Stereoselective synthesis of erythronolide A via nitrile oxide cycloadditions and related studies

Article abstract of DOI:10.1021/jo901817b

(Chemical Equation Presented) An expeditious synthesis of erythronolide A is documented. Key steps of the approach include two magnesium-mediated nitrile oxide cycloadditions, a chelation-controlled Grignard reaction, and a Sharpless asymmetric dihydroxylation. 2009 American Chemical Society.

Full text of DOI:10.1021/jo901817b

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Stereoselective Synthesis of Erythronolide A via Nitrile Oxide
Cycloadditions and Related Studies
Dieter Muri and Erick M. Carreira*
€
Laboratorium fu€r Organische Chemie, ETH Honggerberg, Wolfgang Pauli Strasse 10,
CH-8093 Zu€rich, Switzerland
carreira@org.chem.ethz.ch
Received August 23, 2009
An expeditious synthesis of erythronolide A is documented. Key steps of the approach include two
magnesium-mediated nitrile oxide cycloadditions, a chelation-controlled Grignard reaction, and a
Sharpless asymmetric dihydroxylation.
Introduction
asymmetric centers.”4 The efforts in developing new metho-
dology for polyketide synthesis in the 1960s and 1970s
culminated in the first total synthesis of erythronolide B
(1d) in 1978 by Corey and co-workers.5 This accomplishment
still remains a milestone in synthetic organic chemistry.
Woodward and co-workers then published in 1981 the first
total synthesis of erythromycin A (1a),6 which remained the
only one that involved the attachment of the two sugar
moieties until the mid-1990s, when Toshima and Kinoshita
reported another synthesis of erythromycin A (1a),7 and
Martin accomplished the total synthesis of erythromycin B
(1b).3b The erythronolides have become the molecules of
choice to demonstrate new methodologies of stereoselective
synthesis for polyketide building blocks. Thus, the history of
the development of methods in stereoselective synthesis of
There is hardly a class of molecules that has attracted more
attention than erythromycin A (1a) and B (1b) and especially
their aglycons, erythronolide A (1c) and B (1d) in the history
of synthetic organic chemistry. Erythromycin A, first iso-
lated in 1952 by McGuire and co-workers at Lilly Research
Laboratories from the actinomycete Sacharopolyspora ery-
thraea,1 consists of a 14-membered lactone ring with 10
stereogenic centers and two unusual sugars, L-cladinose at
the C3 position and D-desosamine at the C5 position
(Figure 1). The 14-membered polyketide has attracted the
attention of many synthetic organic chemists and resulted in
more than 15 total syntheses of erythromycin A and its
derivatives.2,3 The starting signal for exploring this molecule
was given by Woodward in his famous statement in 1956:
“Erythromycin, with all our advantages, looks at present quite
hopelessly complex, particularly in view of its plethora of
(5) Corey, E. J.; Trybulski, E. J.; Melvin, L. S. Jr.; Nicolaou, K. C.;
Secrist, J. A.; Lett, R.; Sheldrake, J. R.; Brunell, D. J.; Haslanger, M. F.;
Kim, S.; Yoo, S.-e. J. Am. Chem. Soc. 1978, 100, 4618–4620. Corey, E. J.;
Kim, S.; Yoo, S.-e.; Nicolaou, K. C.; Lawrence, S. M. Jr; Brunelle, D. J.;
Falck, J. R.; Trybulski, E. J.; Lett, R.; Sheldrake, P. W. J. Am. Chem. Soc.
1978, 100, 4620–4622.
(1) Mc Guire, M.; Bunch, R. L.; Anderson, R. C.; Boaz, H. E.; Flynn, E.
H.; Powell, H. M.; Smith, J. W. Antibiot. Chemother. 1952, 2, 281–283.
(2) For reviews on early synthetic work, see: Paterson, I; Mansuri, M. M.
Tetrahedron 1985, 41, 3569–3624. Mulzer, J. Angew. Chem. 1991, 103,
Angew. Chem., Int. Ed. Engl. 1991, 30, 1452-1454.
(6) Woodward, R. B.; Logusch, E.; Nambiar, K. P.; Sakan, K.; Ward, D.
E.; Au-Yeung, B.-W.; Balaram, P.; Browne, L. J.; Card, P. J.; Chen, C. H.;
^
(3) For recent studies on the syntheses of erythromycins and erythrono-
lides, see: (a) St€urmer, R.; Ritter, K.; Hoffmann, R. W. Angew. Chem. 1993, 105,
112; Angew. Chem., Int. Ed. Engl. 1993, 32, 101. (b) Martin, S. F.; Hida, T.;
Kym, P. R.; Loft, M.; Hodgson, A. J. Am. Chem. Soc. 1997, 119, 3193. (c) Evans,
D. A.; Kim, A. S.; Metternich, R.; Novack, V. J. J. Am. Chem. Soc. 1998, 120,
5921. (d) Hergenrother, P. J.; Hodgson, A.; Judd, A. S.; Lee, W.-C.; Martin, S. F.
Angew. Chem. 2003, 115, 3400; Angew. Chem., Int. Ed., 2003, 3278. (e) Peng,
Z.-H.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 6018.
Chenevert, B.; Fliri, A.; Frobel, K.; Gais, H.-J.; Garratt, D. G.; Hayakawa,
K.; Heggie, W.; Hesson, S. P.; Hoppe, D.; Hoppe, I.; Hyatt, J. A.; Ikeda, D.;
Jacobi, P. A.; Kim, K. S.; Kobuke, Y.; Kojima, K.; Krowicki, K.; Lee, V. J.;
Leutert, T.; Malchenko, S.; Martens, J.; Mathews, R. S.; Ong, B. S.; Press, J.
B.; Rajan Babu, T. V.; Rousseau, B.; Sauter, H. M.; Suzuki, M.; Tatsuta, K.;
Tolbert, L. M.; Truesdale, E. A.; Uchida, I.; Ueda, Y.; Uyehara, T.; Vasella,
A. T.; Vladuchick, W. C.; Wade, P. A.; Williams, R. M.; Wong, N.-C. J. Am.
Chem. Soc. 1981, 103, 3210-3213; 3213-3215; 3215-3217.
(4) Woodward, R. B. In Perspectives in Organic Synthesis; Todd, A., Ed.;
Interscience Publishers: New York, 1956; p 155 (see p 160).
(7) Toshima, K.; Nozaki, Y.; Mukaiyama, S.; Tamai, T.; Nakata, M.;
Tatsuta, K.; Kinoshita, M. J. Am. Chem. Soc. 1995, 117, 3717–3727.
DOI: 10.1021/jo901817b
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Published on Web 10/19/2009
J. Org. Chem. 2009, 74, 8695–8712 8695
2009 American Chemical Society

Muri and Carreira
JOCArticle
with hydroxylamine hydrochloride in py/EtOH occurred
smoothly in 70% yield over three steps.
The preparation of enantiomerically enriched allylic alco-
hol 14 started with the addition of acetaldehyde to commer-
cially available propynylmagnesium bromide (Aldrich, 0.5
M in THF). The reaction afforded the propargylic alcohol in
93% yield. Ketone 12 was obtained in 73% yield after
oxidation, using Ley’s TPAP/NMO procedure.11 To access
enantioenriched propargylic alcohol, we decided to employ
Noyori’s transfer hydrogenation protocol (79% yield, 92%
ee, as determined by GC analysis).12 For the Z-selective
reduction of the triple bond, we followed a modified proce-
dure previously reported by Hamed,13 using Lindlar’s cata-
lyst14 and pentane as solvent. The target (R)-allylic alcohol
14 was obtained in 73% yield after distillation.
To initiate the cycloaddition sequence, oxime 11 was
treated with tert-butylhypochlorite15 at -78 °C to form the
hydroximoyl chloride in situ, which was slowly added to a
solution of allylic alcohol 14, 2-PrOH, and EtMgBr at 0 °C,
providing the desired cycloadduct 15 in 86% yield as a single
diastereomer (1H NMR) (Scheme 2). Oxidation to the
corresponding ketone 16 proceeded smoothly using NMO
and catalytic TPAP (82% yield). With ketone 16 in hand, the
first substrate for the Grignard coupling was generated.
Bromide 18, the second reaction partner, was prepared in
three steps from Roche ester 9.16 Protection of the primary
hydroxyl group as p-methoxybenzyl ether was achieved
under acidic conditions with PMB-imidate and catalytic
amounts of CSA (10 mol %) in 86% yield. The methyl ester
was reduced to the corresponding alcohol 17 with DIBAl-H
(84% yield), and subsequent reaction with Br2, PPh3, and
imidazole provided bromide 18 in 89% yield.
The Grignard coupling reagent was generated from 18
through a transmetalation sequence by treatment of a solution
of bromide 18 (1.3 equiv) in Et2O with t-BuLi (1.7 M in
pentane, 2.7 equiv) and subsequently with MgBr2 (1 M in
Et2O/PhH, 1.5 equiv) at -78 °C (Scheme 3).17 The off-white
suspension was treated with a solution of ketone 16 (1 equiv) in
THF. After stirring for 1 h at -78 °C, the colorless solution
was quenched with satd aq NH4Cl and 65% of the coupling
product 19 was isolated as a 20:1 mixture of diastereomers as
assayed by 1H NMR (98% yield based on recovered ketone).
In order to determine the configuration at C6, the correspond-
ing substituted tetrahydrofuran 21 was formed; this sequence
is initiated by cleavage of the PMB-ether in 19, mesylation, and
subsequent ring formation. Analysis of the NOE spectrum
revealed a through-space interaction between the methyl
group at C6 and the C8-H, indicating a chelation-controlled
addition for the Grignard coupling and thereby the desired
configuration of the C6-stereocenter.
FIGURE 1. Structures of the erythromycins and erythronolides.
polyketides can be traced from the synthesis of erythro-
nolides.
We now report the total synthesis of erythronolide A (1c)
by taking advantage of the Kanemasa hydroxy-directed
nitrile oxide cycloaddition,8 as well as a full account of our
studies and observations, leading to a short and expedient
synthesis.
Synthetic Planning
Erythronolide A (1c) is ideally suited for the application
and extension of methods involving magnesium-mediated
nitrile oxide cycloaddition reactions, which we have studied
in detail.9 As the isoxazolines can serve as protected
β-hydroxy ketone surrogates, the N-O bond reduction
and hydrolysis can be effected at a late stage of the synthesis.
Macrocyclization was intended to proceed by lactonization
of an ω-hydroxy acid 3. We envisioned that seco-acid 3
would be formed by a nitrile oxide cycloaddition. Oxime 4,
a nitrile oxide precursor, is derived from ketone 5 and
bromide 6 and assembled by a Grignard coupling. Ketone
5 is accessible from oxime 7 and allylic alcohol 8 by cycload-
dition followed by oxidation.
Results and Discussion
The synthesis of erythronolide A started with the prepara-
tion of oxime 11 and allylic alcohol 14 (Scheme 1). Oxime 11
was easily prepared via a high-yielding three-step se-
quence from Roche ester 9. Protection of the primary
hydroxyl group furnished the corresponding TBS ether,
which was reduced to aldehyde 10 by careful addition of
DIBAl-H to a solution of the ester in Et2O at -78 °C.10
Conversion of aldehyde 10 to the corresponding oxime 11
(8) (a) Kanemasa, S.; Kobayashi, S.; Nishiuchi, M.; Yamamoto, H.;
Wasa, E. Tetrahedron Lett. 1991, 32, 6367–6370. (b) Kanemasa, S.;
Nishiushi, M.; Wada, E. Tetrahedron Lett. 1992, 33, 1357–1360. (c) Kane-
masa, S.; Nishiuchi, M.; Kamimura, A.; Hori, K. J. Am. Chem. Soc. 1994,
116, 2324–2339.
(9) For previous investigations from our laboratory involving nitrile
oxide cycloadditions with allylic alcohols, see: (a) Bode, J. W.; Fraefel, N.;
Muri, D.; Carreira, E. M. Angew. Chem., Int. Ed. 2001, 40, 2082. (b) Bode, J.
W.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 3611. (c) Bode, J. W.;
Carreira, E. M. J. Org. Chem. 2001, 66, 6410. (d) Fader, L. D.; Carreira, E.
M. Org. Lett. 2004, 14, 2485. (e) Muri, D.; Lohse-Fraefel, N.; Carreira, E. M.
Angew. Chem., Int. Ed. 2005, 44, 4036. (f) Lohse-Fraefel, N.; Carreira, E. M.
Org. Lett. 2005, 7, 2011. (g) Becker, N.; Carreira, E. M. Org. Lett. 2007, 9,
3857. (h) Szpilman, A. M.; Cereghetti, D. M.; Wurtz, N. R.; Manthorpe, J.
M.; Carreira, E. M. Angew. Chem. 2008, 47, 4335. (i) Szpilman, A. M.;
Manthorpe, J. M.; Carreira, E. M. Angew. Chem. 2008, 47, 4339. (j)
Kleinbeck, F.; Carreira, E. M. Angew. Chem., Int. Ed. 2009, 48, 578.
(10) Direct reduction to the aldehyde was suitable up to 5 g. On a larger
scale, complete reduction to the alcohol and reoxidation to the aldehyde
under Ley’s condition gave better results.
(11) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639–666.
(12) (a) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R.
Angew. Chem., Int. Ed. Engl. 1997, 36, 285–287. (b) Matsumura, K.;
Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738–
8739.
(13) Hamed, O.; Henry, P. M. Organometallics 1997, 16, 4903–4909.
(14) Lindlar, H. Helv. Chim. Acta 1952, 35, 446.
(15) Mintz, M. J.; Walling, C. Org. Synth. 1969, 49, 9–12.
(16) The bromide 167 was already prepared earlier: Meyer, S. D.; Miwa,
T.; Nakatsuka, M.; Schreiber, S. L. J. Org. Chem. 1992, 57, 5058–5060.
(17) For an example of a lithium-halogen exchange and subsequent
transmetallation with MgBr2, see: Nakatsuka, M.; Ragan, J. A.; Sammakia,
T.; Smith, D. B.; Uehling, D. E.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112,
5583–5601.
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FIGURE 2. Retrosynthetic analysis.
SCHEME 1
SCHEME 2
Protection of the tertiary hydroxyl group of 19 as a
triethylsilyl ether was accomplished under standard condi-
tions with TESOTf and 2,6-lutidine (93% yield) (Scheme 4).
Oxidative cleavage of the PMB-ether (DDQ, pH 7 buffer) of
22 afforded 23. To our surprise, a dimeric byproduct was
formed, whose NMR spectrum was consistent with 25
(51%). Under acidic conditions (10 mol % CSA, MeOH),
it could easily be converted to the desired product 23
(85% yield). Oxidation of the alcohol to the aldehyde was
achieved under TEMPO/NaOCl conditions and pH 8.6
buffer.18 The previously used Ley oxidation procedure11
was not suitable for this substrate because epimerization of
the C8-stereocenter was detected. Conversion to oxime 24
with t-BuOCl leads to its oxidation to the corresponding
hydroxymoyl chloride, which was then in turn treated with a
preformed solution of methylene chloride including allylic
alcohol 14 under standard reaction conditions (EtMgBr, i-
PrOH) (Scheme 5). Cycloadduct isoxazoline 26 was isolated
in 86% yield, as a single diastereomer as assayed by 1H NMR
spectroscopy. Subsequent oxidation of the secondary alco-
hol (TEMPO/NaOCl)18 furnished ketone 27 in 77% yield,
which upon exposure to PrPPh3Br (t-BuLi, THF) provided
olefin 28 in 71% yield as a 30:1 mixture of Z and E isomers
(1H NMR). The installation of the remaining diol was
effected through application of the asymmetric dihydroxyl-
ation reaction of Sharpless.19 Treatment of 28 with
was performed with H2NOH HCl/pyridine in 81% yield
3
over 2 steps.
The preparation of oxime 24 sets the stage for a second
Mg-mediated 1,3-dipolar cycloaddition reaction to enjoin
the C(1)-C(9) and the C(10)-C(15) fragments and assem-
ble the entire carbon skeleton. Treatment of oxime 24
(18) (a) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem.
1987, 52, 2559–2562. (b) For a review on the use of stable nitroxyl radicals for
the oxidation of alcohols, see: de Nooy, A. E. J.; Besemer, A. C.; van
Bekkum, H. Synthesis 1996, 1153–1174.
(19) For excellent reviews, see: (a) Kolb, H. C.; VanNieuwenhze, M. S.;
Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547. (b) Johnson, R. A.;
Sharpless, K. B. Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, J., Ed.;
Wiley-VCH: New York, 2000; pp 357-398.
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SCHEME 3
no reaction (DMSO, NEt3, cyanuric acid;22 Pt black, O2;23
DMS, NCS, NEt324), formation of methyl ketone 32
(PDC;25 H2SO4, CrO326), or decomposition (IBX, NHS,
DMSO;27 bisacetoxyiodobenzene, TEMPO;28 DMSO,
(COCl)2, NEt329) occurred. Fortunately, successful results
were observed with Dess-Martin periodinane (DMP).30
Under conditions excluding H2O, a solution of alcohol 30
in CH2Cl2 was treated with 4 equiv of DMP (Scheme 6).
After 1 h at 0 °C, the solvent was removed under vacuum
and the unstable aldehyde was immediately subjected to
Lindgren oxidation,31 providing the seco-acid 31 in 65%
yield without affecting the secondary alcohol.
The stage was set to investigate whether bisisoxazoline
seco-acid 31 would undergo cyclization to afford the targeted
macrocycle. The idiosyncracies of ring closure in the forma-
tion of macrolactones have been appreciated since the classic
work of Woodward involving the cyclization of erythromy-
cin A seco-acids.6 Analysis of simple models convinced us
that the isoxazolines bridging C3-C5 and C9-C11 would
lead to conformations enabling macrolactonization. In the
event through the use of a modified Yamaguchi protocol,32
desired macrolactone 33 was isolated in 55% yield
(Scheme 7).
SCHEME 4
With macrolactone 33 in hand, we were at a stage to finish
erythronolide A (1c) in 3 steps: reductive cleavage of the
isoxazolines, reduction of the ketone at C3, and deprotection
of the triethylsilyl ether. However, isoxazoline opening
already proved challenging. Under standard conditions de-
scribed by Curran, employing Raney Ni, boric acid, and
hydrogen, no conversion was observed.33 Under similar
conditions, using acetic acid instead of boric acid, no product
was formed.34 Stirring for several days slowly led to decom-
position of the starting material. The use of different palla-
dium35 and rhodium sources36 for hydrogenation did not
lead to satisfactory results, and only starting material could
be isolated. Homogeneous conditions such as SmI2 in
THF,37 SmI2/HMPA in THF, and Mo(CO)6 in CH3CN/
H2O38 were unsuccessful. The SmI2-procedures led to the
recovery of 33, the latter led only to deprotection of the
triethylsilyl ether, and the diketone 34 was never obtained.
With these unsatisfactory results a revision of the route
had to be considered. An early reduction of the isoxazo-
line at C3-C5 to the 1,3-diol and subsequent protection
might bring the necessary flexibility to the 14-membered
(DHQD)2PHAL (0.1 equiv), K3Fe(CN)6 (3 equiv), K2CO3
(3 equiv), methanesulfonamide (3 equiv), and K2OsO4
3
2H2O (0.04 equiv) gave diol 29 in 82% as a single diaster-
eomer. Exposure of 29 to HF pyridine/pyridine (1:3) led to
3
selective deprotection of the primary tert-butyldimethylsilyl
ether (83% yield).20
The simple transformation of alcohol 30 to the corre-
sponding aldehyde turned out to play a crucial role in the
continuation of the synthesis. Several protocols for selective
oxidation of primary alcohols over secondary ones were
examined,21 and the previously employed TEMPO-cata-
lyzed procedure should have been well-suited for such a
problem.18 However, these reaction conditions were unsuc-
cessful, and only methyl ketone byproduct 32 could be
isolated. Similar results were obtained for Ley’s TPAP
procedure. Several other well-established oxidation proce-
dures were examined but did not lead to any success. Either
(24) Corey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586–7587.
(25) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 5, 399–402.
(26) Bowden, K.; Heilbron, I. M.; Jones, E. R. H.; Weedon, B. C. L. J.
Chem. Soc. 1946, 39–45.
€
(27) Mazitschek, R.; Mulbaier, M.; Giannis, A. Angew. Chem., Int. Ed.
2002, 41, 4059–4061.
(28) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G.
J. Org. Chem. 1997, 62, 6974–6977.
(29) Mancuso, A. J.; Swern, D. Synthesis 1981, 165–185.
(30) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
(31) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888–890.
(32) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989–1993.
(20) For an excellent review on selective deprotection of silyl ethers, see:
Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031–1069.
(21) (a) With zirconocene complexes: Nakano, T.; Terada, T.; Ishii, Y.;
Ogawa, M. Syntheses 1986, 774–776. (b) TEMPO/sodium bromite: Inoku-
chi, T.; Matsumoto, S.; Nishiyama, T.; Torii, S. J. Org. Chem. 1990, 55, 462–
466. (c) TEMPO/trichloroiso-cyanuric acid: De Luca, L.; Giacomelli, G.;
Porcheddu, A. Org. Lett. 2001, 3, 3041–3043. (d) TEMPO/peroxodisulfate/
(33) Curran, D. P.; Zhang, J. J. Chem. Soc., Perkin Trans. 1 1991, 2613–
2625.
€
silver nitrate: Kochkar, H.; Lassalle, L.; Morawietz, M.; Holderich, W. F. J.
Catal. 2000, 194, 343–351. (e) TEMPO/NCS: Einhorn, J.; Einhorn, C.;
Ratajczak, R.; Pierre, J.-L. J. Org. Chem. 1996, 61, 7452–7454. (f) TEMPO/
NaOBr: Chan, P. S.; Robyt, J. F. J. Carbohydr. Chem. 1996, 15, 819–830.
(22) De Luca, L.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2001, 66,
7907–7909.
(34) Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826–5833.
(35) Souza, F. E. S.; Rodrigo, R. Chem. Commun. 1999, 1947–1948.
(36) Kim, B. H.; Jacobs, P. B.; Elliott, R. L.; Curran, D. P. Tetrahedron
1988, 44, 3079–3092.
(37) Bode, J. W.; Carreira, E. M. Org. Lett. 2001, 3, 1587–1590.
(38) Baraldi, P. G.; Barco, A.; Benetti, S.; Manfredini, S.; Simoni, D.
Synthesis 1987, 276–278.
(23) Hutchinson, D. K.; Fuchs, P. L. J. Am. Chem. Soc. 1987, 109, 4755–
4756.
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SCHEME 5
SCHEME 6
SCHEME 8
SCHEME 7
Zn(BH4)2 afforded the syn-1,3-diol in 60% yield and a
diastereomeric ratio greater than 95:5 (by 1H NMR).39 Other
reduction procedures such as Prasad’s conditions40 or
DIBAl-H41 led to significantly decreased selectivities. The
diol was protected as its benzylidene acetal 37 (PhCH-
(OMe)2, CSA, 87% yield). The PMB ether was removed
with DDQ at 0 °C (85% yield) and then oxidized to the
aldehyde under TEMPO/NaOCl conditions.18 Subsequent
conversion to oxime 39 was accomplished with H2NOH
HCl/py in 85% yield (over 2 steps).
3
The cycloaddition afforded 40 in 86% yield as single
diastereomer (determined by 1H NMR) (Scheme 9). Oxida-
tion of the secondary alcohol under TEMPO/NaOCl condi-
tions (93% yield), and Wittig reaction provided olefin
42 in 78% yield and a 33:1 Z:E diastereoselectivity. Sharp-
less asymmetric dihydroxylation to 43 (81% yield, dr
>97:3, determined by 1H NMR) and selective deprotection
macrocycle for a successful late-stage opening of the second
isoxazoline at C9-C11.
Final Route to Erythronolide A
Reductive opening of the isoxazoline 22 to the β-hydroxy
ketone was accomplished with Raney Ni, B(OH)3 in 89%
(Scheme 8).33 Reduction of β-hydroxy ketone 35 with
(40) Chen, K.-M.; Gunderson, K. G.; Hardtmann, G. E.; Prasad, K.;
Repic, O.; Shapiro, M. J. Chem. Lett. 1987, 16, 1923–1926.
(41) Kiyooka, S.; Kuroda, H.; Shimasaki, Y. Tetrahedron Lett. 1986, 27,
3009–3012.
(39) Ito, Y.; Yamaguchi, M. Tetrahedron Lett. 1983, 24, 5385–5386.
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SCHEME 9
improved. Using the same conditions as for the previously
described macrolactonizations, lactone 46 was formed in
SCHEME 10
78% yield (Scheme 10). Then careful deprotection of the
42
triethylsilyl ether with HF NEt3 and NEt3 at 30 °C over
3
3 days was necessary. Smooth reductive opening of the
isoxazoline in 10 min, using Raney Ni and AcOH in EtOH,
provided macrolactone 47 in 93% yield. The completion of
the synthesis of 47 represents a formal total synthesis of
erythronolide A.
Buoyed by Kinoshita’s report on the deprotection of
the benzylidene acetal using Pd black/H2 in MeOH over
30 min to give erythronolide A in 85% yield, we set out to
reproduce this result.43 After stirring substrate 47 for 30 min
in a mixture of Pd black in MeOH under an atmosphere
of H2, only starting material was observed. After prolonged
stirring, a new product was formed. Isolation of this pro-
duct showed successful removal of the benzylidene acetal,
but comparison of the 1H NMR spectrum with Kinoshita’s
analysis revealed none of the expected erythronolide
A. Examination of the mass spectrum indicated loss of
water, and no signal at 220 ppm was detected by 13C NMR
spectroscopic analysis, indicating the absence of the ketone
at C9. Instead, unexpected signals at 151 and 102 ppm
revealed the formation of a cyclic enol ether. Further
analysis by COSY, HSQC, and HMBC suggested the
formation of the six-membered cyclic enol ether 48a
(Scheme 11). After stirring the reaction mixture for 15 h,
of the tert-butyldimethylsilyl ether, using HF py/py (1:3)
3
furnished the primary alcohol in 80% yield. seco-Acid
45 was obtained in 83% yield by formation of the
aldehyde, using TEMPO/NaOCl, followed by Lindgren
oxidation.31
With the benzylidene acetal protecting group at the C3/C5
position, the yield of the macrolactonization significantly
€
(42) Bode, J. W. Ph.D. thesis, Diss. ETH No. 14115, 2001, ETH, Zurich.
(43) (a) Kinoshita, M.; Arai, M.; Ohsawa, N.; Nakata, M. Tetrahedron
Lett. 1986, 27, 1815–1818. (b) Bull. Chem. Soc. Jpn. 1989, 62, 2618-2635.
8700 J. Org. Chem. Vol. 74, No. 22, 2009

