Formal synthesis of (-)-Neopeltolide featuring a highly stereoselective oxocarbenium formation/reduction sequence

Article abstract of DOI:10.1021/jo100443h

The formal synthesis of the unnatural (-)-neopeltolide core is discussed in detail. Efficient application of the Evans protocol for the synthesis of 1,3-syn-diols via an intramolecular hetero-Michael addition followed by reductive deprotection of the resulting benzylidene acetal allowed for swift access to the δ-lactone. Central to the synthetic approach is a tandem nucleophilic addition-diastereoselective axial reduction of an in situ generated oxocarbenium cation to assemble the β-C-glycoside moiety of the neopeltolide core.

Full text of DOI:10.1021/jo100443h

pubs.acs.org/joc
Formal Synthesis of (-)-Neopeltolide Featuring a Highly Stereoselective
Oxocarbenium Formation/Reduction Sequence
Dionicio Martinez-Solorio and Michael P. Jennings*
Department of Chemistry, 250 Hackberry Lane, The University of Alabama, Tuscaloosa,
Alabama 35487-0336
jenningm@bama.ua.edu
Received March 12, 2010
The formal synthesis of the unnatural (-)-neopeltolide core is discussed in detail. Efficient
application of the Evans’ protocol for the synthesis of 1,3-syn-diols via an intramolecular hetero-
Michael addition followed by reductive deprotection of the resulting benzylidene acetal allowed for
swift access to the δ-lactone. Central to the synthetic approach is a tandem nucleophilic addition-
diastereoselective axial reduction of an in situ generated oxocarbenium cation to assemble the
β-C-glycoside moiety of the neopeltolide core.
Introduction
Marine-derived secondary metabolites have rendered a
myriad of molecular architectures that have proven an
invaluable source of therapeutically promising leads. One
such compound is (þ)-neopeltolide, which was first isolated
from deep-water sponges most closely related to the genus
Daedalopelta Sollas and subsequently disclosed in 2007 by
Wright as shown in Figure 1.1 Neopeltolide is an extremely
potent inhibitor of in vitro proliferation of A-549 human
lung adenocarcinoma, NCI/ADR-RES ovarian sarcoma,
and P388 murine leukemia cell lines with IC50 values in the
nanomolar range (1.2, 5.1, and 0.56 nM, respectively). This
polyketide natural product also demonstrates inhibitory
effects in PANC-1 pancreatic and DLD-1 colorectal cell
lines as well as potent inhibition (MIC = 0.625 μg/mL) of
FIGURE 1. Structure of (þ)-neopeltolide.
the fungal pathogen Candida albicans, which can greatly
threaten the health of advanced AIDS patients.2
Due to its unique structure, exceptional potency, and line-
selective anticancer activity, (þ)-neopeltolide has been the
subject of numerous synthetic studies.3-6 Panek was the first
to disclose the total synthesis of (þ)-neopeltolide exploiting
(1) Wright, A. E.; Botelho, J. C.; Guzman, E.; Harmody, D.; Linley, P.;
McCarthy, P. J.; Pitts, T. P.; Pomponi, S. A.; Reed, J. K. J. Nat. Prod. 2007,
70, 412.
(2) Wright, A. E.; Pomponi, S. A.; McCarthy, P. J. U.S. Patent
7179828B2, 2007; European Patent 1644380, 2007.
(3) (a) Youngsaye, W.; Lowe, J. T.; Pohlki, F.; Ralifo, P.; Panek, J. S.
Angew. Chem., Int. Ed. 2007, 46, 9211. (b) Custar, D. W.; Zabawa, T. P.;
Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 804. (c) Fuwa, H.; Naito, S.;
Goto, T.; Sasaki, M. Angew. Chem., Int. Ed. 2008, 47, 4737. (d) Paterson, I.;
Miller, N. A. Chem. Commun. 2008, 4708. (e) Woo, S. K.; Kwon, M. S.; Lee,
E. Angew. Chem., Int. Ed. 2008, 47, 3242. (f) Guinchard, X.; Roulland, E.
Org. Lett. 2009, 4700. (g) Fuwa, H.; Saito, A.; Sasaki, M. Angew. Chem., Int.
