4, 36.4, 35.0,
34.1, 30.1, 29.7, 29.3, 25.6, 21.3, 21.1, 19.0, 13.0, 12.2, 8.2;
HRMS (ESI) calcd for C31H48NO8 (M þ NH4)þ 562.3374,
found 562.3365.
(þ)-Ambruticin S (1a). A suspension of PtO2 (20 mg) in water
(15 mL) was treated with hydrogen at 100 psi using a stainless
steel autoclave for 1 h. The mixture of Pt (black) in water was
then added to a solution of triol 46 (10 mg, 0.022 mmol) and
NaHCO3 (20 mg) in acetone (12 mL) and 2-propanol (3 mL).
The reaction mixture was heated to 50 °C while oxygen was
bubbled through the solution, until analysis by LC-MS indic-
ated complete conversion of triol 36 (about 2-3 h). The catalyst
was filtered off, and the solution was concentrated to dryness.
The residue was dissolved in EtOAc, washed with saturated
NH4Cl and brine, dried (Na2SO4), and concentrated in vacuo.
The residue thus obtained was purified by preparative TLC
(EtOAc/i-PrOH/H2O, 85:10:5) to give 9.5 mg (91%) of (þ)-
1
ambruticin S (1a) as an amorphous, off-white solid: H NMR
(700 MHz, CD3OD) δ 5.61-5.60 (m, 1H), 5.52 (dd, J = 15.4,
6.6 Hz, 1H), 5.48 (dd, J = 15.2, 6.5 Hz, 1H), 5.39 (dd, J = 15.4,
8.7 Hz, 1H), 5.27 (dq, J = 9.0, 1.1 Hz, 1H), 5.18 (ddd, J = 15.3,
8.8, 1.1 Hz, 1H), 4.11 (br s, 1H), 3.90-3.87 (m, 1H), 3.85 (dd,
J = 10.8, 2.9 Hz, 1H), 3.56 (ddd, J = 11.5, 8.8, 5.0 Hz, 1H), 3.53
(dd, J = 9.2, 7.0 Hz, 1H), 3.13-3.09 (m, 1H), 2.99 (dd, J = 9.0,
9.0 Hz, 1H), 2.52 (dd, J = 15.3, 7.6 Hz, 1H), 2.46 (dd, J = 15.5,
5.3 Hz, 1H), 2.16-2.11 (m, 1H), 2.06 (ddd, J = 12.6, 5.0, 1.6 Hz,
1H), 1.91-1.86 (m, 1H), 1.81-1.75 (m, 1H), 1.66 (d, J = 1.3 Hz,
3H), 1.62 (d, J = 1.1 Hz, 3H), 1.59-1.52 (m, 1H), 1.51-1.48 (m,
1H), 1.36 (q, J = 12.0 Hz, 1H), 1.15-1.13 (m, 1H), 1.07-1.06
(m, 3H), 1.06 (d, J = 6.8 Hz, 3H), 1.06-1.04 (m, 1H), 0.91 (t,
J = 7.3 Hz, 3H); 13C NMR (176 MHz, CD3OD) δ 174.8, 138.2,
136.20, 136.18, 136.0, 130.9, 126.9,126.1, 122.1, 81.8, 79.5, 79.4,
77.0, 73.32, 73.27, 41.6, 40.2, 36.3, 31.7, 31.1, 29.8, 26.6, 22.3,
21.7, 19.1, 13.4, 12.6, 8.7; IR (film, NaCl) 3368, 2959, 2920, 2851,
1713, 1452, 1378, 1063, 963 cm-1; [R]D þ54.2° (c 0.24, CHCl3);
HRMS (ESI) calcd for C28H41O6 (M-H)- 473.2909, found
473.2895.
Acknowledgment. We thank Syngenta (Basel, Switzerland)
for generous financial assistance and testing of analogues. We
also acknowledge funding from NSERC and FQRNT. We
^
thank Benoıt Deschenes Simard for X-ray structure determi-
nations and the “Centre regional de spectroscopie de masse de
l’Universite de Montreal” for the mass spectral analysis.
Supporting Information Available: Experimental proce-
dures for compounds 5, 29, and 48-50, spectroscopic data,
details of the crystallographic analysis, including CIF files, of
compounds 28 and 47, and copies of 1H and 13C NMR spectra
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(2S,3R,4S,6R)-2-((E)-2-((1S,2S,3R)-2-((R,1E,4E)-5-((2R,6R)-
6-Ethyl-5-methyl-3,6-dihydro-2H-pyran-2-yl)-3-methylhexa-1,4-
dien-1-yl)-3-methylcyclopropyl)vinyl)-6-(2-(formyloxy)ethyl)-tet-
rahydro-2H-pyran-3,4-diyl Diformate (47). To a cold (0 °C)
5618 J. Org. Chem. Vol. 75, No. 16, 2010