Muri and Carreira
JOCArticle
SCHEME 11
Experimental Section
(2R)-3-{[tert-Butyl(dimethyl)silyl]oxy}-2-methylpropanal
Oxime (11).
To a solution of imidazole (15.4 g, 226 mmol, 2.50 equiv) and
TBSCl (16.3 g, 108 mmol, 1.20 equiv) in dry DMF (15.0 mL) was
added dropwise a solution of (R)-methyl 3-hydroxy-2-methylpro-
pionate (9)(10.0 mL, 90.2 mmol, 1.00 equiv) in DMF (15 mL). The
mixture was stirred for 6 h at rt, before Et2O (250 mL) and H2O
(60.0 mL) were added. The layers were separated, and the organic
phase was washed with H2O (3 ꢀ 60 mL) and brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure to give the intermediate TBS ether. The resulting colorless oil
was used without further purification. Neat DIBAl-H (48.2 mL, 271
mmol, 3.00 equiv) was added dropwise to the unpurified TBS ether
in CH2Cl2 (600mL) at-78 °C. The mixture was stirred for 90 min at
-78 °C and was then quenched carefully by addition of MeOH (10
mL). After stirring for 10 min, saturated, aqueous sodium potassium
tartrate (300 mL) was added. The mixture was treated with Et2O
(600 mL), allowed to warm to rt, and stirred for 12 h. The two layers
were separated, and the aqueous layer was extracted with Et2O (2 ꢀ
300 mL). The combined organic solutions were dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure to
give the intermediate primary alcohol, which was used without
further purification. To the unpurified alcohol in CH2Cl2 (400 mL)
SCHEME 12
the formation of a second byproduct could be detec-
ted. Isolation of this compound and analysis of the
1H NMR and 13C NMR spectra provided evidence for the
generation of bicyclic acetal 49a, which was confirmed by
COSY, HSQC, and HMBC analysis.44 Similar results
were also obtained with the triethylsilyl protecting group
still in place.
The desired effect could not be achieved by raising the
pressure of H2 up to 6 bar. To our surprise, by changing the
palladium source to Pd/C (10%) or Pd(OH)2/C (10%), the
reaction rate could be significantly enhanced, but the desired
product was not detected. However, in situ preparation of Pd
black from Pd(OAc)2 led to the desired result. Erythronolide
A (1c) could be isolated in 40% yield by treating 47 with H2,
excess Pd(OAc)2, MeOH, and catalytic amounts of water
(Scheme 12). The material accessed by the described route
was identical in all respects to that reported for previous
syntheses and the natural product.
˚
at rt were added NMO (15.9 g, 135 mmol, 1.50 equiv) and 4 A M.S.
(45.0 g), and the slurry was stirred for 30 min at rt before TPAP
(0.984 g, 2.80 mmol, 3.00 mol %) was slowly added as a solid at rt.
The mixture was stirred at rt for 30 min. Pentane (400 mL) was
added, and the mixture filtered over a short column of silica gel,
eluting with 2:1 pentane/Et2O (1000 mL). Concentration provided
the intermediate aldehyde 10 as a slightly yellow liquid that was used
immediately without further purification.45 To a solution of unpur-
ified aldehyde 10 in EtOH (800 mL) at rt was added NH2OH HCl
3
(9.41 g, 135 mmol, 1.50 equiv) in pyridine (110 mL). The mixture
was stirred at rt for 14 h and subsequently concentrated under
reduced pressure. To the resulting residue were added EtOAc
(600 mL) and H2O (200 mL), and the organic layer was washed
with H2O (2 ꢀ 200 mL) and brine, and dried over anhydrous
Na2SO4. The pyridine was removed by azetropical coevaporation
with cyclohexane (6 ꢀ 200 mL). Purification by chromatography on
silica gel (hexane/EtOAc 10:1) gave oxime 11 as colorless oil (10.7 g,
55% yield over 4 steps from (R)-methyl 3-hydroxy-2-methyl-
Conclusion
1
propionate). [R]20.0D (c 1.100, CHCl3) = -5.7°. H NMR (300
In summary, a synthesis of erythronolide A is docu-
mented that relies on the implementation of tactics involv-
ing the dipolar cycloaddition reaction of nitrile oxides
and allylic alcohols. The successful use of two Mg(II)-
mediated nitrile oxide cycloaddition reactions results in a
synthesis of erythronolide A that is the shortest to date,
proceeding in 21 linear steps and 4% overall yield. The
work we have delineated establishes the nitrile oxide
cycloaddition reaction with allylic alcohols as a means of
joining complex fragments and thus as a salient, power-
ful tactic for the synthesis of polyketide-derived natural
products. The derived isoxazoline cycloadducts can
function as β-hydroxyketone surrogates that can be un-
masked late in a synthesis within a densely functionalized
structure.
MHz, CDCl3, * denotes minor cis/trans isomeric peak) δ: 7.41 (d, 1
H, J = 6.2 Hz), 6.66* (d, 1 H, J = 7.2 Hz), 3.66-3.56 (m, 2 H),
3.32-3.19* (m, 1 H), 2.62-2.48 (m, 1 H), 1.09 (d, 3 H, J = 6.9 Hz),
1.08* (d, 3 H, J = 6.9 Hz), 0.89 (s, 9 H), 0.05 (s, 3 H), 0.04 (s, 3 H).
13C NMR (75 MHz, CDCl3, * denotes minor cis/trans isomeric
peak) δ: 155.1*, 154.5, 66.0, 65.2*, 37.3, 25.8, 18.3, 14.2, 13.9*, -5.4.
IR (thin film) 3306, 2956, 2930, 2885, 2858, 1472, 1462, 1389, 1362,
1257, 1104, 1032, 1007 (cm-1). Anal. Calcd for C10H23NO2Si: C,
55.25; H, 10.66; N, 6.44. Found: C, 55.43; H, 10.64; N, 6.47.
3-Pentyn-2-ol.
Propynylmagnesium bromide (0.5 M in THF, 800 mL, 400
mmol, 1.00 equiv) was concentrated to 400 mL and treated with
(44) Corey already described the acid sensitivity of erythronolide A and
the subsequent formation of a tricyclic ketal: Schomburg, D.; Hopkins, P. B.;
Lipscomb, W. N; Corey, E. J. J. Org. Chem. 1980, 43, 1544–1546.
(45) This aldehyde was described earlier: Gaucher, A.; Ollivier, J.;
€
Marguerite, J.; Paugam, R.; Salaun, J. Can. J. Chem. 1994, 72, 1312–1327.
J. Org. Chem. Vol. 74, No. 22, 2009 8701