Ed. 2010, 49, 3041. For a review, see: (h) Gallon, J.; Reymond, S.; Cossy, J.
Chemie 2008, 11, 1463.
(4) (a) Vintonyak, V. V.; Maier, M. A. Org. Lett. 2008, 10, 1239. (b)
Kartika, R.; Gruffi, T. R.; Taylor, R. E. Org. Lett. 2008, 10, 5047. (c) Kim,
H.; Park, Y.; Hong, J. Angew. Chem., Int. Ed. 2009, 48, 7577. (d) Tu, W.;
Floreancig, P. E. Angew. Chem., Int. Ed. 2009, 48, 4567. (e) Yadav, J. S.;
Krishana, G. G.; Kumar, S. N. Tetrahedron. 2010, 66, 480.
(5) (a) Fuwa, H.; Saito, A.; Naito, S.; Konoki, K.; Yotsu-Yamashita, M.;
Sasaki, M. Chem.;Eur. J. 2009, 15, 12807. (b) Custar, D. W.; Zabawa, T. P.;
Hines, J.; Crews, C. M.; Scheidt, K. A. J. Am. Chem. Soc. 2009, 131, 12406.
(c) Vintonyak, V. V.; Kunze, B.; Sasse, F.; Maier, M. A. Chem.;Eur. J.
2008, 14, 11132.
(6) Ulanovskaya, O. A.; Janjic, J.; Suzuki, M.; Sabharwal, S. S.;
Schumacker, P. T.; Kron, S. J.; Kozmin, S. A. Nat. Chem. Biol. 2008, 4, 418.
DOI: 10.1021/jo100443h
r
Published on Web 05/26/2010
J. Org. Chem. 2010, 75, 4095–4104 4095
2010 American Chemical Society

Martinez-Solorio and Jennings
JOCArticle
SCHEME 1. Retrosynthetic Analysis of (-)-Neopeltolide (1)
an elegant [4 þ 2]-allylsilane annulation as the key step and
led to stereochemical revisions of the originally proposed
structure.3a A subsequent report by Scheidt confirmed the
stereochemical reassignments and utilized an innovative
Lewis acid catalyzed cyclization to generate the cis-tetrahy-
dropyran ring and the macrocycle concomitantly.3b Most
recently, Fuwa reported a very efficient synthesis (12 steps in
14% yield to the macrocycle) of (þ)-neopeltolide featuring a
chemo- and diastereoselective cross-metathesis reaction fol-
lowed by an oxy-Michael addition to forge the β-C-glycoside
subunit.3g In addition to their total synthesis, the Scheidt
group has also helped shed light on the structure-activity
relationships of (þ)-neopeltolide.5b Their studies determined
that both the ester side chain and the macrolide core bound
together are needed for biological activity, since neither are
active independently. Furthermore, the group found that
stereochemistry on the macrolide is crucial for potency as the
originally proposed structure for (þ)-neopeltolide is 84- to
100-fold less potent than the natural product. Maier’s SAR
studies have found that shortening the distance between the
lactone and the oxazole side chain greatly reduces the
biological activity.5c Further SAR studies of this promising
compound should give clues as to the mode of action and
what key pharmacophore(s) are crucial for its impressive
biological activity.
successfully demonstrated in a variety of previous synthetic
ventures, the efficient formation of these building blocks
capitalizing on a stereoselective oxocarbenium cation for-
mation/reduction protocol starting from δ-lactones.7 We
were hopeful that this synthetic approach would deliver the
targeted β-C-glycoside, which in principle, could be trans-
formed to the neopeltolide core. To the best of our knowl-
edge, no biological testing of unnatural (-)-neopeltolide (1)
has been performed, and based on our previous experience
with (-)-dactylolide,8 we thought it might be prudent to
synthesize the antipode of the natural product core in order
to potentially advance SAR studies of this promising com-
pound. Along this line, recall that the unnatural (-)-dactylo-
lide is roughly 2- to 3-fold more active against the SK-OV-3
line than that of (þ)-dactylolide. Also, (-)-dactylolide exhi-
bited GI50 values in the nanomolar (25-99 ng/mL) range
against the four cell lines HL-60, K-562, HCC-2998, and SF-
539 while displaying modest LC50 values. Our previous results
with (-)-dactylolide illustrate the need for synthetic natural
product molecules (or in this case the antipode) for the under-
taking of more comprehensive in vitro biological screening.