Muri and Carreira
JOCArticle
Et2O (400 mL). A solution of acetaldehyde (45.0 mL, 800 mmol,
2.00 equiv) in Et2O (400 mL) was added at 0 °C. The brown
solution was warmed to rt and stirred for 5 h. The reaction
solution was quenched with satd aq NH4Cl (400 mL), washed
with brine (200 mL), dried over anhydrous Na2SO4, and con-
centrated at 40 °C/700 mbar. The remaining brown liquid was
distilled under reduced pressure (50 mbar, 90 °C) to give the
racemic title alcohol (29.1 g, 87% yield) as a clear, colorless
liquid. 1H NMR (300 MHz, CDCl3) δ: 4.49 (m, 1H), 1.84 (d, 3H,
J = 2.07 Hz), 1.42 (d, 3H, J = 6.4 Hz). The spectral data were
identical with those previously reported.46
(m, 1H), 1.68 (d, 3H, J = 6.4 Hz), 1.24 (d, 3H, J = 6.3 Hz). The
spectral data were identical with those previously reported.46
(1R)-1-[(4S,5R)-3-((1R)-2-{[tert-Butyl-(dimethyl)-silyl]oxy}-
1-methylethyl)-4-methyl-4,5-dihydroisoxazol-5-yl]ethanol (15).
To a solution of (R)-(-)-(Z)-3-penten-2-ol (14) (0.475 g, 5.52
mmol, 1.20 equiv) and 2-propanol (1.17 mL, 15.2 mmol, 3.30
equiv) in CH2Cl2 (250 mL) at 0 °C was added EtMgBr (3 M in
Et2O, 4.60 mL, 13.8 mmol, 3.00 equiv). The reaction mixture
turned momentarily cloudy, becoming clear and colorless upon
stirring at 0 °C for 30 min. At this time, the hydroxymoyl
chloride, prepared by addition of t-BuOCl (0.580 mL,
5.06 mmol, 1.10 equiv) to a solution of oxime (-)-11 (1.00 g,
4.60 mmol, 1.00 equiv) in CH2Cl2 (46 mL) at -78 °C and stirring
for 1.5 h, was added dropwise via cannula to the reaction to give
a slightly yellow solution. It was allowed to warm to rt and
stirred for 16 h. The reaction was quenched by the addition of
satd aq NH4Cl (200 mL), and the two layers were separated. The
aqueous layer was extracted with CH2Cl2 (3 ꢀ 50 mL). The
combined organic solutions were washed with brine (50 mL),
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. Purification by chromatography on silica gel (hexane/
EtOAc 3:1) provided isoxazoline 15 (1.20 g, 86% yield) as a clear
colorless oil. No other diastereoisomer could be detected, as
determined by examination of the diastereotopic signals of
the proton at C5 (4.0 -4.2 ppm) of 15 in the 1H NMR
spectrum of the crude material. Rf = 0.21 (3:1 hexane/EtOAc).
[R]25.0D(c 1.060, CHCl3) = -13°. 1H NMR (300 MHz, CDCl3)
δ: 4.16 (dd, 1H, J = 9.3, 5.3 Hz), 3.98-3.90 (m, 1H), 3.66-3.58
(m, 2H), 3.31-3.23 (m, 1H), 2.67-2.60 (m, 1H), 2.06 (d(br), 1H,
J = 6.2 Hz), 1.25 (d, 3H, J = 6.5 Hz), 1.19 (d, 3H, J = 6.9 Hz),
1.17 (d, 3H, J = 7.2 Hz), 0.87 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H).
13C NMR (75 MHz, CDCl3) δ: 166.6, 85.9, 67.1, 66.1, 45.3, 34.7,
25.9, 20.3, 18.3, 14.6, 10.7, -5.4. IR Spectroscopy (thin film)
3408, 2930, 2857, 1462, 1389, 1255, 1091, 900, 837, 776 (cm-1).
EI-MS (m/z): 300.3 ([M]þ), 244.1(20), 240.1(12), 172.1, (17),
142.0(31), 122.0(13), 115.0(31), 96.0(16), 84.0(23), 75.0(100),
73.0(30). Anal. Calcd for C15H31NO3Si: C, 59.76; H, 10.36.
Found: C, 59.69; H, 10.48.
3-Pentyn-2-one (12).
To a suspension of 3-pentyn-2-ol (15.0 g, 178 mmol, 1.00
˚
equiv), NMO (31.3 g, 232 mmol, 1.30 equiv), and 4 A M.S.
(90.0 g) in CH2Cl2 (350 mL) was added TPAP (1.88 g, 5.35
mmol, 0.03 equiv) over a period of 30 min. After 2 h of stirring at
ambient temperature, pentane (400 mL) was added. The dark
brown mixture was filtered over a plaque of silica gel (pentane/
Et2O 1:1). The solvent was evaporated at 900 mbar, 40 °C. The
liquid was purified by fractionated distillation (70 mbar, 80 °C)
to afford 3-pentyn-2-one (12) (10.9 g, 73% yield) as a clear,
1
colorless liquid. H NMR (300 MHz, CDCl3) δ: 2.31 (s, 3H),
2.01 (s, 3H). The spectral data were identical with those pre-
viously reported.46
(R)-(þ)-3-pentyn-2-ol.
A mixture of 3-pentyn-2-one (9.9 g, 0.12 mol, 1.0 equiv) and
Ru[(1R,2R)-p-TsNCH(C6H5)CH(C6H5)NH]
(η6-p-cymene)
(13)11 (0.36 g, 0.60 mmol, 0.0050 equiv) in 2-propanol
(250 mL) was stirred under nitrogen at 25 °C for 1 day before
more catalyst (0.36 g, 0.60 mmol, 0.0050 equiv) was added.
Another addition of catalyst was carried out after 2 days (0.72 g,
1.2 mmol, 0.010 equiv) and 4 days (0.36 g, 0.60 mmol, 0.0050
equiv). After 6 days, distillation of the crude reaction mixture at
80 °C at 50 mbar provided (R)-(þ)-3-pentyn-2-ol (8.0 g, 79%
yield). The enantiomeric excess of the alcohol was determined to
be 92% by chiral capillary GC analysis using a Supelco-Beta-Dex
120 column (50 °C isotherm). tR (R enantiomer): 7.54 min. tR
(S enantiomer): 8.48 min. 1H NMR (300 MHz, CDCl3) δ: 4.49
(m, 1H), 1.84 (d, 3H, J = 2.07 Hz), 1.42 (d, 3H, J = 6.4 Hz). The
spectral data were identical with those previously reported.46
(R)-(-)-(Z)-3-Penten-2-ol (14).
(1R)-1-[(4S,5R)-3-((1R)-2-{[tert-Butyl-(dimethyl)-silyl]oxy}-
1-methylethyl)-4-methyl-4,5-dihydroisoxazol-5-yl]ethanone (16).
To isoxazoline 15 (1.18 g, 3.91 mmol, 1.00 equiv) in CH2Cl2
(8 mL) at rt was added NMO (0.69 g, 5.09 mmol, 1.30 equiv) and
˚
4 A molecular sieves (2 g). Then TPAP (0.041 g, 0.12 mmol,
0.030 equiv) was added as a solid in two portions to give a green
mixture. After 10 min, the reaction had become dark red, and
after 20 min, more TPAP (0.020 g, 0.057 mmol, 0.015 equiv) was
added. After stirring for 1.5 h at rt, the dark red mixture was
diluted with pentane (8 mL) and filtered over a plug of silica gel,
eluting with 3:2 pentane/ether. The solution was concentrated
and a green oil was obtained. Purification by chromatography
on silica gel (hexane/EtOAc 5:1) provided ketone 16 (0.96 g,
82% yield) as a clear, colorless oil. Rf = 0.44 (3:1 hexane/
EtOAc). [R]28.7D (c 0.950, CHCl3) = þ51°. 1H NMR (300 MHz,
CDCl3) δ: 4.76 (d, 1H, J = 10.9 Hz), 3.71-3.58 (m, 3H),
2.72-2.61 (m, 1H), 2.26 (s, 3H), 1.23 (d, 3H, J = 7.2 Hz),
1.08 (d, 3 Hz, J = 7.5 Hz), 0.88 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H).
13C NMR (75 MHz, CDCl3) δ: 208.2, 165.0, 87.0, 67.0, 47.7,
34.7, 28.4, 25.9, 18.3, 14.5, 12.1, -5.4. IR (thin film) 2955, 2931,
2858, 1716, 1463, 1359, 1255, 1136, 1095, 1007, 970, 838, 777
To a solution of (R)-(þ)-3-pentyn-2-ol (7.70 g, 91.5 mmol,
1.00 equiv) in pentane (25 mL) were added Pd on CaCO3 with Pb
(Lindlar catalyst)14 and quinoline (0.4 mL). The gray mixture
was purged with H2 and stirred for 5 days. The suspension was
filtered over Celite, and the solvent was removed at 800 mbar,
40 °C. Distillation of the liquid (75 mbar, 63 °C) provided
(R)-(-)-(Z)-3-penten-2-ol (14) (5.67 g, 72% yield) as a clear,
colorless liquid. The enantiomeric excess of the alcohol was
determined to be 91% by chiral capillary GC analysis using
a
Supelco-Beta-Dex 120 column (50 °C isotherm). tR
(R enantiomer): 3.88 min. tR (S enantiomer): 4.16 min. 1H
NMR (300 MHz, CDCl3) δ: 5.56-5.40 (m, 2H), 4.73-4.64
(46) Hamed, O.; Henry, P. M. Organometallics 1997, 16, 4903–4909.
8702 J. Org. Chem. Vol. 74, No. 22, 2009

Muri and Carreira
JOCArticle
(cm-1). EI-MS (m/z): 300.1 ([M þ H]þ), 243.1(19), 240.1(26),
142.0(67), 115.0(50), 112.0(18). Anal. Calcd for C15H29NO3Si:
C, 60.16; H, 9.76. Found: C, 60.10; H, 9.60.
H2O2 (3% in H2O, 50 mL). The organic layer was washed with
brine, dried over anhydrous Na2SO4, and concentrated in
vacuo. The light brown mixture was filtered over a plaque of
silica gel (pentane/Et2O 4:1) and concentrated under reduced
pressure to afford bromide 18 (14.2 g, 89% yield) as a clear,
colorless oil. 1H NMR (300 MHz, CDCl3) δ: 7.27 (d, 2H, J =
8.8 Hz), 6.89 (d, 2H, J = 8.7 Hz), 4.45 (s, 2H), 3.81 (s, 3H),
3.55-3.45 (m, 2H), 3.43-3.34 (m, 2H), 2.17-2.07 (m, 1H), 1.03
(d, 3H, J = 6.8 Hz). The spectral data were identical with those
previously reported.49
(2R)-3-(4-Methoxyphenoxy)-2-methylpropan-1-ol (17).
p-Methoxybenzylalcohol (14.4 mL, 116 mmol, 1.00 equiv)
was slowly added to a suspension of NaH (0.278 g, 11.5 mmol,
0.100 equiv) in Et2O (45 mL). After stirring for 30 min, the
reaction mixture was cooled to 0 °C, and trichloroacetonitrile
(11.6 mL, 116 mmol, 1.00 equiv) was added. The reaction was
allowed to warm to rt and stirred for another 4 h. After
evaporation of the solvent, the residue was dissolved in MeOH
(1 mL) and hexane (40 mL). The suspension was filtered over
Celite and concentrated under reduced pressure. The crude
imidate was used without further purification. To a solution
of (R)-methyl 3-hydroxy-2-methylpropionate (4.00 g, 33.9 mmol,
1.00 equiv) in CH2Cl2 (70.0 mL) were added PMB-imidate
(14.4 g, 50.8 mmol, 1.50 equiv) and CSA (0.787 g, 3.39 mmol,
0.100 equiv). The light brown solution was stirred for 15 h
and quenched with H2O (30 mL). The aqueous layer was
extracted with CH2Cl2 (3 ꢀ 30 mL). The combined organics
were washed with brine (20 mL), dried over anhydrous Na2SO4,
and concentrated in vacuo. Purification by chromatography on
silica gel (hexane/EtOAc 3:1) provided the product (6.97 g, 86%
(2R,4R)-2-[(4S,5R)-3-((1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-
1-methylethyl)-4-methyl-4,5-dihydroisoxazol-5-yl]-5-[(4-methoxy-
benzyl)oxy]-4-methylpentan-2-ol (19).
To a solution of bromide 18 (0.24 g, 0.87 mmol, 1.3 equiv) in
Et2O (4.8 mL) at -78 °C was added t-BuLi (1.76 M solution in
pentane, 1.0 mL, 1.8 mmol, 2.7 equiv). The colorless suspension
was stirred for 20 min at -78 °C before MgBr2 (1.0 M solution in
ether/benzene (3:1), 1.00 mL, 1.0 mmol, 1.50 equiv) was added.
The colorless reaction mixture was stirred for 10 min and treated
with a solution of ketone 16 (0.20 g, 0.67 mmol, 1.0 equiv) in
THF (3.4 mL). After stirring for 1 h at -78 °C, the colorless
suspension was quenched with satd aq NH4Cl (5 mL) and
extracted with EtOAc (3 ꢀ 10 mL). The organic solution was
washed with brine, dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. Analysis of the signals of the
1
yield) as a clear, colorless oil. H NMR (300 MHz, CDCl3) δ:
7.23 (d, 2H, J = 8.5 Hz), 6.87 (d, 2H, J = 8.7 Hz), 4.45 (s, 2H),
3.80 (s, 3H), 3.69 (s, 3H), 3.63 (dd, 1H, J = 9.2, 7.4 Hz), 3.45
(dd, 1H, J = 9.1, 5.9 Hz), 2.80-2.73 (m, 1H), 1.17 (d, 3H, J =
7.0 Hz). The spectral data were identical with those previously
reported.47 At -78 °C, DIBAl-H (20.4 mL, 113 mmol,
2.20 equiv) was added to a solution of the PMB ester (12.2 g,
51.2 mmol, 1.00 equiv) in CH2Cl2 (100 mL). The clear solution
was warmed to 0 °C and quenched after 30 min by the addition
of ethyl formate (5 mL). The mixture was cooled to -78 °C and
diluted with ether (150 mL). Saturated, aqueous Na/K-tartrate
(200 mL) was added, and the solution was vigorously stirred at
ambient temperature for 15 h. The two layers were separated,
and the aqueous phase was extracted with Et2O (3 ꢀ 50 mL).
The combined organic solutions were washed with H2O (50 mL)
and brine (50 mL), dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. Purification by chromatography
on silica gel (hexane/EtOAc 3:1 to 1:1) afforded alcohol 17
(9.00 g, 84% yield) as a clear, colorless oil. 1H NMR (300 MHz,
CDCl3) δ: 7.25 (d, 2H, J = 7.7 Hz), 6.88 (d, 2H, J = 8.6 Hz),
4.45 (s, 2H), 3.81 (s, 3H), 3.63-3.57 (m, 1H), 3.53 (dd, 1H, J =
9.0, 4.6 Hz), 3.39 (m, 1H), 2.57 (dd, 1H, J = 7.0, 4.4 Hz),
2.10-2.01 (m, 1H), 0.87 (d, 3H, J = 6.9 Hz). The spectral data
were identical with those previously reported.48
1
proton at C5 (4.0-4.2 ppm) in the H NMR spectrum of the
crude material indicated a 20:1 ratio of diastereomers. Purifica-
tion by chromatography on silica gel (hexane/EtOAc 5:1 to 3:1)
provided pure 19 (0.21 g, 64% yield, >50:1 dr), accompanied
with ketone 16 (0.065 g, 33% recovered starting material). Rf =
0.33 (3:1 hexane/EtOAc). [R]3D0.0 (c 2.570, CHCl3) = þ3.5°. 1H
NMR (300 MHz, CDCl3) δ: 7.26 (d, 2H, J = 8.7 Hz), 6.87
(d, 2H, J = 8.7 Hz), 4.49 (d, 1H, J = 11.5 Hz), 4.43 (d, 1H, J =
11.5 Hz), 4.03 (d, 1H, J = 8.7 Hz), 3.80 (s, 3H), 3.64 (d, 2H, J =
6.5 Hz), 3.46 (s(br), 1H), 3.36 (dd, 1H, J = 8.7, 5.0 Hz),
3.24-3.14 (m, 2H), 2.68-2.59 (m, 1H), 2.10-2.05 (m, 1H),
1.96 (dd, 1H, J = 14.6, 6.9 Hz), 1.44 (dd, 1H, J = 14.3, 3.4 Hz),
1.27 (s, 3H), 1.24 (d, 3H, J = 5.0 Hz), 1.21 (d, 3H, J = 4.4 Hz),
0.95 (d, 3H, J = 6.9 Hz), 0.89 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H).
13C NMR (75 MHz, CDCl3) δ: 167.6, 159.0, 129.9, 129.2, 113.7,
88.5, 76.4, 72.9, 72.2, 67.3, 55.3, 45.5, 34.9, 28.9, 25.9, 23.9, 19.8,
18.3, 14.7, 12.7, -5.3. IR (thin film) 3436, 2954, 2931, 2857,
1613, 1514, 1361, 1301, 1249, 1174, 1089, 1036, 938, 837, 777
(cm-1). HRMS-MALDI (m/z) calcd for [C27H47NO5SiNa]þ,
516.3116; found, 516.3111. Anal. Calcd for C27H47NO5Si: C,
65.68; H, 9.59. Found: C, 65.78; H, 9.57.
(4S,5R)-3-((1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methyl-
ethyl)-5-{(1R,3R)-4-[(4-methoxybenzyl)oxy]-1,3-dimethyl-1-[(tri-
ethylsilyl)oxy]butyl}-4-methyl-4,5-dihydroisoxazole (22).
1-{[(2S)-3-Bromo-2-methylpropyl]oxy}-4-methoxybenzene (18).
To a solution of PPh3 (23.0 g, 87.7 mmol, 1.50 equiv) and
imidazole (11.9 g, 175 mmol, 3.00 equiv) in CH2Cl2 (250 mL)
was added bromine (4.21 mL, 81.9 mmol, 1.40 equivl) at 0 °C.
After 15 min of stirring, alcohol 17 (12.3 g, 58.5 mmol, 1.00
equiv) was added, and the stirring was maintained for 30 min at
0 °C before additional triphenylphosphine (7.00 g, 26.7 mmol,
0.456 equiv) and bromine (1.2 mL, 23.3 mmol, 0.398 equiv) had
to be added. The light brown suspension was quenched with
At 0 °C, triethylsilyl triflate (3.20 mL, 14.0 mmol, 1.30 equiv)
was added to a solution of alcohol 19 (5.30 g, 10.7 mmol, 1.00
equiv) and 2,6-lutidine (3.80 mL, 32.2 mmol, 3.00 equiv) in
CH2Cl2 (30 mL). The yellow solution was stirred for 1 h at 0 °C
and quenched with water (30 mL). The two layers were
(47) Walkup, R. D.; Kahl, J. D.; Kane, R. K. J. Org. Chem. 1998, 63,
9113–9116.
(48) Organ, M. G.; Wang, J. J. Org. Chem. 2003, 68, 5568–5574.
(49) Smith, P. M.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1998,
3541–3556.
J. Org. Chem. Vol. 74, No. 22, 2009 8703

Muri and Carreira
JOCArticle
separated, and the aqueous layer was extracted with CH2Cl2.
The organic solution was washed with 1 N HCl (60 mL) and
brine (30 mL), dried over anhydrous Na2SO4, and concentrated
in vacuo. Purification by chromatography on silica gel (hexane/
EtOAc 6:1) afforded 22 (6.01 g, 93% yield) as a clear, colorless
oil. Rf = 0.67 (3:1 hexane/EtOAc). [R]3D0.0 (c 1.0450, CHCl3) =
-4.8°. 1H NMR (300 MHz, CDCl3) δ: 7.24 (d, 2H, J = 8.1 Hz),
6.86 (d, 2H, J = 8.4 Hz), 4.41 (s, 2H), 4.12 (d, 1H, J = 9.0 Hz),
3.80 (s, 3H), 3.62 (d, 2H, J = 6.5 Hz), 3.32 (dd, 1H, J = 8.7, 6.2
Hz), 3.21-3.12(m, 2H), 2.63-2.56(m, 1H), 1.95-1.90 (m, 1H),
1.68 (dd, 1H, J = 13.9, 4.0 Hz), 1.48 (dd, 1H, J = 14.0, 6.5 Hz),
1.34 (s, 3H), 1.20 (d, 3H, J = 6.9 Hz), 1.13 (d, 3H, J = 7.4 Hz),
1.02 (d, 3H, J = 6.7 Hz), 0.94 (t, 9H, J = 7.8 Hz), 0.88 (s, 9H),
0.63 (q, 6H, J = 7.7 Hz), 0.05 (s, 3H), 0.04 (s, 3H). 13C NMR (75
MHz, CDCl3) δ: 166.9, 158.9, 130.8, 129.0, 113.6, 88.3, 76.6,
76.5, 76.5, 72.6, 67.3, 55.3, 45.3, 43.6, 34.9, 29.8, 25.9, 19.6, 18.3,
14.7, 12.7, 7.4, 6.9, -5.3. IR (thin film) 2953, 2875, 1614, 1514,
1463, 1361, 1301, 1249, 1094, 1008, 838, 776, 741 (cm-1).
HRMS-MALDI (m/z) calcd for [C33H61NO5Si2Na]þ,
630.3980; found, 630.3975.
11.0 mL, 5.45 mmol, 2.00 equiv) at 0 °C. After 15 min, NaOCl
(0.5 M in H2O, 11.0 mL, 5.45 mmol, 2.00 equiv) had to be added
again. After another 10 min, H2O (10 mL) and CH2Cl2 (10 mL)
were added. The two layers were separated, and the aqueous layer
was extracted with CH2Cl2 (3 ꢀ 10 mL). The organic solution was
washed with brine (10 mL), dried over Na2SO4, and concentrated
in vacuo. The light orange oil was used without further purifica-
tion. A solution of H2NOH HCl (0.380 g, 5.47 mmol, 2.00 equiv)
3
in py (2 mL) was added to a solution of the crude aldehyde (1.33 g,
2.74 mmol, 1.00 equiv) in EtOH (10.0 mL) and stirred for 15 min at
rt. The light green solution was quenched with 1 N HCl (30 mL),
and the aqueous layer was extracted with EtOAc (3 ꢀ 10 mL). The
combined organic solutions were washed with brine (10 mL), dried
over Na2SO4, and concentrated under reduced pressure. Purifica-
tion by chromatography on silica gel (hexane/EtOAc 5:1) provided
oxime 24 (1.12 g, 81% yield over two steps) as a mixture of E/Z
isomers (∼2:1). Rf = 0.49 (3:1 hexane/EtOAc). [R]D23.9 (c 0.675,
CHCl3) = -0.54°. 1H NMR (300 MHz, CDCl3,*denotes minor
isomer) δ: 7.30, (d, 1H, J = 7.5 Hz), 7.26 (s(br), 1H), 6.60* (d, 1H,
J = 7.7 Hz) 4.18* (d, 1H, J = 9.2 Hz), 4.14 (d, 1H, J = 9.2 Hz),
3.63* (d, 2H, J= 6.6 Hz), 3.63 (d, 2H, J = 6.5 Hz), 3.31-3.26* (m,
1H), 3.25-3.17 (m, 1H), 2.68-2.59 (m, 2H), 1.86-1.63 (m, 2H),
1.33 (s, 3H), 1.32* (s, 3H), 1.23* (d, 3H, J = 6.9 Hz), 1.21 (d, 2 ꢀ
3H, J = 7.0 Hz), 1.10 (d, 3H, J = 6.9 Hz), 1.07* (d, 3H, J = 6.9
Hz), 0.94 (t, 9H, J = 7.9 Hz), 0.89 (s, 9 Hz), 0.63 (q, 6H, J = 7.5
Hz), 0.62* (q, 6H, J = 7.6 Hz), 0.05 (s, 3H), 0.04 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ: 166.7, 158.0*, 157.2, 87.7, 87.6*, 76.3*, 76.2,
67.2, 45.6*, 45.5, 44.9*, 44.7, 34.8, 30.7, 26.4, 26.1*, 25.9, 20.7,
19.1*, 18.3, 14.6, 12.8, 7.3, 6.9, -5.4. IR (thin film) 3306, 2954,
2877, 1461, 1379, 1253, 1091, 107, 941, 837, 777, 724 (cm-1).
HRMS-MALDI (m/z) calcd for [C25H52N2O4Si2Na]þ, 523.3358;
found, 523.3366. Anal. Calcd for C25H52N2O4Si2: C, 59.95; H,
10.46. Found: C, 60.09; H, 10.26.
(4S,5R)-3-((1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methyl-
ethyl)-5-{(1R,3R)-4-hydroxy]-1,3-dimethyl-1-[(triethylsilyl)oxy]-
butyl}-4-methyl-4,5-dihydroisoxazole (23).
At 0 °C, DDQ (0.859 g, 3.78 mmol, 1.15 equiv) was added
to a solution of 22 (2.00 g, 3.29 mmol, 1.00 equiv) in CH2Cl2
(30.0 mL). After addition of pH 7 buffer (0.020 mL), the reaction
mixture was stirred for 40 min, and more DDQ (0.400 g,
1.76 mmol, 0.54 equiv) was added. After an additional 1 h at
0 °C, the brown suspension was quenched with satd aq Na2S2O3
(20 mL) and satd aq NaHCO3 (30 mL). The biphasic red
solution was extracted with CH2Cl2. The combined organic
solutions were extracted with CH2Cl2 (5 ꢀ 10 mL), washed with
brine (10 mL), dried over anhydrous Na2SO4, and concentrated
under reduced pressure. Purification by chromatography on
silica gel (hexane/EtOAc 3:1) provided 23 (0.74 g, 46%) as a
clear, colorless oil. Dimerized byproduct 25 (0.91 g, 51%) was
also isolated. Rf = 0.26 (3:1 hexane/EtOAc). [R]2D8.6 (c 0.905,
CHCl3) = þ11°. 1H NMR (300 MHz, CDCl3) δ: 4.14 (d, 1H,
J = 8.9 Hz), 3.68-3.58 (m, 2H), 3.51 (dd, 1H, J = 10.4, 5.5 Hz),
3.35 (dd, 1H, J = 10.3, 6.9 Hz), 3.23-3.13 (m, 1H), 2.65-2.58
(m, 1H), 2.34 (s, 1H), 1.92-1.84 (m, 1H), 1.67 (dd, 1H, J = 14.2,
6.0 Hz), 1.49 (dd, 1H, J = 14.2, 4.7 Hz), 1.38 (s, 3H), 1.19 (d, 3H,
J = 8.0 Hz), 1.17 (d, 3H, J = 8.6 Hz), 0.96 (d, 3H, J = 6.8 Hz),
0.94 (t, 9H, J = 7.5 Hz), 0.87 (s, 9H), 0.67 (q, 6H, J = 7.8 Hz),
0.04 (s, 3H), 0.03 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 167.5,
88.9, 77.4, 69.0, 67.5, 45.9, 43.4, 35.0, 31.6, 26.0, 25.5, 19.7, 18.4,
14.7, 12.8, 7.4, 6.8, -5.3. IR (thin film) 3436, 2954, 2876, 1460,
1378, 1253, 1135, 1092, 1060, 1007, 837, 777, 742, 668 (cm-1).
HRMS-MALDI (m/z) calcd for [C25H53NO4Si2Na]þ, 510.3405;
found, 510.3402. Anal. Calcd for C25H53NO4Si2: C, 61.55; H,
10.95. Found: C, 61.55; H, 10.96.
(1R)-1-((4S,5R)-3-{(1R,3R)-3-[(4S,5R))-3-((1R)-2-{[tert-Butyl-
(dimethyl)silyl]oxy}-1-methylethyl)-4-methyl-4,5-dihydroisoxa-
zol-5-yl]-1-methyl-3-[(triethylsilyl)oxy]butyl}-4-methyl-4,5-dihy-
droisoxazol-5-yl)ethanol (26).
To a solution of (R)-(-)-(Z)-3-penten-2-ol (14) (0.262 g, 3.04
mmol, 1.30 equiv) and 2-propanol (0.594 mL, 7.71 mmol, 3.30
equiv) in CH2Cl2 (150 mL) at 0 °C was added EtMgBr (3 M in
Et2O, 2.33 mL, 7.07 mmol, 3.00 equiv). The reaction mixture
turned momentarily cloudy, becoming clear and colorless upon
stirring at 0 °C for 30 min. At this time, the hydroxymoyl
chloride, prepared by addition of t-BuOCl (0.280 mL, 2.45
mmol, 1.05 equiv) to a solution of oxime 24 (1.17 g, 2.33 mmol,
1.00 equiv) in CH2Cl2 (23 mL) at -78 °C and stirring for 1.5 h,
was added dropwise via cannula to the reaction to give a slightly
yellow solution. It was allowed to warm to ambient temperature
and stirred for 16 h. The reaction was quenched by the addition
of satd aq NH4Cl (100 mL), and the two layers were separated.
The aqueous layer was extracted with CH2Cl2 (3 ꢀ 50 mL). The
combined organic solutions were washed with brine (50 mL),
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. Purification by chromatography on silica gel (hexane/
EtOAc 3:1) provided isoxazoline 26 (1.20 g, 88% yield) as a
clear, colorless oil. No other diastereoisomer could be detected,
as determined by examination of the diastereotopic signals of
(2R,4R)-2-[(4S,5R)-3-((1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-
1-methylethyl)4-methyl-4,5-dihydroisoxazol-5-yl]-4-[(triethylsilyl)-
oxy]-2-methylpentanal Oxime (24).
1
the proton at C11 (4.0-4.2 ppm) of 26 in the H NMR of the
crude material. Rf = 0.23 (3:1 hexane/EtOAc). [R]D31.5 (c 1.050,
CHCl3) = -16°. 1H NMR (300 MHz, CDCl3) δ: 4.20 (dd, 1H,
J = 9.7, 5.0 Hz), 4.10 (d, 1H, J = 8.9 Hz), 3.96-3.88 (m, 1H),
3.66-3.58 (m, 1H), 3.63 (dd, 1H, J = 6.5, 2.9 Hz), 3.33-3.25 (m,
1H), 3.23-3.12 (m, 1H), 2.79-2.73 (m, 1H), 2.65-2.56 (m, 1H),
To a biphasic solution of 23 (1.33 g, 2.73 mmol, 1.00 equiv),
TEMPO (0.0085 g, 0.054 mmol, 0.020 equiv), and KBr (0.0316 g,
0.273 mmol, 0.100 equiv) in CH2Cl2 (14 mL) and pH 8.6
buffer (14 mL) was slowly added NaOCl (0.5 M in H2O,
8704 J. Org. Chem. Vol. 74, No. 22, 2009

Muri and Carreira
JOCArticle
2.32 (dd, 1H, J = 14.2, 6.2 Hz), 1.98 (d, 1H, J = 6.5 Hz), 1.84
(dd, 1H, J = 14.2, 4.5 Hz), 1.33 (s, 3H), 1.27 (d, 3H, J = 6.4 Hz),
1.22 (d, 3H, J = 4.8 Hz), 1.21 (d, 3H, J = 7.0 Hz), 1.20 (d, 3H,
J = 5.2 Hz), 1.18 (d, 3H, J = 7.4 Hz), 0.95 (t, 9H, J = 8.0 Hz),
0.89 (s, 9H), 0.64 (q, 6H, J = 7.9 Hz), 0.05 (s, 3H), 0.05 (s, 3H).
13C NMR (75 MHz, CDCl3) δ: 167.9, 166.9, 87.8, 85.9, 76.1,
67.1, 66.1, 45.3, 44.1, 43.0, 34.9, 27.8, 26.2, 25.9, 21.5, 20.4, 18.3,
14.7, 12.8, 10.7, 7.3, 6.9, -5.4. IR (thin film) 3436, 2954, 2877,
1612, 1461, 1378, 1254, 1134, 1091, 1007, 900, 838, 776, 742
(cm-1). HRMS-MALDI (m/z) calcd for [C30H60N2O5Si2Na]þ,
607.3933; found, 607.3940. Anal. Calcd for C30H60N2O5Si2: C,
61.60; H, 10.34; N, 4.79. Found: C, 61.78; H, 10.47; N, 4.86.
1-((4S,5R)-3-{(1R,3R)-3-[(4S,5R))-3-((1R)-2-{[tert-Butyl(dime-
thyl)silyl]oxy}-1-methylethyl)-4-methyl-4,5-dihydroisoxazol-5-yl]-
1-methyl-3-[(triethylsilyl)oxy]butyl}-4-methyl-4,5-dihydroisoxa-
zol-5-yl)ethanone (27).
cooled to -78 °C before a solution of ketone 27 (1.23 g, 2.11
mmol, 1.00 equiv) in THF (20 mL) was added dropwise via
cannula. The red mixture was slowly warmed to rt and stirred
for 15 h. To the orange suspension was added H2O (50 mL) and
Et2O (100 mL) and the two layers were separated. The aqueous
phase was extracted with Et2O (3 ꢀ 30 mL). The combined
organics were washed with H2O2 (3% in H2O, 100 mL) and
brine (20 mL), dried over Na2SO4, and concentrated under
reduced pressure. Purification by chromatography on silica gel
(hexane/EtOAc 10:1 to 5:1) provided olefin 28 (0.91 g, 71%
yield) as a clear, colorless oil and 30:1 mixture of Z/E diaster-
eomers, accompanied with 0.16 g of recovered ketone 27 (13%).
The diastereomeric ratio was determined by examination of the
proton at C11 (5.2-5.3 ppm) of 28 in the 1H NMR spectrum of
the crude material. Rf = 0.62 (3:1 hexane/EtOAc). [R]2D3.6 (c
1.225, CHCl3) = þ21°. 1H NMR (300 MHz, CDCl3) δ: 5.33 (dt,
1H, J = 7.8, 1.2 Hz), 5.30 (d, 1H, J = 10.7 Hz), 4.12 (d, 1H, J =
8.9 Hz), 3.68-3.58 (m, 2H), 3.39-3.29 (m, 1H), 3.23-3.13 (m,
1H), 2.93-2.77 (m, 1H), 2.66-2.59 (m, 1H), 2.32 (dd, 1H, J =
14.2, 5.8 Hz), 2.09-1.88 (m, 2H), 1.84 (dd, 1H, J = 14.2, 5.2
Hz), 1.67 (d, 3H, J = 1.3 Hz), 1.36 (s, 3H), 1.23 (d, 3H, J = 7.1
Hz), 1.23 (d, 3H, J = 6.9 Hz), 1.19 (d, 3H, J = 7.4 Hz), 1.01 (d,
3H, J = 7.5 Hz), 0.97 (t, 3H, J = 7.5 Hz), 0.95 (t, 9H, J = 7.6
Hz), 0.88 (s, 9H), 0.65 (m, 6H), 0.05 (s, 3H), 0.05 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ: 166.9, 166.3, 131.0, 130.9, 88.0, 82.2,
76.1, 67.1, 45.5, 45.3, 43.1, 35.0, 28.0, 26.1, 25.9, 21.5, 21.2, 20.3,
18.3, 14.7, 14.4, 12.8, 11.8, 7.3, 6.9, -5.3. IR (thin film) 2956,
2876, 1459, 1378, 1253, 1135, 1095, 1060, 1007, 958, 880,
838, 776, 741 (cm-1). HRMS-MALDI (m/z) calcd for
[C33H64N2O4Si2Na]þ, 631.4297; found, 631.4304. Anal. Calcd
for C33H64N2O4Si2: C, 65.08; H, 10.59; N, 4.60. Found: C,
65.05; H, 10.710; N, 4.80.
To a biphasic solution of 26 (1.94 g, 3.32 mmol, 1.00 equiv),
TEMPO (0.0104 g, 0.0664 mmol, 0.0200 equiv), and KBr
(0.0385 g, 0.332 mmol, 0.100 equiv) in CH2Cl2 (35.0 mL) and
pH 8.6 buffer (35 mL) was slowly added NaOCl (0.5 M in H2O,
20 mL, 9.95 mmol, 3.00 equiv) at 0 °C. Fifteen minutes and
30 min later, more NaOCl (0.5 M in H2O, 20 mL, 9.95 mmol,
3.00 equiv (2 ꢀ)) and pH 8.6 buffer (35 mL (2 x)) had to be
added. After stirring for another 30 min at 0 °C, the two layers
were separated, and the aqueous layer was extracted with
CH2Cl2 (3 ꢀ 30 mL). The organic solution was washed with
brine (20 mL), dried over Na2SO4, and concentrated in vacuo.
Purification by chromatography on silica gel (hexane/EtOAc
5:1) afforded 27 (1.49 g, 77% yield) as a clear, colorless oil. Rf =
0.46 (3:1 hexane/EtOAc). [R]2D3.8 (c 1.050, CHCl3) = þ22°. 1H
NMR (300 MHz, CDCl3) δ: 4.76 (d, 1H, J = 11.1 Hz), 4.10 (d,
1H, J = 8.8 Hz), 3.67-3.56 (m, 1H), 3.62 (d, 2H, J = 6.5 Hz),
3.24-3.13 (m, 1H), 2.87-2.79 (m, 1H), 2.66-2.57 (m, 1H), 2.35
(dd, 1H, J = 14.3, 6.4 Hz), 2.24 (s, 3H), 1.81 (dd, 1H, J = 14.3,
4.6 Hz), 1.36 (s, 3H), 1.22 (d, 3H, J = 7.3 Hz), 1.21 (d, 3H, J =
6.8 Hz), 1.19 (d, 3H, J = 7.8 Hz), 1.10 (d, 3H, J = 7.5 Hz), 0.95
(t, 9H, J = 7.5 Hz), 0.88 (s, 9H), 0.64 (q, 6H, J = 7.5 Hz), 0.05
(s, 3H), 0.04 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 208.3, 166.9,
166.3, 88.0, 87.1, 75.9, 67.1, 46.6, 45.5, 43.2, 34.8, 28.3, 27.6,
26.3, 25.9, 21.4, 18.3, 14.6, 12.7, 11.9, 7.3, 6.8, -5.4. IR (thin
film) 2955, 2877, 1716, 1458, 1418, 1379, 1359, 1253, 1167, 1135,
1093, 1006, 974, 941, 838, 777, 741 (cm-1). HRMS-MALDI
(m/z) calcd for [C30H58N2O5Si2Na]þ, 605.3777; found,
605.3784. Anal. Calcd for C30H58N2O5Si2: C, 61.81; H, 10.03;
N, 4.81. Found: C, 61.98; H, 10.15; N, 4.98.
(2R,3R)-2-((4S,5R)-3-{(1R,3R)-3-[(4S,5R)-3-((1R)-2-{[tert-
Butyl(dimethyl)silyl]oxy}-1-methylethyl)-4-methyl-4,5-dihydroi-
soxazol-5-yl]-1-methyl-3-[(triethylsilyl)oxy]butyl}-4-methyl-4,5-
dihydroisoxazol-5-yl)pentane-2,3-diol (29).
To a solution of olefin 28 (0.880 g, 1.44 mmol, 1.00 equiv) in t-
BuOH (7.0 mL) and H2O (7.0 mL) were added (DHQD)2PHAL
(0.112 g, 0.144 mmol, 0.100 equiv), K3Fe(CN)6 (1.43 g, 4.33 mmol,
3.00 equiv), K2CO3 (0.599 g, 4.33 mmol, 3.00 equiv), and meth-
anesulfonylamide (0.426 g, 4.33 mmol, 3.00 equiv). The biphasic
(4S,5R)-3-((1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methyl-
ethyl)-4-methyl-5-{(1R,3R)-1-methyl-3-{(4S,5R)-4-methyl-5-[(1Z)-
1-methylbut-1-en-1-yl]-4,5-dihydroisoxazol-3-yl}-1-[(triethyl-
silyl)oxy]butyl}-4,5-dihydroisoxazole (28).
mixture was cooled to 0 °C before K2OsO4 H2O (0.0106 g, 0.0289
3
mmol, 0.0200 equiv) was added. The suspension slowly turned
brown and was stirred for 3.5 h at 0 °C. Then it was quenched with
satd aq Na2S2O3 (10 mL) and extracted with EtOAc (4 ꢀ 10 mL).
The organic solution was washed with brine (10 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. Purification by
chromatography on silica gel (hexane/EtOAc 4:1) provided diol 29
(0.762 g, 82% yield) as a clear, colorless oil. No other diastereo-
isomer could be detected, as determined by examination of the
proton at C11 (4.0 -4.2 ppm) of 29 in the 1H NMR spectrum of the
crude material. Rf = 0.25 (3:1 hexane/EtOAc). [R]2D2.5 (c 1.030,
CHCl3) = þ11°. 1H NMR (300 MHz, CDCl3) δ: 4.26 (d, 1H, J =
8.5 Hz), 4.11 (d, 1H, J = 8.9 Hz), 3.63 (d, 2H, J = 6.4 Hz), 3.27
(s, 1H), 3.24-3.15 (m, 3H), 2.78-2.72 (m, 1H), 2.66-2.60 (m, 1H),
2.34 (dd, 1H, J = 14.1, 5.7 Hz), 2.20 (d, 1H, J = 11.1 Hz), 1.85 (dd,
1H, J = 14.1, 5.0 Hz), 1.72-1.62 (m, 1H), 1.46-1.36 (m, 1H), 1.34
(s, 3H), 1.30 (d, 3H, J = 7.3 Hz), 1.25 (d, 3H, J = 7.6 Hz), 1.23
(s, 3H), 1.22 (d, 3H, J = 6.9 Hz), 1.19 (d, 3H, J = 8.5 Hz), 1.09
At -78 °C, t-BuLi (1.76 M in pentane, 7.20 mL, 12.7 mmol,
6.00 equiv) was added to a suspension of propyltriphenyl-
phosphonium bromide (5.69 g, 14.8 mmol, 7.00 equiv) in THF
(200 mL). The reaction mixture slowly turned red, was allowed
to warm to rt, and stirred for 2 h. The dark red suspension was
J. Org. Chem. Vol. 74, No. 22, 2009 8705