The following work describes the formal synthesis of 1.
(7) (a) Jennings, M. P.; Clemens, R. T. Tetrahedron Lett. 2005, 46, 2021.
(b) Ding, F.; Jennings, M. P. Org. Lett. 2005, 7, 2321. (c) Clemens, R. T.;
Jennings, M. P. Chem. Commun. 2006, 2720. (d) Sawant, K. B.; Jennings,
M. P. J. Org. Chem. 2006, 71, 7911. (e) Sawant, K. B.; Ding, F.; Jennings,
M. P. Tetrahedron Lett. 2006, 47, 939. (f) Sawant, K. B.; Ding, F.; Jennings,
M. P. Tetrahedron Lett. 2007, 48, 5177. (g) Carrick, J. D.; Jennings, M. P.
Org. Lett. 2009, 11, 769.
Results and Discussion
Not withstanding its impressive biological profile, our
attraction to neopeltolide stemmed from the β-C-glycoside
moiety embedded within the macrolactone core. We have
(8) Ding, F.; Jennings, M. P. J. Org. Chem. 2008, 73, 5965.
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SCHEME 2. Synthesis of the Reformatsky Precursor Ketone 14
SCHEME 4. Synthesis of Aldehyde 23 via Partial DIBAL
Reduction of Amide 7
SCHEME 3. SmI2-Mediated Molander-Reformatsky
Reaction of 14
with an asymmetric allylation-oxidation of 10 utilizing
Brown’s (-)-Ipc2Ballyl reagent to provide the homoallylic
alcohol 11 in 70% yield and 91% ee.10 The ensuing benzyl
protection under basic conditions (NaH, BnBr, and TBAI)
of 11 followed by ozonolysis of the corresponding alkene
moiety delivered the previously reported aldehyde 9 with a
70% yield over two steps from 11.3e As first reported by
Keck,11 chelation-controlled TiCl-mediated allylation of 9
was carried out at -78 °C, and a 20:1 dr resulted in favor of
the desired benzyl protected 1,3-anti-diol 12 in 90% yield.
Subsequent treatment of 12 with bromoacetyl bromide and
pyridine provided the corresponding ester 13 in 86% yield in
anticipation of the intramolecular Molander-Reformatsky
reaction. Much to our delight, an ensuing Wacker oxidation
of 13 under the standard aerobic O2-PdII-CuII catalysis
protocol in DMF/H2O (7:1) afforded the desired ketone 14
in 70% yield and set the stage for the intramolecular SmI2-
mediated cyclization.
Retrosynthetic Analysis of (-)-Neopeltolide (1). Our retro-
synthetic analysis of 1 followed Panek’s initial disconnection
of the oxazole-containing side chain in that it could be
introduced via a two-step procedure involving a Still-
Gennari olefination as delineated in Scheme 1.3a As our
key step, we envisaged the β-C-glycoside (3) would emerge
from a stereoselective reduction of an endocyclic oxocarbe-
nium cation mediated by the treatment of an appropriate
hemiketal with a Lewis acid. This hemiketal could be derived
from a nucleophilic addition of the allyl Grignard reagent to
the appropriate δ-lactone (4). Working backward, lactone 4
would be derived from acetal 5 and access to 5 was envi-
sioned to arise from the precursor homoallylic alcohol 6 and
methyl acrylate via a cross-metathesis. Alcohol 6 would
evolve from an asymmetric allylation of the corresponding
aldehyde, which would be provided by means of the Weinreb
amide 7. Along this line, amide 7 would potentially be
furnished via ring-opening of lactone 8 which could be
synthesized via a variety of synthetic strategies by way of
the benzyl-protected β-hydroxy aldehyde 9.