Muri and Carreira
JOCArticle
(t, 3H, J = 7.2 Hz), 0.95 (t, 9H, J = 7.8 Hz), 0.88 (s, 9 Hz), 0.65
(q, 6H, J = 7.8 Hz), 0.05 (s, 3H), 0.04 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ: 169.9, 167.0, 87.8, 85.9, 82.2, 76.1, 73.6, 67.2, 45.5, 45.4,
42.9, 34.9, 27.9, 26.3, 25.9, 25.4, 22.1, 21.0, 18.3, 14.7, 13.1, 12.8,
11.7, 7.3, 6.9, -5.3. IR (thin film) 3435, 2955, 2877, 1459, 1380,
1253, 1220, 1099, 1007, 976, 940, 738, 775, 742 (cm-1). HRMS-
MALDI (m/z) calcd for [C33H66N2O6Si2Na]þ, 665.4352; found,
665.4360.
(2R,3R)-2-((4S,5R)-3-{(1R,3R)-3-[(4S,5R)-3-[(1R)-2-Hydro-
xy-1-methylethyl)-4-methyl-4,5-dihydroisoxazol-5-yl]-1-methyl-
3-[(triethylsilyl)oxy]butyl}-4-methyl-4,5-dihydroisoxazol-5-yl)-
pentane-2,3-diol (30).
brine (5 mL), dried over anhydrous Na2SO4, and concentrated
under reduced pressure. Purification by chromatography on
silica gel (hexane/EtOAc 1:3 to 1:3 þ 1% AcOH) provided seco-
acid 31 (0.069 g, 56% yield) as a clear, colorless oil. Rf = 0.17
(1:3 hexane/EtOAc þ 1% AcOH). [R]2D2.1 (c 1.695, CHCl3) =
þ2.8°. 1H NMR (300 MHz, CDCl3) δ: 4.30 (d, 1H, J = 8.8 Hz),
4.09 (d, 1H, J = 8.4 Hz), 3.43 (q, 1H, J = 7.1 Hz), 3.38-3.28
(m, 2H), 3.25-3.18 (m, 1H), 2.96-2.92 (m, 1H), 2.45 (dd, 1H,
J = 14.4, 7.3 Hz), 1.69-1.61 (m, 2H), 1.50 (d, 3H, J = 7.4 Hz),
1.47-1.40 (m, 1H), 1.37 (s, 3H), 1.33 (d, 3H, J = 7.4 Hz), 1.22
(s, 3H), 1.18 (d, 3H, J = 7.2 Hz), 1.08 (d, 3H, J = 7.4 Hz), 1.06
(t, 3H, J = 7.2 Hz), 9.53 (t, 9H, J = 7.9 Hz), 0.73-0.58 (m, 6H).
13C NMR (75 MHz, CDCl3) δ: 174.9, 169.2, 163.3, 88.6, 85.7,
82.3, 75.6, 73.9, 45.7, 43.9, 43.7, 38.0, 26.6, 26.0, 25.3, 22.8, 21.2,
13.5, 13.1, 12.5, 11.6, 7.3, 6.9. IR (thin film) 3446, 2959, 2877,
1728, 1616, 1458, 1414, 1380, 1295, 1239, 1205, 1131, 1106, 1050,
1009, 977, 940, 908, 825, 745, 666.
(2R,4R,5R,9R,12R,13R,14R,17S,18S)-12-Ethyl-4-13-dihy-
droxy-2,4,9,13,17,18-hexamethyl-6,11,15-trioxa-7,16-diayatricy-
clo[12.2.1.15,8]octadeca-1(16),7-dien-10-one (33).
At 0 C, HF pyridine (3.0 mL) was added to a solution of diol
3
29 (0.740 g, 1.15 mmol, 1.00 equiv) in pyridine (9.0 mL). The
solution was stirred for 3 h at 0 °C and then quenched with H2O
(10 mL) and solid NaHCO3 (5 g) (caution!). The biphasic
mixture was extracted with EtOAc (5 ꢀ 10 mL). The combined
organic solutions were washed with 1 N HCl (100 mL) and brine
(10 mL), dried over anhydrous Na2SO4, and concentrated under
reduced pressure. Purification by chromatography on silica gel
(hexane/EtOAc 1:3) afforded triol 30 (0.510 g, 83% yield) as a
clear, colorless oil. Rf = 0.26 (1:3 hexane/EtOAc). [R]D23.3
(c 1.010, CHCl3) = þ15°. 1H NMR (300 MHz, CDCl3) δ:
4.31 (d, 1H, J = 8.8 Hz), 4.11 (d, 1H, J = 8.8 Hz), 3.75 (dd, 1H,
J = 10.8, 4.8 Hz), 3.67 (dd, 1H, J = 10.7, 6.4 Hz), 3.43 (s(br),
1H), 3.30-3.16 (m, 3H), 2.86-2.80 (m, 1H), 2.69-2.61 (m, 1H),
2.40 (dd, 1H, J = 14.3, 6.5 Hz), 2.33 (d(br), 1H, J = 10.4 Hz),
2.24 (s(br), 1H), 1.75 (dd, 1H, J = 14.3, 4.0 Hz), 1.69-1.62 (m,
1H), 1.45-1.39 (m, 1H), 1.36 (s, 3H), 1.32 (d, 3H, J = 7.4 Hz),
1.24 (d, 3H, J = 7.0 Hz), 1.22 (d, 3H, J = 7.2 Hz), 1.21 (s, 3H),
1.18 (d, 3H, J = 7.5 Hz), 1.08 (t, 3H, J = 7.3 Hz), 0.96 (t, 9H,
J = 7.8 Hz), 0.69-0.61 (m, 6H). 13C NMR (75 MHz, CDCl3) δ:
169.5, 166.8, 87.7, 85.8, 82.0, 48.7, 73.7, 66.2, 45.4, 45.1, 43.3,
34.9, 27.2, 26.1, 25.3, 22.3, 20.8, 14.6, 13.0, 12.7, 11.7, 7.3, 6.9. IR
(thin film) 3412, 2959, 2877, 1616, 1457, 1414, 1379, 1239, 1167,
1130, 1056, 1009, 977, 939, 885, 742 (cm-1). HRMS-MALDI
(m/z) calcd for [C27H52N2O6SiNa]þ, 551.3487; found, 551.3493.
(2R)-2-((4S,5R)-5-{(1R,3R)-3-{(4S,5R)-5-[(1R,2R)-1,2-Dihy-
droxy-1-methylbutyl]-4-methyl-4,5-dihydroisoxazol-3-yl}-1-methyl-
1-[(triethylsilyl)oxy]butyl}-4-methyl-4,5-dihydroisoxazol-3-yl)propa-
noic Acid (31).
To a solution of acid 31 (32 mg, 0.059 mmol, 1.0 equiv) in
THF (3.0 mL) was added triethylamine (50 μL, 0.35 mmol, 6.0
equiv) and 2,4,6-trichlorobenzoylchloride (46 μL, 0.29 mmol,
5.0 equiv) at 0 °C. The solution turned cloudy and was stirred for
30 min. The colorless suspension was allowed to warm to rt, and
toluene (9.0 mL) was added. This cloudy reaction mixture was
added to a 50 °C solution of DMAP (72 mg, 0.59 mmol, 10
equiv) in toluene (18 mL) via syringe pump over 3 h. After
addition, the colorless suspension was filtered over a plug of
silica gel (eluent hexane/EtOAc 1:1). The filtrate was concen-
trated under reduced pressure and purified by chromatography
on silica gel (hexane/EtOAc 10:1 to 6:1 to 3:1) providing
macrolactone 33 (17 mg, 55% yield) as a colorless solid. Rf =
0.39 (1:3 hexane/EtOAc); mp = 178-179 °C; [R]2D5.1 (c 0.850,
CHCl3) = -93°. 1H NMR (300 MHz, CDCl3) δ: 4.84 (dd, 1H,
J = 11.2, 2.0 Hz), 4.40 (dd, 1H, J = 10.2, 1.9 Hz), 4.19-3.99
(m, 2H), 3.62-3.53 (m, 1H), 3.50 (q, 1H, J = 7.1 Hz), 3.05-2.95
(m, 1H), 2.47 (dd, 1H, J = 14.4, 9.6 Hz), 2.26-2.10 (m, 1H),
1.67-1.60 (m, 1H), 1.52-1.45 (m, 1H), 1.47 (d, 3H, J = 6.9 Hz),
1.47 (d, 3H, J = 8.4 Hz), 1.37 (s, 3H), 1.23 (s, 3H), 1.06 (d, 3H,
J = 7.3 Hz), 1.00 (d, 3H, J = 6.7 Hz), 0.97 (t, 3H, J = 7.4 Hz),
0.94 (t, 9H, J = 7.9 Hz), 0.74-0.56 (m, 6H). 13C NMR (75 MHz,
CDCl3) δ: 174.4, 166.4, 164.1, 89.4, 84.4, 84.1, 78.4, 75.2, 45.3,
45.2, 43.5, 38.6, 26.1, 26.0, 25.4, 22.7, 21.4, 13.3, 12.1, 11.7, 10.6,
7.5, 6.9. IR (thin film) 3496, 2960, 2876, 1734, 1458, 1378, 1306,
1260, 1206, 1159, 1128, 1075, 1051, 1016, 954, 886, 742 (cm-1).
HRMS-MALDI (m/z) calcd for [C27H48N2O6SiNa]þ, 547.3176;
found, 547.3182. Anal. Calcd for C27H48N2O6Si: C, 61.80; H,
9.22; N, 5.34. Found: C, 61.98; H, 9.00; N, 5.11.
1-O-[tert-Butyl(dimethyl)silyl]-2,4,7,8-tetradeoxy-9-O-(4-meth-
oxybenzyl)-2,4,8-trimethyl-6-C-methyl-6-O-(triethylsilyl)-L-gly-
cero-D-gulo-non-3-ulose (35).
At 0 °C, Dess-Martin periodinane (0.385 g, 0.908 mmol, 4.00
equiv) was added to a solution of triol 30 (0.120 g, 0.227 mmol,
1.00 equiv) in CH2Cl2 (4.0 mL). After 2 h of stirring at 0 °C, the
solvent was removed under high vacuum. Then a solution of
NaClO2 (0.123 g, 1.36 mmol, 6.00 equiv) and 2-methyl-2-butene
(0.240 mL, 2.27 mmol, 10.0 equiv) in t-BuOH (7.0 mL) and pH
3.8 buffer (1.4 mL) was added. The light yellow suspension was
allowed to warm to rt and stirred for 30 min, before more pH 3.8
buffer (4 mL) was added. The biphasic mixture was extracted
with EtOAc (7 ꢀ 5 mL). The organic solution was washed with
After addition of boric acid (0.102 g, 1.65 mmol, 5.00 equiv)
and Raney Ni (W2, spatula tip) to a biphasic mixture of 22
8706 J. Org. Chem. Vol. 74, No. 22, 2009