As first described by Molander,12 treatment of bromo
ester 14 with SmI2 in THF at -78 °C formed a Sm(III)
enolate which subsequently underwent an intramolecular
aldol reaction with the pendant ketone via the highly ordered
double six-membered transition state, depicted as 15 in
Scheme 3, to provide the β-hydroxy lactone 16 in 95% yield
Initially, our synthetic strategy enlisted a Wacker oxida-
tion/intramolecular Molander-Reformatsky sequence en
route to the construction of the required hydroxy lactone
8, as shown in Scheme 2.9 Thus, the synthesis commenced
(10) (a) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401. (b)
Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem. 1986,
51, 432.
(11) Keck, G. E.; Castellino, S.; Wiley, M. R. J. Org. Chem. 1986, 51,
5478.
(9) (a) Yokokawa, F.; Asano, T.; Shioiri, T. Tetrahedron 2001, 57, 6311.
(b) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217.
(12) Molander, G. A.; Etter, J. B.; Harring, L. S.; Thorel, P. J. J. Am.
Chem. Soc. 1991, 113, 8036.
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SCHEME 5. Stereocontrolled Synthesis of β-C-Glycoside 3 via Oxocarbenium Reduction
and excellent diastereoselectivity at the newly generated
stereocenter (>20:1 by 1H NMR). In order to arrive at the
desired R,β-unsaturated lactone 17, an elimination of the
newly generated stereocenter was then performed. Thus,
treatment of 16 with thionyl chloride and pyridine furnished
17 in a 52% yield. Although this synthetic sequence was
viable, our necessity for gram quantities of 17 forced us to
pursue an alternative and more efficient strategy.
With our reformulated synthetic blueprint as described in
Scheme 4, previously synthesized aldehyde 9 was subjected
to TiCl4-mediated methallylation and provided the homo-
allylic alcohol 18 (10:1 dr by 1H NMR) in 90% yield.3e
Ensuing treatment of 18 with acryloyl chloride and Hunig’s
base furnished acrylate ester 19 which was sequentially
treated with Grubbs’ second-generation catalyst13 20 to
afford the requisite R,β-unsaturated lactenone 17 in 94%
yield via a ring-closing metathesis reaction. As skillfully
described by Roulland on a very similar substrate, diastereo-
selective reduction of the resulting alkene in 17 with con-
comitant removal of the benzyl protecting group was accom-
plished by means of a Pd/C-catalyzed hydrogenation
and delivered lactone 8 in quantitative yield as a single
diastereomer.3f
The secondary hydroxyl moiety of 8 was reprotected as a
TBDPS ether with imidazole and a catalytic amount of DMAP
to afford 21 in 97% yield. Subsequently, lactone 21 was
subjected to transamidation conditions (MeO(NH)Me HCl
3
and Me3Al)14 and provided the unstable Weinreb amide 22,
which tended to relactonize back to 21 during purification.
Therefore, the resulting free hydroxyl group of amide 22 was
immediately treated with Meerwein’s salt (Me3Oþ BF4-), 1,8-
˚
bis(dimethylamino)naphthalene (proton sponge), and 4 A
molecular sieves to provide methoxy ether 7 in 55% yield over
three steps from 8.3f An ensuing partial DIBAL reduction of 7
furnished aldehyde 23 in 92% yield and set the stage for chain
elongation en route to macrocycle 2.
(13) (a) For a very recent review, see: Vougioukalakis, G. C.; Grubbs,
R. H. Chem. Rev. 2010, 110, 1746. (b) Scholl, M.; Ding, S.; Lee, C. W.;
Grubbs, R. H. Org. Lett. 1999, 1, 953.