Muri and Carreira
JOCArticle
(0.202 g, 0.33 mmol, 1.00 equiv) in MeOH/H2O (5:1, 4.0 mL),
the Schlenk flask was purged several times with H2. The
black suspension was stirred rapidly under an atmosphere of
H2 for 2 h. The black reaction mixture was filtered over Celite
and eluted with CH2Cl2. The biphasic mixture was washed
with H2O. The organic solution was dried over anhydrous
Na2SO4 and concentrated in vacuo. Purification by chromatog-
raphy on silica gel (hexane/EtOAc 7:1) provided β-hydroxy-
ketone 35 (0.181 g, 89% yield) as a clear, colorless oil. Rf = 0.54
(3:1 hexane/EtOAc). [R]3D0.1 (c 1.530, CHCl3) = þ12°. 1H NMR
(300 MHz, CDCl3) δ: 7.25 (d, 2H, J = 8.6 Hz), 6.87 (d, 2H, J =
8.7 Hz), 4.42 (s, 2H), 3.87-3.83 (m, 1H), 3.81-3.75 (m, 1H),
3.80 (s, 3H), 3.53 (dd, 1H, J = 9.7, 5.9 Hz), 3.27-3.16 (m, 2H),
2.99-2.88 (m, 2H), 2.49 (d, 1H, J = 7.8 Hz), 1.81-1.76 (m, 1H),
1.66-1.50 (m, 2H), 1.18 (s, 3H), 1.16 (d, 3H, J = 7.2 Hz), 1.04
(d, 3H, J = 6.8 Hz), 1.01 (d, 3H, J = 6.5 Hz), 0.95 (t, 9H, J = 8
Hz) 0.87 (s, 9H), 0.61 (q, 6H, J = 8 Hz) 0.03 (s, 3H), 0.02 (s, 3H).
13C NMR (75 MHz, CDCl3) δ: 216.4, 158.9, 130.7, 129.0, 113.6,
79.2, 76.4, 73.1, 72.6, 65.6, 55.3, 47.1, 47.0, 44.0, 30.0, 26.0, 25.2,
19.4, 18.5, 14.2, 11.2, 7.3, 7.0, -5.3, -5.3. IR (thin film) 3524,
2954, 2876, 1701, 1613, 1587, 1513, 1463, 1361, 1302, 1249, 1172,
1095, 1005, 837, 775, 741, 724, 666 (cm-1). HRMS-MALDI
(m/z) calcd for [C33H62O6Si2Na]þ, 633.3983; found, 633.3972.
Anal. Calcd for C33H62O6Si2: C, 64.87; H, 10.23. Found: C,
64.69; H, 10.46.
3,5-O-Benzylidene-1-O-[tert-butyl(dimethyl)silyl]-2,4,7,8-tet-
radeoxy-9-O-(4-methoxybenzyl)-2,4,8-trimethyl-6-C-methyl-6-
O-(triethylsilyl)-L-threo-L-ido-nonitol (37).
To a solution of 36 (0.580 g, 0.946 mmol, 1.00 equiv) in
toluene (10 mL) were added benzaldehyde dimethyl acetal
(0.213 mL, 1.42 mmol, 1.50 equiv) and CSA (0.0220 g, 0.0946
mmol, 0.100 equiv). The solution was stirred at rt and 70 mbar
for 1.5 h, and then satd aq NaHCO3 (10 mL) and EtOAc (10 mL)
were added. The layers were separated, and the aqueous
phase was extracted with EtOAc (3 ꢀ 10 mL). The combined
organic phases were washed with brine (10 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue
was purified by chromatography on silica gel (hexane/EtOAc
15:1) to provide 37 (0.58 g, 87% yield) as a clear, colorless oil.
Rf = 0.64 (3:1 hexane/EtOAc). [R]2D3.6 (c 1.225, CHCl3) = -1.5°.
1H NMR (300 MHz, CDCl3) δ: 7.53-7.50 (m, 2H), 7.38-7.31
(m, 3H), 7.27-7.23 (m, 2H), 6.90-6.85 (m, 2H), 5.50 (s, 1H),
4.43 (s, 2H), 3.81 (s, 3H), 3.60 (d, 1H, J = 1.9 Hz), 3.55-3.50
(m, 3H), 3.36 (dd, 1H, J = 8.71, 5.6 Hz), 3.15 (dd, 1H, J = 8.7,
7.5 Hz), 1.96-1.86 (m, 3H), 1.55 (dd, 1H, J = 13.7, 4.4 Hz),
1.42 (dd, 1H, J = 13.7, 5.9 Hz), 1.29 (s, 3H), 1.05 (d, 3H, J = 6.5
Hz), 1.05 (d, 3H, J = 6.5 Hz), 1.02 (d, 3H, J = 6.9 Hz), 0.90
(s, 9H), 0.86 (t, 9H, J = 8.1 Hz) 0.51 (q, 6H, J = 8.1 Hz), 0.04
(s, 3H), 0.03 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 158.8,
139.1, 130.9, 128.9, 128.3, 127.8, 126.2, 113.6, 102.1, 87.1,
85.0, 78.0, 76.7, 72.5, 64.1, 55.3, 43.2, 36.3, 31.4, 29.4, 26.0,
24.9, 19.9, 18.3, 14.6, 8.4, 7.3, 6.8, -5.3, -5.4. IR (thin film)
2953, 2874, 1612, 1587, 1514, 1406, 1360, 1302, 1249, 1141, 1101,
1035, 1010, 972, 836, 776, 741, 698 (cm-1). HRMS-MALDI
(m/z) calcd for [C40H68O6Si2Na]þ, 723.4447; found, 723.4439.
Anal. Calcd for C40H68O6Si2: C, 68.52; H, 9.78. Found: C,
68.44; H, 9.79.
9-O-[tert-Butyl(dimethyl)silyl]-2,3,6,8-tetradeoxy-1-O-(4-meth-
oxybenzyl)-2,6,8-trimethyl-4-C-methyl-4-O-(triethylsilyl)-L-threo-
L-ido-nonitol (36).
At -78 °C, Zn(BH4)2 (0.145 M solution in Et2O, 12.0 mL,
1.73 mmol, 2.50 equiv) was added to a solution of β-hydroxy
ketone 35 (0.424 g, 0.694 mmol, 1.00 equiv) in CH2Cl2 (35 mL).
The clear, colorless solution was stirred at -30 °C for 2 h before
more Zn(BH4)2 (0.145 M solution in Et2O, 2.40 mL, 0.345
mmol, 0.500 equiv) was added. The solution was stirred for
another 30 min before it was quenched with MeOH/H2O (1:1,
10 mL). The biphasic mixture was stirred for 1 h at rt, and then
1 N HCl (5 mL) was added. The aqueous layer was separated
and extracted with CH2Cl2 (3 ꢀ 10 mL). The combined organics
were washed with brine (10 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure. Purification by chro-
matography on silica gel (hexane/EtOAc 10:1 to 7:1) afforded
pure 1,3-diol 36 (0.260 g, 60% yield) as a clear, colorless oil. No
other diastereoisomer could be detected, as determined by
examination of the diastereotopic signals of the protons at C3
3,5-O-Benzylidene-1-O-[tert-butyl(dimethyl)silyl]-2,4,7,8-tetra-
deoxy-2,4,8-trimethyl-6-C-methyl-6-O-(triethylsilyl)-L-threo-L-
ido-nonitol (38).
At 0 °C, a solution of benzylidene acetal 37 (0.650 g, 0.927
mmol, 1.00 equiv) in CH2Cl2 (18 mL) was treated with DDQ
(0.253 g, 1.11 mmol, 1.2 equiv) and pH 7 buffer (30 μL). The
green suspension slowly turned light brown. After stirring for
2 h at 0 °C, the reaction was quenched with satd aq Na2S2O3
(5 mL) and satd aq NaHCO3 (60 mL). The two layers were
separated, and the aqueous layer was extracted with CH2Cl2
(3 ꢀ 20 mL). The organic solution was washed with brine
(20 mL), dried over anhydrous Na2SO4, filtered over Na2SO4,
and concentrated under reduced pressure. The light yellow
residue was purified by chromatography on silica gel (hexane/
EtOAc 7:1) to afford primary alcohol 38 (0.461 g, 85% yield)
as a clear, colorless oil. Rf = 0.51 (3:1 hexane/EtOAc). [R]D31.4
(c 1.055, CHCl3) = þ8.1°. 1H NMR (300 MHz, CDCl3) δ:
7.53-7.50 (m, 2H), 7.40-7.33 (m, 3H), 5.51 (s, 1H), 3.67 (d, 1H,
J = 1.9 Hz), 3.58-3.48 (m, 4H), 3.38-3.30 (m, 1H), 2.44 (t, 1H,
J = 5.5 Hz), 2.00-1.87 (m, 3H), 1.66 (dd, 1H, J = 14.3, 5.91
Hz), 1.41 (dd, 1H, J = 14.0, 4.1 Hz), 1.34 (s, 3H), 1.06 (d, 3H,
J = 6.5 Hz), 1.03 (d, 3H, J = 6.5 Hz), 0.98 (d, 3H, J = 6.9 Hz),
1
and C5 (3.1-3.7 ppm) of 36 in the H NMR spectrum of the
crude material. Rf = 0.48 (3:1 hexane/EtOAc). [R]2D7.6 (c 1.035,
CHCl3) = þ10°. 1H NMR (300 MHz, CDCl3) δ: 7.25 (d, 2H,
J = 7.8 Hz), 6.87 (d, 2H, J = 8.7 Hz), 4.42 (s, 2H), 3.81 (s, 3H),
3.74 (s, 1H), 3.67-3.63 (m, 1H), 3.62 (dd, 1H, J = 10.0, 4.1 Hz)
3.56-3.49 (m, 2H), 3.25-3.16 (m, 2H) 2.72 (d, 1H, J = 9.3 Hz),
1.93-1.87 (m, 1H), 1.81-1.73 (m, 1H), 1.71-1.45 (m, 3H),
1.23 (s, 3H), 1.02-0.97 (m, 9H), 0.95 (t, 9H, J = 7.8 Hz), 0.88 (s,
9H), 0.62 (q, 6H, J = 7.8 Hz), 0.038 (s, 6H). 13C NMR (75 MHz,
CDCl3) δ: 158.9, 130.6, 129.0, 113.6, 79.6, 79.2, 77.5, 76.3,
72.6, 67.0, 55.3, 44.6, 37.4, 35.8, 30.3, 26.0, 24.7, 19.4, 18.3,
13.0, 7.5, 7.3, 7.0, -5.4, -5.4. IR (thin film) 3502, 2955, 2876,
1613, 1587, 1514, 1463, 1415, 1389, 1361, 1302, 1249, 1172,
1097, 1004, 972, 837, 776, 742, 668 (cm-1). HRMS-MALDI
(m/z) calcd for [C33H64O6Si2Na]þ, 635.4139; found, 635.4127.
Anal. Calcd for C33H64O6Si2: C, 64.66; H, 10.52. Found:
C, 64.40; H, 10.66.
J. Org. Chem. Vol. 74, No. 22, 2009 8707

Muri and Carreira
JOCArticle
0.90 (s, 9H), 0.86 (t, 9H, J = 7.5 Hz), 0.59-0.51 (m, 6H), 0.05 (s,
3H), 0.05 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 139.2, 128.8,
128.3, 126.7, 102.6, 88.2, 85.5, 78.8, 69.3, 64.5, 43.5, 36.5, 31.7,
31.2, 26.1, 24.4, 20.0, 18.5, 14.7, 8.5, 7.3, 6.6, -5.3, -5.3. IR (thin
film) 3436, 2954, 2875, 1947, 1458, 1406, 1376, 1349, 1311, 1253,
1213, 1111, 1065, 1033, 1010, 915, 837, 776, 742, 698, 674 (cm-1).
HRMS-MALDI (m/z) calcd for [C32H60O5Si2Na]þ, 603.3872;
found, 603.3870. Anal. Calcd for C32H60O5Si2: C, 66.15; H,
10.41. Found: C, 66.27; H, 10.58.
3,5-O-Benzylidene-7-O-[tert-butyl(dimethyl)silyl]-1,4,6-tri-
deoxy-2-C-((2R)-2-{(4S,5R)-5-[(1R)-1-hydroxyethyl]-4-methyl-
4,5-dihydroisoxazol-3-yl}propyl)-4,6-dimethyl-2-O-(triethylsilyl)-
L-glycero-D-gulo-heptitol (40).
5,7-O-Benzylidene-9-O-[tert-butyl(dimethyl)silyl]-2,3,6,8-tet-
radeoxy-2,6,8-trimethyl-4-C-methyl-4-O-(triethylsilyl)-L-threo-
L-ido-nonose (39).
To a solution of (R)-(-)-(Z)-3-penten-2-ol (14) (0.091 g, 1.1
mmol, 1.3 equiv) and 2-propanol (0.21 mL, 2.7 mmol, 3.3 equiv) in
CH2Cl2 (40mL) at0°C was added EtMgBr (3 M in Et2O, 0.81 mL,
2.4 mmol, 3.0 equiv). The reaction mixture turned momentarily
cloudy, becoming clear and colorless upon stirring at 0 °C for
30 min. At this time, the hydroxymoyl chloride, prepared by
addition of t-BuOCl (0.10 mL, 0.89 mmol, 1.1 equiv) to a solution
of oxime 39 (0.48 g, 0.81 mmol, 1.0 equiv) in CH2Cl2 (8.0 mL) at
-78 °C and stirring for 1.5 h, was added dropwise via cannula to
the reaction to give a slightly yellow solution. The yellow solution
was allowed to warm to rt and stirred for 2 h. The reaction was
quenched by the addition of satd aq NH4Cl (20 mL), and the two
layers were separated. The aqueous layer was extracted with
CH2Cl2 (3ꢀ 20 mL). The combined organic solutions were washed
with brine (20 mL), dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. Purification by chromatography on
silica gel (hexane/EtOAc 4:1) provided isoxazoline 40 (0.52 g, 86%
yield) as a clear, colorless oil. No other diastereomer could be
detected, as determined by examination of the diastereotopic
signals of the proton at C11 (4.0-4.2 ppm) of 40 in the 1H
NMR spectrum of the crude material. Rf = 0.31 (3:1 hexane/
EtOAc). [R]2D8.0 (c 1.080, CHCl3) = -13°. 1H NMR (300 MHz,
CDCl3) δ: 7.60-7.50 (m, 2H), 7.39-7.32 (m, 3H), 5.50 (s, 1H),
4.19 (dd, 1H, J = 9.7, 5.0 Hz), 3.97-3.89 (m, 1H), 3.6 (d, 1H, J =
1.9 Hz), 3.56-3.46 (m, 3H), 3.33-3.23 (m, 1H), 2.82-2.77 (m,
1H), 2.20 (dd, 1H, J = 14.0, 5.3 Hz), 1.98 (d, 1H, J = 6.5 Hz),
1.95-1.88 (m, 2H), 1.77 (dd, 1H, J = 13.7, 5.3 Hz), 1.30 (s, 3H),
1.27 (d, 3H, J = 6.5 Hz), 1.23 (d, 3H, J = 6.2 Hz), 1.18 (d, 3H, J =
7.5 Hz), 1.08 (d, 3H, J = 6.9 Hz), 1.05 (d, 3H, J = 6.5 Hz), 0.90 (s,
9H), 0.88 (t, 9H, J= 7.5 Hz), 0.55 (q, 6H, J=7.8Hz), 0.05(s, 6H).
13C NMR (75 MHz, CDCl3) δ: 168.2, 139.0, 128.4, 127.9, 126.2,
102.2, 87.0, 86.0, 85.1, 77.6, 66.2, 64.1, 44.2, 42.3, 36.5, 31.4, 27.8,
26.0, 25.3, 21.8, 20.4, 18.4, 14.6, 10.9, 8.5, 7.3, 6.8, -5.3. IR (thin
film) 3458, 2955, 2933, 2876, 1616, 1458, 1406, 1377, 1348, 1253,
1212, 1134, 1110, 1031, 1007, 975, 901, 837, 776, 743, 698, 671
(cm-1). HRMS-MALDI (m/z) calcd for [C37H67NO6Si2Na]þ,
700.4339; found, 700.4408.
To a biphasic solution of 38 (0.461 g, 0.793 mmol, 1.00 equiv),
TEMPO (0.0186 g, 0.119 mmol, 0.150 equiv), and KBr (0.0092
g, 0.079 mmol, 0.100 equiv) in CH2Cl2 (8.0 mL) and pH 8.6
buffer (8.0 mL) was slowly added NaOCl (0.5 M in H2O, 6.35
mL, 3.17 mmol, 4.00 equiv) at 0 °C. After 10 min, H2O (5 mL)
and CH2Cl2 (10 mL) were added. The two layers were separated,
and the aqueous layer was extracted with CH2Cl2 (3 ꢀ 10 mL).
The organic solution was washed with brine (10 mL), dried over
Na2SO4, and concentrated in vacuo. The light orange oil was
used without further purification. Rf = 0.65 (3:1 hexane/
1
EtOAc). H NMR (300 MHz, CDCl3) δ: 9.48 (d, 1H, J = 3.1
Hz), 7.52-7.49 (m, 2H), 7.40-7.33 (m, 3H), 5.46 (s, 1H), 3.62 (d,
1H, J = 1.9 Hz), 3.58-3.48 (m, 3H), 2.67-2.61 (m, 1H), 2.15
(dd, 1H, J = 14.0, 9.3 Hz), 1.96-1.87 (m, 2H), 1.45 (dd, 1H, J =
14.3, 3.11 Hz), 1.32, (s, 3H), 1.08 (d, 3H, J = 5.3 Hz), 1.06 (d,
3H, J = 7.16 Hz), 1.04 (d, 3H, J = 7.2 Hz), 0.91 (s, 9H), 0.87 (t,
9H, J = 7.5 Hz), 0.53 (q, 6H, J = 7.5 Hz), 0.05 (s, 3H), 0.05 (s,
3H). A solution of H2NOH HCl (0.110 g, 1.59 mmol, 2.00
3
equiv) in py (1.6 mL) was added to a solution of unpurified
aldehyde (0.459 g, 0.793 mmol, 1.00 equiv) in EtOH (8.0 mL),
and the mixture was stirred for 20 min at rt. The light green
solution was quenched with 1 N HCl (20 mL), and the aqueous
layer was extracted with EtOAC (3 ꢀ 10 mL). The combined
organic solutions were washed with brine (10 mL), dried over
Na2SO4, and concentrated under reduced pressure. Purification
by chromatography on silica gel (hexane/EtOAc 7:1) provided
oxime 39 (0.402 g, 85% yield over 2 steps) as a mixture of E/Z
isomers (∼1.5:1). Rf = 0.56, 0.51* (3:1 hexane/EtOAc, *denotes
minor isomer). [R]D24.0 (c 1.185, CHCl3) = -5.9°. 1H NMR (300
MHz, CDCl3, *denotes minor isomer) δ: 7.53-7.50 (m, 2H),
7.39-7.29 (m, 3H), 6.75* (s(br), 1H), 6.63 (d, 1H, J = 7.8 Hz),
5.53* (s, 1H), 5.51 (s, 1H), 3.68* (d, 1H, J = 1.9 Hz), 3.63 (d, 1H,
J = 1.9 Hz), 3.60-3.49 (m, 3H), 3.34-3.30* (m, 1H), 2.70-2.61
(m, 1H), 1.94-1.87 (m, 1H), 1.77-1.71 (m, 1H), 1.68-1.60* (m,
1H), 1.29 (s, 3H), 1.29* (s, 3H), 1.11 (d, 3H, J = 6.9 Hz), 1.07
(d, 3H, J = 6.54 Hz), 1.06* (d, 3H, J = 6.54 Hz), 1.04 (d, 3H,
J = 6.5 Hz), 0.91* (s, 9H), 0.91 (s, 9H), 0.88 (t, 9H, J = 7.5 Hz),
0.55 (q, 6H, J = 7.8 Hz), 0.06* (s, 3H), 0.05 (s, 3H), 0.05 (s, 3H).
13C NMR (75 MHz, CDCl3, *denotes minor isomer) δ: 158.5*,
157.6, 139.4*, 139.4, 128.7*, 128.2, 126.5, 102.4, 87.2, 87.1*,
85.4, 64.4, 45.2*, 44.7, 36.6, 36.5*, 31.6, 30.6, 26.1, 26.0,
25.5, 25.2*, 20.9, 19.5, 18.5, 14.6, 8.6, 7.4, 6.9, 6.8*, -5.2,
-5.3. IR (thin film) 3255, 3036, 2955, 2875, 1948, 1805, 1662,
1457, 1407, 1377, 1348, 1311, 1252, 1212, 1111, 1068, 1030, 971,
911, 837, 811, 776, 741, 698, 672 (cm-1). HRMS-MALDI (m/z)
calcd for [C32H59NO5Si2Na]þ, 616.3824; found, 616.3823. Anal.
Calcd for C32H59NO5Si2: C, 64.71; H, 10.01. Found: C, 64.48;
H, 9.93.
2-C-{(2R)-2-[(4S,5R)-5-Acetyl-4-methyl-4,5-dihydroisoxazol-3-
yl]propyl}-3,5-O-benzylidene-7-O-[tert-butyl(dimethyl)silyl]-1,4,6-tri-
deoxy-4,6-dimethyl-2-O-(triethylsilyl)-L-glycero-D-gulo-heptitol (41).
To a biphasic solution of isoxazoline 40 (0.52 g, 0.77 mmol, 1.0
equiv), TEMPO (0.018 g, 0.12 mmol, 0.15 equiv), and KBr
8708 J. Org. Chem. Vol. 74, No. 22, 2009