(14) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
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SCHEME 6. Formal Synthesis of (-)-Neopeltolide
As shown in Scheme 5, a mismatched Brown allylation of
23 afforded the homoallylic alcohol 6 with a 6:1 dr at the
newly generated stereocenter in 84% yield. An ensuing
highly diastereoselective cross-metathesis of the resulting
alkene moiety resident in 6 with methyl acrylate and 20 as
described by O’Doherty provided the E-R,β-unsaturated
ester 24 in 90% yield.15 Following the Evans’ protocol for
the diastereoselective synthesis of 1,3-syn-diols, ester 24 was
treated with benzaldehyde and catalytic amounts of K-t-
OBu in THF at 0 °C and provided 5 in 80% yield with an
excellent level of diastereoselectivity (>20:1) for the syn-
benzylidine acetal.16 We surmised that upon reductive de-
protection of the benzylidene acetal moiety resident in 5,
coupled with acidic reaction conditions, the ensuing sub-
strate should readily cyclize to the desired β-hydroxy lactone
4. Upon dissolution of 5 in HOAc and in the presence of
Pearlman’s catalyst [Pd(OH)2] under an atmosphere of H2,
deprotection occurred, but cyclization of the resultant diol to
lactone 4 was slow. Once the crude material was filtered to
remove the catalyst and the filtrate refluxed (70 °C) in HOAc
and H2O (4:1), lactone 4 was isolated in 70% yield from
acetal 5. Ensuing MOM protection of the free hydroxyl
group of 4 using Hunig’s base in CH2Cl2 furnished the highly
desired δ-lactone 25 in nearly quantitative yield. Hence, the
stage was set for the oxocarbenium formation-reduction
sequence as shown in Scheme 5. Upon treatment of 25 with
excess allylmagnesium bromide at -78 °C, the resultant
lactol 26 was formed as determined by the consumption of
25 by TLC analysis, and with the subsequent addition of
TFA, 26 presumably was transformed to the corresponding
oxocarbenium cation (27 and 28) which was consequently
reduced stereoselectively (via reactive conformer 28) with
Et3SiH to deliver the β-C-glycoside subunit 3 in 72% yield
and excellent dr (>20:1).
Consistent with our previous observations and based on
Woerpel’s models, the observed product was assumed to
arise from the more reactive conformer (i.e., 28) that places
the alkyl side chain at C5 in the pseudoequatorial position
and the MOM-protected hydroxyl moiety at C3 in the axial
position.7,17 This reactive conformer allows for the stereo-
selective axial approach of the nucleophilic hydride via a
chairlike transition state. With 3 in hand, attention was
directed to the completion of the formal synthesis of 1 via
stepwise transformations analogous to those previously
reported.3,4
As shown in Scheme 6, ozonolysis of the terminal alkene of
3 followed by reductive workup with PPh3 resulted in the
production of aldehyde 29 in 83% yield. The corresponding
aldehyde moiety of 29 was immediately subjected to a
Lindgren-Kraus-Pinnick oxidation followed by TBAF-
mediated cleavage of the TBDPS ether to furnish the Yama-
guchi precursor hydroxy acid 30.18 The seco-acid 30 was then
subjected to the previously reported conditions to provide
(17) (a) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem.
Soc. 2000, 122, 168. (b) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco,
S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521.
(18) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888. (b)
Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175. (c) Kraus, G. A.;
Roth, B. J. Org. Chem. 1980, 45, 4825. (d) Pinnick, H. W.; Childers, W. E.;
Bal, B. S. Tetrahedron 1981, 37, 2091.
(15) O’Doherty, G. A.; Hunter, T. J. Org. Lett. 2001, 3, 1049.
(16) (a) Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446.
(b) Rotulo-Sims, D.; Prunet, J. Org. Lett. 2007, 9, 4147.
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the MOM-protected macrolide ester 31 in 83% yield.19 Final
deprotection of the MOM acetal of 31 was accomplished
using Maier’s conditions (concd HCl in MeOH) to afford 2
in 90% yield, thus constituting a formal synthesis of 1.3a,4a
concentrated in vacuo. Flash chromatography (silica, 1% ethyl
acetate in hexanes) afforded the benzyl ether as yellowish oil (2.15 g,
92% yield): Rf at 1% ethyl acetate in hexanes 0.35.
A stream of ozone was bubbled through a solution of the
benzyl ether (2.15 g, 10.5 mmol, 1.00 equiv) dissolved in a 4:1
mixture of CH2Cl2/MeOH (100 mL) at -78 °C until complete
consumption of starting material was observed by TLC analysis
(30 min). To the reaction mixture was added PPh3 (8.30 g, 31.6
mmol, 3.00 equiv) at -78 °C, and the resulting mixture was
stirred initially for 30 min and then for an additional 2.5 h at rt.