Muri and Carreira
JOCArticle
(0.0089 g, 0.077 mmol, 0.10 equiv) in CH2Cl2 (8.0 mL) and pH
8.6 buffer (8.0 mL) was slowly added NaOCl (0.5 M in H2O, 6.1
mL, 3.1 mmol, 4.0 equiv) at 0 °C. After stirring for 1 h at 0 °C,
the two layers were separated, and the aqueous layer was
extracted with CH2Cl2 (3 ꢀ 10 mL). The organic solution was
washed with brine (10 mL), dried over Na2SO4, and concen-
trated in vacuo. The residue was purified by chromatography on
silica gel (hexane/EtOAc 6:1) to afford ketone 41 (0.48 g, 93%
yield) as colorless oil. Rf = 0.50 (3:1 hexane/EtOAc). [R]D23.2
(c 1.205, CHCl3) = þ13°. 1H NMR (300 MHz, CDCl3) δ:
7.52-7.49 (m, 2H), 7.40-7.33 (m, 3H), 5.50 (s, 1H), 4.75 (d, 1H,
J = 10.9 Hz), 3.60 (m, 4H), 3.52 (d, 1H, J = 4.1 Hz), 2.90-2.85
(m, 1H), 2.25 (s, 3H), 2.21 (dd, 1H, J = 14.0, 5.3 Hz), 1.93-1.88
(m, 2H), 1.76 (dd, 1H, J = 14.0, 5.3 Hz), 1.33 (s, 3H), 1.23
(d, 3H, J = 7.2 Hz), 1.08 (d, 3H, J = 6.2 Hz), 1.06 (d, 3H,
J = 7.2 Hz), 1.05 (d, 3H, J = 6.5 Hz), 0.90 (s, 9H), 0.86 (t, 9H,
J = 7.8 Hz), 0.55 (q, 6H, J = 7.8 Hz), 0.06 (s, 6H). 13C NMR
(75 MHz, CDCl3) δ: 208.4, 166.7, 138.9, 128.5, 128.0, 126.2, 102.3,
87.5, 87.2, 85.1, 77.5, 64.1, 46.7, 42.3, 36.5, 31.4, 28.4, 27.6, 26.0,
25.2, 21.7, 18.4, 14.6, 12.1, 8.5, 7.3, 6.8, -5.3. IR (thin film) 2955,
2876, 1716, 1458, 1407, 1377, 1356, 1252, 1135, 1111, 1031, 1007,
973, 914, 837, 811, 776, 742, 698, 674 (cm-1). HRMS-MALDI
(m/z) calcd for [C37H65NO6Si2Na]þ, 698.4243; found, 698.4234.
3,5-O-Benzylidene-7-O-[tert-butyl(dimethyl)silyl]-1,4,6-tride-
oxy-4,6-dimethyl-2-C-((2R)-2-{(4S,5R)-4-methyl-5-[(1Z)-1-methyl-
but-1-en-1-yl]-4,5-dihydroisoxazol-3-yl}propyl-2-O-(triethylsilyl)-
L-glycero-D-gulo-heptitol (42).
26.0, 25.2, 21.7, 21.2, 20.4, 18.4, 14.6, 14.4, 11.9, 8.4, 7.3, 6.8, -5.3.
IR (thin film) 2956, 2932, 2875, 1616, 1457, 1406, 1378, 1348, 1252,
1211, 1111, 1092, 1031, 1007, 973, 924, 837, 776, 742, 698, 671
(cm-1). HRMS-MALDI (m/z) calcd for [C40H71NO5Si2Na]þ,
724.4763; found, 724.4755.
3,5-O-Benzylidene-7-O-[tert-butyl(dimethyl)silyl]-1,4,6-tride-
oxy-2-C-((2R)-2-{(4S,5R)-5-[(2R)-2-hydroxy-1,1-dimethylbutyl]-
4-methyl-4,5-dihydroisoxazol-3-yl}propyl)-4,6-dimethyl-2-O-(tri-
ethylsilyl)-L-glycero-D-gulo-heptitol (43).
To a solution of olefin 42 (380 mg, 0.54 mmol, 1.0 equiv) in
t-BuOH (5.0 mL) and H2O (5.0 mL) were added (DHQD)2-
PHAL (84 mg, 0.11 mmol, 0.20 equiv), K3Fe(CN)6 (530 mg, 1.6
mmol, 3.0 equiv), K2CO3 (220 mg, 1.6 mmol, 3.0 equiv), and
methanesulfonylamide (160 mg, 1.6 mmol, 3.0 equiv). The biphasic
mixture was cooled to 0 °C before K2OsO4 H2O (8.0 mg, 0.020
3
mmol, 0.040 equiv) was added. The suspension slowly turned
brown and was stirred for 3.5 h at 0 °C. Then it was quenched
with satd aq Na2S2O3 (10 mL) and extracted with EtOAc (4 ꢀ 10
mL). The organic solution was washed with brine (10 mL), dried
over anhydrous Na2SO4, and concentrated in vacuo. Purification
by chromatography on silica gel (hexane/EtOAc 6:1 to 3:1)
provided diol 43 (320 mg, 81% yield) as a clear, colorless oil. No
other diastereomer could be detected, as determined by examina-
1
tion of the proton at C11 (4.0-4.2 ppm) of 43 in the H NMR
spectrum of the crude material. Rf = 0.30 (3:1 hexane/EtOAc).
[R]D24.0 (c 0.590, CHCl3) = þ9.9°. 1H NMR (300 MHz, CDCl3) δ:
7.53-7.49 (m, 2H), 7.39-7.32 (m, 3H), 5.50 (s, 1H), 4.25 (d, 1H,
J = 8.4 Hz), 3.61 (d, 1H, J = 1.6 Hz), 3.55-3.46 (m, 3H), 3.28 (s,
1H), 3.24-3.12 (m, 2H), 2.82-2.76 (m, 1H), 2.26-2.19 (m, 2H),
1.92-1.88 (m, 2H), 1.78 (dd, 1H, J = 14.0, 5.6 Hz), 1.71-1.65 (m,
1H), 1.46-1.33 (m, 1H), 1.31 (s, 3H), 1.29 (d, 3H, J = 8.4 Hz), 1.23
(d, 3H, J = 7.2 Hz), 1.23 (s, 3H), 1.09 (t, 3H, J = 7.2 Hz), 1.08 (d,
3H, J = 6.9 Hz), 1.05 (d, 3H, J = 6.5 Hz), 0.90 (s, 9H), 0.88 (t, 9H,
J = 7.8 Hz), 0.55 (q, 6H, J = 7.8 Hz), 0.05 (s, 6H). 13C NMR (75
MHz, CDCl3) δ: 170.5, 139.3, 128.7, 128.2, 126.5, 102.5, 87.2, 86.0,
85.3, 82.4, 77.8, 73.7, 64.2, 45.7, 42.6, 36.6, 31.6, 28.0, 26.1, 25.5, 25.5,
22.4, 21.1, 18.4, 14.7, 13.3, 11.8, 8.5, 7.4, 6.9, -5.2. IR (thin film)
3531, 2956, 1610, 1457, 1406, 1379, 1347, 1252, 1110, 1035, 1008,
975, 910, 837, 776, 735, 698, 672 (cm-1). HRMS-MALDI (m/z)
calcd for [C40H73NO7Si2Na]þ, 758.4818; found, 758.4810.
3,5-O-Benzylidene-1,4,6-trideoxy-2-C-((2R)-2-{(4S,5R)-5-[(1R,
2R)-1,2-dihydroxy-1-methylbutyl]-4-methyl-4,5-dihydroisoxazol-
3-yl}propyl)-4,6-dimethyl-2-O-(triethylsilyl)-L-glycero-D-gulo-
heptitol (44).
At -78 °C, t-BuLi (1.70 M in pentane, 1.88 mL, 3.20 mmol, 5.00
equiv) was added to a suspension of propyltriphenylphosphonium
bromide (1.48 g, 3.84 mmol, 6.00 equiv) in THF (60 mL). The
reaction mixture slowly turned red, was allowed to warm to rt, and
stirred for 2 h. The dark red suspension was cooled to -78 °Cbefore
a solution of ketone 41 (0.433 g, 0.640 mmol, 1.00 equiv) in THF
(6.0 mL) was added dropwise via cannula. The red mixture was
slowly warmed to rt and stirred for 15 h. To the orange suspension
were added H2O (50 mL) and Et2O (50 mL,) and the two layers
were separated. The aqueous phase was extracted with Et2O(3 ꢀ 20
mL). The combined organics were washed with H2O2 (3% in H2O,
50 mL) and brine (20 mL), dried over Na2SO4, and concentrated
under reduced pressure. Purification by chromatography on silica
gel (hexane/EtOAc 15:1) provided olefin 42 (0.353 g, 78% yield) as a
clear, colorless oil and as 33:1 mixture of Z/E diastereomers,
accompanied with 0.020 g of recovered ketone 41 (5%). The dia-
stereomeric ratio was determined by examination of the proton at
1
C11 (5.2-5.3 ppm) of 42 in the H NMR spectrum of the crude
material. Rf = 0.65 (3:1 hexane/EtOAc). [R]2D5.4 (c 1.190, CHCl3) =
þ13°. 1H NMR (300 MHz, CDCl3) δ: 7.53-7.49 (m, 2H),
7.39-7.30 (m, 3H), 5.51 (s, 1H), 5.35 (t, 1H, J = 7.3 Hz), 5.30
(d, 1H, J = 10.6 Hz), 3.61 (d, 1H, J = 1.9 Hz), 3.57-3.46 (m, 3H),
3.40-3.29 (m, 1H), 2.86-2.78 (m, 1H), 2.20 (dd, 1H, J = 14.0, 5.0
Hz), 2.10-1.96 (m, 1H), 1.93-1.84 (m, 3H), 1.77 (dd, 1H,
J = 14.0, 5.6 Hz), 1.68 (d, 3H, J = 1.6 Hz), 1.32 (s, 3H), 1.23
(d, 3H, J = 7.2 Hz), 1.08 (d, 3H, J = 7.8 Hz), 1.05 (d, 3H, J = 6.5
Hz), 1.00 (t, 3H, J = 7.5 Hz), 0.96 (d, 3H, J = 7.5 Hz), 0.90 (s, 9H),
0.87 (t, 9H, J = 7.8 Hz), 0.55 (q, 6H, J = 7.8 Hz), 0.52 (s, 6H). 13
C
NMR (75 MHz, CDCl3) δ: 166.5, 139.0, 131.1, 130.8, 128.4, 127.9,
126.2, 102.2, 87.1, 85.1, 82.1, 77.6, 64.0, 45.5, 42.5, 36.5, 31.4, 28.0,
At 0 °C, HF pyridine (1.0 mL) was added to a solution of diol
3
43 (325 mg, 0.441 mmol, 1.00 equiv) in pyridine (3.0 mL). The
J. Org. Chem. Vol. 74, No. 22, 2009 8709