The solution was concentrated in vacuo, and flash chromato-
graphy (silica, 5% ethyl acetate in hexanes) afforded aldehyde 9
as a yellow oil (1.74 g, 80% yield):3e Rf at 5% ethyl acetate in
Conclusion
In closing, a formal synthesis of (-)-neopeltolide (2) has
been achieved in 19 linear steps from the previously reported
aldehyde 9 in a total overall yield of 5.6%. Efficient applica-
tion of the Evans’ protocol for the synthesis of 1,3-syn diols
via an intramolecular hetero-Michael addition followed by
reductive deprotection of the resulting benzylidene acetal
allowed for swift access to the δ-lactone 4. Central to the
synthetic approach was a tandem nucleophilic addition-
diastereoselective axial reduction of an in situ generated
oxocarbenium cation to assemble the β-C-glycoside moiety
of the neopeltolide core.
1
hexanes 0.3; H NMR (360 MHz, CDCl3) δ 9.81 (t, 1H, J =
2.1 Hz), 7.32 (m, 5H), 4.56 and 4.52 (ABq, 2H, J = 11.3 Hz),
3.95 (m, 1H), 2.68 (dd, 1H, J = 7.1, 7.3 Hz), 2.56 (dd, 1H, J =
4.7, 5.1 Hz), 1.68 (m, 1H), 1.54 (m, 1H), 1.41 (m, 2H), 0.93 (t, 3H,
J = 7.3 Hz).
6(R)-(Benzyloxy)non-1-en-4(R)-ol (12). To a stirred solution
of aldehyde 9 (700 mg, 3.39 mmol, 1.00 equiv) in CH2Cl2 (17.0mL)
at -78 °C under Ar was slowly added TiCl4 (1.00 M solution in
CH2Cl2, 3.39 mmol, 1.00 equiv). The resulting yellow solution was
allowed to stir for 10 min. To this mixture was added allyltriphe-
nylstannane (2.66 g, 6.79 mmol, 2.00 equiv) dissolved in CH2Cl2
(4.00 mL) dropwise over a 15 min period. After 4 h, the reaction
was quenched at -78 °C by a dropwise addition of a saturated
solution of NaHCO3 (20.0 mL) and allowed to reach rt. The
mixture was then diluted with CH3CN (50.0 mL) and stirred with
the addition of KF (1.23 g, 20.9 mmol, 6.15 equiv) for 12 h. The
suspension was then filtered through a pad of Celite, and the
aqueous layer was extracted with EtOAc (3 ꢀ75.0 mL). The
combined organic extracts were dried over Na2SO4, filtered, and
concentrated in vacuo. Flash chromatography (silica, 5% ethyl
acetate in hexanes) afforded the homoallylic alcohol 12 as a clear
viscous oil (750 mg, 90% yield):20 Rf at 10% ethyl acetate in
hexanes 0.25; 1H NMR (500 MHz, CDCl3) δ 7.30 (m, 5H), 5.83
(m, 1H), 5.12 (m, 1H), 5.08 (t, 1H, J = 1.2 Hz), 4.57 and 4.53
(ABq, 2H, J = 11.2 Hz), 3.97 (m, 1H), 3.72 (m, 1H), 2.77 (d, 1H,
J = 3.4 Hz), 2.22 (m, 2H), 1.67 (m, 3H), 1.51 (m, 1H), 1.36 (m,
2H), 0.93 (t, 3H, J = 7.3 Hz).
Experimental Section
All of the reactions were performed under an inert atmo-
sphere of Ar in flame-dried glassware. Anhydrous tetrahydro-
furan (THF) and dimethoxyethane (DME) were obtained from
commercial sources and used without purification. Deuterated
˚
chloroform (CDCl3) was stored over molecular sieves (4 A). All
of the NMR spectra were recorded on either a 360 or 500 MHz
spectrometer. 1H NMR spectra were obtained using CDCl3 as
the solvent with either tetramethylsilane (TMS: 0 ppm) or
chloroform (CHCl3: 7.26 ppm) as the internal standard. Col-
umn chromatography was performed using 60-200 μm silica
gel. Analytical thin-layer chromatography was performed on
silica coated glass plates with F-254 indicator. Visualization was
accomplished by UV light (254 nm), KMnO4, or ceric sulfate-
PMA stain.