Muri and Carreira
JOCArticle
solution was stirred for 3 h at 0 °C and then quenched with H2O
(2 mL) and solid NaHCO3 (2.5 g) with care. The biphasic
mixture was extracted with EtOAc (5 ꢀ 5 mL). The combined
organic solutions were washed with 1 N HCl (50 mL) and brine
(5 mL), dried over anhydrous Na2SO4, and concentrated under
reduced pressure. Purification by chromatography on silica gel
(hexane/EtOAc 1:1 to 1:3) afforded triol 44 (220 mg, 80% yield)
as a colorless foam. Rf = 0.18 (1:1 hexane/EtOAc). [R]D24.5
(c 2.650, CHCl3) = -14°. 1H NMR (300 MHz, CDCl3) δ:
7.53-7.49 (m, 2H), 7.39-7.32 (m, 3H), 5.50 (s, 1H), 4.34 (d, 1H,
J = 8.7 Hz), 3.70 (d, 1H, J = 1.0 Hz), 3.68-3.53 (m, 4H),
3.32-3.18 (m, 2H), 2.92-2.86 (m, 1H), 2.43-2.22 (m, 3H),
2.06-2.00 (m, 1H), 1.90-1.83 (m, 1H), 1.74-1.67 (m, 1H), 1.62
(dd, 1H, J = 14.5, 4.9 Hz), 1.45-1.40 (m, 1H), 1.36 (d, 3H, J =
7.6 Hz), 1.34 (s, 3H), 1.24 (d, 3H, J = 8.9 Hz), 1.23 (s, 3H), 1.08
(t, 3H, J = 7.1 Hz), 1.09 (d, 3H, J = 6.5 Hz), 1.02 (d, 3H, J = 6.7
Hz), 0.85 (t, 9H, J = 7.8 Hz), 0.51 (q, 6H, J = 7.8 Hz). 13C NMR
(75 MHz, CDCl3) δ: 170.1, 138.8, 128.5, 127.9, 126.3, 102.5,
86.8, 85.7, 84.3, 81.4, 78.0, 73.9, 63.3, 45.3, 42.6, 36.0, 31.2, 27.0,
26.0, 25.1, 22.5, 20.5, 14.1, 13.1, 11.7, 8.1, 7.3, 6.7. IR (thin film)
3414, 2957, 2875, 1457, 1406, 1376, 1350, 1311, 1238, 1215, 1132,
1105, 1050, 1029, 1013, 974, 743, 698 (cm-1). HRMS-MALDI
(m/z) calcd for [C34H59NO7SiNa]þ, 644.3953; found, 644.3945.
3,5-O-Benzylidene-2,4,7-trideoxy-6-C-((2R)-2-{(4S,5R)-5-[(2R)-
2-hydroxy-1,1-dimethylbutyl]-4-methyl-4,5-dihydroisoxazol-3-yl}-
propyl)-2,4-dimethyl-3,5-O-(1-methylethylidene)-6-O-(triethyl-
silyl)-L-glycero-L-ido-heptonic Acid (45).
169.3, 138.5, 128.7, 128.0, 126.4, 102.6, 86.7, 85.8, 82.0, 81.8,
78.2, 74.2, 45.2, 42.3, 41.4, 32.1, 26.9, 26.1, 24.9, 22.5, 20.7,
14.8, 12.9, 11.7, 8.1, 7.3, 6.7. IR (thin film) 3450, 2957, 2876,
1722, 1457, 1407, 1379, 1348, 1312, 1274, 1239, 1215, 1129, 1105,
1065, 1028, 1007, 976, 938, 912, 884, 757, 698, 668 (cm-1).
HRMS-MALDI (m/z) calcd for [C34H57NO8SiNa]þ, 658.3746;
found, 658.3739.
(1R,2R,4R,8R,9R,10R,13R,14S,18S,19S)-10-Ethyl-9-hydroxy-
2,4,9,13,18,19-hexamethyl-16-phenyl-2-[(triethylsilyl)oxy]-7,11,15,
17-tetraoxa-6-azatricyclo[12.3.1.15,8]nonadec-5-en-12-one (46).
To a solution of acid 45 (136 mg, 0.214 mmol, 1.00 equiv) in
THF (4.0 mL) were added NEt3 (179 μL, 1.28 mmol, 6.00 equiv)
and 2,4,6-trichlorobenzoylchloride (167 μL, 1.07 mmol, 5.00
equiv) at 0 °C. The solution turned cloudy and was stirred for 30
min. The colorless suspension was allowed to warm to rt, and
toluene (12 mL) was added. This cloudy reaction mixture was
added to a 50 °C solution of DMAP (261 mg, 2.14 mmol, 10.0
equiv) in toluene (24.0 mL) via syringe pump over 3 h. After
addition, the stirring was maintained for another 45 min at 50 °C
before the colorless suspension was filtered over a plug of silica
gel (eluent hexane/EtOAc 1:1). The filtrate was concentrated
under reduced pressure. Purification by chromatography on
silica gel (hexane/EtOAc 10:1 to 6:1 to 3:1) provided macro-
lactone 46 (103 mg, 78% yield) as a colorless foam and as a mix-
ture of two atropisomers (7:2). Rf = 0.28 and 0.37* (3:1 hexane/
EtOAc, *denotes minor isomer). [R]2D2.6 (c 0.730, CHCl3) =
-49°. 1H NMR (300 MHz, CDCl3, *denotes minor isomer) δ:
7.53-7.46 (m, 2H), 7.39-7.30 (m, 3H), 5.58 (s, 1H), 5.43* (s,
1H), 5.03 (dd, 1H, J = 10.6, 2.5 Hz), 4.83* (dd, 1H, J = 9.0, 1.9
Hz), 4.49* (d, 1H, J = 9.5 Hz), 4.15 (d, 1H, J = 6.3 Hz), 4.10 (d,
1H, J = 1.4 Hz), 3.95 (dd, 1H, J = 8.2, 1.1 Hz), 3.90* (dd, 1H,
J = 6.3, 1.4 Hz), 3.62* (d, 1H, J = 1.3 Hz), 3.60-3.50 (m, 1H),
2.91-2.82 (m, 1H), 2.79-2.69 (m, 1H), 2.17-2.05* (m, 1H),
2.04 (s, 1H), 1.93-1.80 (m, 1H), 1.81 (dd, 1H, J = 15.1, 7.9 Hz),
1.72-1.64* (ddd, 1H, J = 14.4, 7.5, 2.1 Hz), 1.65-1.45 (m, 3H),
1.41* (dd, 1H, J = 15.0, 1.6 Hz), 1.28 (s, 3H), 1.27 (d, 3H, J =
6.9 Hz), 1.22 (d, 3H, J = 7.0 Hz), 1.18 (s, 3H), 1.17 (d, 3H, J =
7.0 Hz), 1.01 (d, 3H, J = 6.7 Hz), 0.96 (t, 3H, J = 7.4 Hz), 0.85 (t,
9H, J = 8.0 Hz), 0.59-0.39 (m, 6H). 13C NMR (75 MHz,
CDCl3, *denotes minor isomer) δ: 175.4, 172.3, 165.3*, 138.7,
128.5, 127.8, 126.4, 102.7*, 102.5, 86.9*, 85.4, 84.9*, 84.3, 83.3*,
82.3*, 81.8, 79.1, 78.7*, 78.4, 78.2*, 72.8, 47.4, 45.4*, 43.4*, 42.0,
41.0, 34.4*, 34.2, 27.8, 27.0, 26.4*, 26.1*, 25.6*, 23.0*, 22.6*,
21.4, 21.3, 17.5, 14.0, 12.6*, 11.2*, 11.0, 10.3*, 7.8, 7.3, 6.8. IR
(thin film) 3438, 2954, 2876, 1741, 1456, 1379, 1349, 1236,
1159, 1129, 1080, 1007, 972, 908, 741, 699 (cm-1). HRMS-
MALDI (m/z) calcd for [C34H55NO7SiNa]þ, 640.3640; found,
640.3634.
To a biphasic solution of triol 44 (220 mg, 0.35 mmol, 1.0
equiv), TEMPO (8.3 mg, 0.053 mmol, 0.15 equiv), and KBr
(4.1 mg, 0.035 mmol, 0.10 equiv) in CH2Cl2 (4.0 mL) and pH 8.6
buffer (4.0 mL) was slowly added NaOCl (0.5 M in H2O, 2.8 mL,
1.4 mmol, 4.0 equiv) at 0 °C. After stirring for 30 min at 0 °C, the
two layers were separated, and the aqueous layer was extracted
with CH2Cl2 (3 ꢀ 5 mL). The organic solution was washed with
brine (10 mL), dried over Na2SO4, and concentrated in vacuo.
The crude aldehyde was used without further purification. At
0 °C, a premixed solution of 2-methyl-2-butene (0.188 mL, 1.77
mmol, 5.00 equiv) and NaClO2 (96.3 mg, 1.06 mmol, 3.00 equiv)
in t-BuOH (9.0 mL) and pH 3.8 buffer (1.8 mL) was added to the
crude aldehyde (220 mg, 0.355 mmol, 1.00 equiv). After 30 min of
stirring at 0 °C, more pH 3.8 buffer (3.0 mL) was added, and the
solution was extracted with EtOAc (6 ꢀ 5 mL). The organic
solution was washed with brine (5 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure. Purifiaction
by chromatography on silica gel (hexane/EtOAc 2:1 to 2:1 þ 1%
HOAc) provided seco-acid 45 (187 mg, 83% yield over two steps)
as a clear, colorless oil. Rf = 0.38 (1:1 hexane/EtOAc þ 1%
HOAc). [R]2D5.4 (c 2.650, CHCl3) = -32°. 1H NMR (300 MHz,
CDCl3) δ: 7.51-7.46 (m, 2H), 7.40-7.32 (m, 3H), 5.51 (s, 1H),
4.40 (d, 1H, J = 9.1 Hz), 3.75 (s, 1H), 3.73 (dd, 1H, J = 10.0, 0.8
Hz), 3.39 (d, 1H, J = 9.5 Hz), 3.29-3.24 (m, 1H), 2.81-2.74 (m,
2H), 2.45 (dd, 1H, J = 14.7, 3.4 Hz), 1.96-1.91 (m, 1H),
1.74-1.68 (m, 1H), 1.55 (dd, 1H, J = 14.6, 5.0 Hz), 1.48-1.42
(m, 1H), 1.37 (d, 3H, J = 7.4 Hz), 1.33 (s, 3H), 1.27 (d, 3H,
J = 6.7 Hz), 1.24 (s, 3H), 1.23 (d, 3H, J = 5.5 Hz), 1.09 (t, 3H,
J = 6.1 Hz), 1.08 (d, 3H, J = 6.5 Hz), 0.85 (t, 9H, J = 8.0 Hz),
0.50 (q, 6H, J = 8.0 Hz). 13C NMR (75 MHz, CDCl3) δ: 176.6,
(1R,2R,4R,8R,9R,10R,13R,14S,16R,18S,19S)-10-Ethyl-2,9-
dihydroxy-2,4,9,13,18,19-hexamethyl-16-phenyl-7,11,15,17-tet-
raoxa-6-azatricyclo[12.3.1.15,8]nonadec-5-en-12-one.
8710 J. Org. Chem. Vol. 74, No. 22, 2009

Muri and Carreira
JOCArticle
Erythronolide A (1c).
To a solution of macrolactone 46 (39 mg, 0.069 mmol,
1.0 equiv) in CH3CN (0.50 mL) were added NEt3 (0.050 mL)
and HF NEt3 (0.50 mL). The clear solution was stirred for
3
64 h at 30 °C. The reaction was slowly quenched with satd
aq NaHCO3 (5 mL) and extracted with EtOAc (5 ꢀ 5 mL). The
organic solution was washed with brine (2 mL), dried
over anhydrous Na2SO4, and concentrated in vacuo. Purifica-
tion by chromatography on silica gel (hexane/EtOAc 1:1)
afforded the title diol (32 mg, >99% yield) as a clear, colorless
oil and as a 9:1 mixture of atropisomers. Rf = 0.24 (3:1 hexane/
EtOAc). [R]2D9.7 (c 0.190, CHCl3) = -32°. 1H NMR (300 MHz,
CDCl3, *denotes minor isomer) δ: 7.50-7.46 (m, 2H),
7.40-7.35 (m, 3H), 5.64 (s, 1H), 5.46* (s, 1H), 4.97 (dd, 1H,
J = 10.4, 2.7 Hz), 4.84* (dd, 1H, J = 11.0, 1.8 Hz), 4.51* (d, 1H,
J = 10.2 Hz), 4.30 (s, 1H), 4.19 (d, 1H, J = 6.3 Hz), 4.15* (d, 1H,
J = 6.3 Hz), 3.96 (dd, 1H, J = 7.3, 1.1 Hz), 3.64* (s, 1H),
3.59-3.49 (m, 1H), 2.95-2.84 (m, 1H), 2.80 (d, 1H, J =
1.8 Hz), 2.78-2.69 (m, 1H), 2.15-2.07* (m, 1H), 2.02 (s, 1H),
1.92-1.83 (m, 1H), 1.77 (dd, 1H, J = 15.6, 8.6 Hz), 1.66-1.45
(m, 3H), 1.27 (d, 3H, J = 6.6 Hz), 1.26 (s, 3H), 1.24 (d, 3H,
J = 7.2 Hz), 1.2 (s, 3H), 1.19 (d, 3H, J = 7.2 Hz), 1.04 (d, 3H,
J = 6.7 Hz), 0.97 (t, 3H, J = 7.4 Hz). 13C NMR (75 MHz,
CDCl3, *denotes minor isomer) δ: 175.9, 172.6, 139.0*, 138.8,
129.1, 128.4, 126.5, 102.9, 85.6, 85.0*, 83.7, 83.1*, 82.2*, 81.9,
79.8, 79.4*, 75.0, 74.7*, 73.2, 73.0*, 45.5*, 44.3, 42.3, 41.0,
34.5*, 34.3, 28.0, 27.0, 26.5*, 26.1*, 25.7*, 23.1*, 22.2*, 21.8,
21.2, 17.8, 13.4, 12.8, 11.9*, 11.2, 10.7*, 10.4*, 7.8, 7.7*. IR (thin
film) 3437, 2975, 2936, 2878, 1740, 1455, 1378, 1352, 1161, 1124,
1091, 1071, 1049, 1014, 980, 954, 894, 756, 700, 668 (cm-1).
HRMS-MALDI (m/z) calcd for [C28H41NO7Na]þ, 526.2775;
found, 526.2769.
To a solution of 47 (12 mg, 0.024 mmol, 1.0 equiv) in MeOH
(0.40 mL) was added Pd(OAc)2 (20 mg, 0.089 mmol, 3.8 equiv)
and H2O (0.030 mL). The brown solution was purged several
times with H2 and a black precipitate appeared. After 2 h and
after 4 h of stirring, more Pd(OAc)2 (55 mg, 0.24 mmol, 10 equiv
(ꢀ2)) were added. Formation of byproduct can be observed by
TLC analysis. The black suspension was filtered over Celite with
MeOH as eluent. The filtrate was concentrated under reduced
pressure. Purification by chromatography on silica gel (hexane/
acetone 2:1 to 3:2) provided erythronolide A (1c) (4.0 mg, 40%
yield) as a clear, colorless solid, accompanied with 47 (3.0 mg,
25%). Rf = 0.20 (1:3 hexane/EtOAc); mp = 171-172 °C; [R]D23.5
(c 0.54, CH3OH) = -36°. 1H NMR (300 MHz, CD3OD) δ: 5.19
(dd, 1H, J = 11.0, 2.3 Hz), 3.86 (d, J = 1H, 1.5 Hz), 3.55 (d, 1H,
J = 10.5 Hz), 3.50 (d, 1H, J = 3.2 Hz), 3.18-3.11 (m, 1H),
2.74-2.63 (m, 2H), 2.05-2.00 (m, 1H), 1.94-1.85 (m, 2H),
1.55-1.45 (m, 1H), 1.39 (dd, 1H, J = 14.7, 4.2 Hz), 1.29 (s, 3H),
1.18 (d, 3H, J = 7.6 Hz), 1.17 (s, 3H), 1.15 (d, 3H, J = 6.5 Hz),
1.12 (d, 3H, J = 6.6 Hz), 0.98 (d, 3H, J = 7.3 Hz), 0.85 (t, 3H,
J = 7.4 Hz). 13C NMR (75 MHz, CD3OD) δ: 220.1, 176.1, 81.1,
78.7, 77.0, 75.1, 74.3, 69.5, 44.0, 43.9, 39.8, 38.1, 36.3, 25.1, 21.3,
17.1, 16.2, 14.5, 10.9, 9.5, 6.9. IR (thin film) 3466, 2973, 2937,
2879, 1712, 1456, 1376, 1348, 1267, 1181, 1083, 1035, 980, 957,
912, 737, 704 (cm-1). HRMS-MALDI (m/z) calcd for
[C21H38O8Na]þ, 441.2459; found, 441.2452.
3,5-O-Benzylidene erythronolide A (47).
Erythronolide A Enol Ether (48a).
To a solution of diol from the previous experiment (15 mg,
0.030 mmol, 1.0 equiv) in EtOH (0.38 mL) was added acetic
acid (8.5 μL, 0.15 mmol, 5.0 equiv) and Raney Ni (W2, spatula
tip). The Schlenk flask was purged several times with H2.
The black suspension was stirred rapidly under an atmosphere
of H2 for 20 min. The black reaction mixture was filtered over
Celite and eluted with CH2Cl2. The filtrate was concentrated in
vacuo. Purification by chromatography on silica gel (hexane/
EtOAc 2:1) provided 47 (14 mg, 93% yield) as a clear, colorless
oil. Rf = 0.35 (1:1 hexane/EtOAc). [R]2D9.7 (c 0.107, CHCl3) =
-36°. 1H NMR (300 MHz, CDCl3) δ: 7.53-7.49 (m, 2H),
7.43-7.38 (m, 3H), 5.68 (s, 1H), 4.87 (dd, 1H, J = 10.7, 1.8
Hz), 4.01 (d, 1H, J = 1.1 Hz), 3.83 (dd, 1H, J = 10.0, 0.8 Hz),
3.77-3.74 (m, 1H), 3.23 (d, 1H, J = 5.4 Hz), 3.07-3.02 (m, 1H),
2.97 (dd, 1H, J = 10.8, 6.5 Hz), 2.95-2.85 (m, 1H), 2.57 (s, 1H),
2.29 (s, 1H), 2.05-1.93 (m, 1H), 1.79-1.75 (m, 1H), 1.72-1.70
(m, 2H), 1.63-1.52 (m, 1H), 1.35 (d, 3H, J = 6.3 Hz), 1.34
(s, 3H), 1.29 (d, 3H, J = 6.6 Hz), 1.21 (d, 3H, J = 7.1 Hz), 1.18
1H NMR (300 MHz, CDCl3) δ: 5.04 (dd, 1H, J = 11.0, 2.2
Hz), 3.69-3.63 (m, 3H), 3.02 (s(br), 1H), 2.91-2.66 (m, 2H),
2.78 (d, 1H, J = 15.9 Hz), 2.15 (d, 1H, J = 15.8 Hz), 1.99-1.65
(m, 5H), 1.59-1.49 (m, 1H), 1.55 (s, 3H), 1.40 (s, 3H), 1.23
(d, 3H, J = 6.7 Hz), 1.09 (s, 3H), 1.06 (d, 3H, J = 7.3 Hz), 0.96
(d, 3H, J = 7.0 Hz), 0.86 (t, 3H, J = 7.4 Hz). 13C NMR (75 MHz,
CD3OD) δ: 175.4, 151.0, 102.1, 83.5, 82.3, 82.2, 78.5, 75.4, 70.3,
43.7, 42.2, 34.9, 30.5, 28.4, 21.4, 16.3, 15.2, 14 0.1, 12.0, 10.7, 6.2.
Erythronolide A Ketal (49b).
(d, 3H, J = 6.6 Hz), 1.10 (s, 3H), 0.91 (t, 3H, J = 7.3 Hz). 13
C
NMR (75 MHz, CDCl3) δ: 215.3, 176.4, 137.7, 129.1, 128.2,
126.1, 103.3, 86.4, 84.3, 79.0, 75.3, 74.5, 70.3, 46.0, 41.7, 40.9,
38.3, 32.8, 26.8, 21.2, 18.4, 16.2, 13.6, 11.6, 11.0, 7.9. IR (thin
film) 3488, 2978, 2938, 2879, 1707, 1456, 1374, 1282, 1175, 1104,
1074, 1047, 1028, 1005, 975, 907, 835, 758, 700, 667 (cm-1).
HRMS-MALDI (m/z) calcd for [C28H42O8Na]þ, 529.2772;
found, 529.2765.
Rf = 0.23 (1:3 hexane/EtOAc). [R]2D3.1 (c 0.15, CH3OH) =
þ7.4°. 1H NMR (300 MHz, CDCl3) δ: 5.06 (dd, 1H, J = 11.8,
3.7 Hz), 3.69 (d, 1H, J = 9.6 Hz), 3.49 (dd, 1H, J = 11.7, 9.8 Hz),
3.42 (s, 1H), 2.85-2.75 (m, 1H), 2.49-2.39 (m, 1H), 2.31-2.18
(m, 1H), 2.09-2.02 (m, 2H), 1.94-1.81 (m, 1H), 1.78-1.70
J. Org. Chem. Vol. 74, No. 22, 2009 8711

Muri and Carreira
JOCArticle
(m, 1H), 1.62 (dd, 1H, J = 14.4, 3.7 Hz), 1.40 (d, 3H, J = 6.7
Hz), 1.38 (d, 3H, J = 7.3 Hz), 1.32 (s, 3H), 1.25 (s, 3H), 1.24
(d, 3H, J = 7.5 Hz), 1.19 (s, 3H), 0.94 (t, 9H, J = 7.5 Hz), 0.87
(t, 3H, J = 7.4 Hz), 0.59 (q, 6H, J = 7.7 Hz). 13C NMR (75 MHz,
CD3OD) δ: 173.1, 107.9, 89.2, 83.0, 82.2, 79.3, 77.6, 73.4, 50.5,
45.3, 43.5, 42.8, 34.5, 29.7, 27.3, 25.1, 24.1, 18.4, 16.3, 15.2, 14.6,
10.6, 7.1, 6.7. IR (thin film) 3454, 2925, 2877, 1714, 1461, 1382,
1305, 1239, 1184, 1122, 1056, 1000, 745, 723 (cm-1). HRMS-
MALDI (m/z) calcd for [C27H50O7SiNa]þ, 537.3218; found,
generous support of our research program. Mr. Jeffrey W.
€
edged for their support and numerous fruitful discussions
and suggestions. Prof. Bernhard Jaun and Dr. Damien
Jeannerat are gratefully acknowledged for analytical sup-
port.
Bode and Ms. Nina Lohse-Frafel are gratefully acknowl-
Supporting Information Available: Experimental proce-
dures and spectral data for all relevant compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. ETH, SNF, Aventis, Eli Lilly, Merck,
and F. Hoffmann-LaRoche are acknowledged for their
8712 J. Org. Chem. Vol. 74, No. 22, 2009