(R)-Hept-1-en-4-ol (11). To a stirred solution of (-)-Ipc2BOMe
(8.20 g, 25.9 mmol, 1.40 equiv) in Et2O (75.0 mL) at -78 °C under
Ar was added allylmagnesium bromide (1.0 M in Et2O, 24.1 mL,
1.30 equiv). The reaction mixture was allowed to reach rt
and stirred for 1 h, after which time the mixture was recooled to
-78 °C. Butanal (1.67 mL, 18.5 mmol) was then added dropwise
to the reaction mixture, which was allowed to stir for 2 h. The
reaction was warmed to 0 °C. To this mixture were added 3 M
NaOH (5.40 mL) and 30% aq H2O2 (9.40 mL) sequentially. The
reaction mixture was allowed to stir at rt for 6 h, after time which
the aqueous layer was extracted with Et2O (3 ꢀ 75.0 mL). The
organic extracts were dried over MgSO4, filtered, and concen-
trated in vacuo. The crude material was distilled to give homo-
allylic alcohol 11 as a clear oil (1.48 g, 70% yield):12 Rf at 10%
ethyl acetate in hexanes 0.3; 1H NMR (360 MHz, CDCl3), δ 5.80
(m, 1H), 5.11 (m, 1H), 5.07 (m, 1H), 3.62 (m, 1H), 2.25 (m, 1H),
1.87 (s, 1H), 1.39 (m, 4H), 0.90 (t, 3H, J = 7.1 Hz).
3(R)-(Benzyloxy)hexanal (9). NaH (60% dispersion in mineral
oil, 820 mg, 34.2 mmol, 3.00 equiv) was suspended in a 1:1 mixture
of DMF/THF (40.0 mL) and cooled to 0 °C under argon. To this
mixture was added dropwise alcohol 11 (1.30 g, 11.4 mmol, 1.0
equiv) dissolved in THF (9.00 mL) and the resulting mixture
stirred for 30 min. Benzyl bromide was then added (2.05 mL,
17.1 mmol, 1.5 equiv) followed by tetrabutylammonium iodide
(421 mg, 1.14 mmol, 0.100 equiv). The reaction mixture was
allowed to reach rt and stirred for 16 h. An aqueous solution of
NH4Cl (50.0 mL) was added to the reaction mixture at 0 °C.
The aqueous layer was extracted with EtOAc (3 ꢀ 50.0 mL),
and the organic extracts were dried over Na2SO4, filtered, and
Bromoacetic Acid 1(R)-[2(R)-(benzyloxy)pentyl]but-3-enyl
Ester (13). To a solution of alcohol 12 (750 mg, 3.02 mmol,
1.00 equiv) in CH2Cl2 (12.0 mL) at 0 °C under Ar were slowly
added pyridine (0.200 mL, 2.42 mmol, 2.00 equiv) and bromo-
acetyl bromide (0.210 mL, 2.42 mmol, 2.00 equiv). After 6 h, the
reaction was quenched with a saturated aqueous solution of
NH4Cl (20 mL), and the aqueous layer was extracted with
CH2Cl2 (3 ꢀ 30.0 mL). The combined organic extracts were
dried over Na2SO4, filtered, and concentrated in vacuo. Flash
chromatography (silica, 1% ethyl ether in hexanes) afforded
bromoacetyl bromide 13 as a yellow oil (940 mg, 86% yield): Rf
at 5% ethyl acetate in hexanes 0.15; 1H NMR (500 MHz,
CDCl3) δ 7.35 (m, 4H), 7.28 (m, 1H), 5.75 (m, 1H), 5.26 (m,
1H), 5.10 (d, 1H, J = 5.1 Hz), 5.07 (s, 1H), 4.53 and 4.40 (ABq,
2H, J = 11.1 Hz), 3.72 (s, 2H), 3.47 (m, 1H), 2.37 (m, 2H), 1.75
(m, 2H), 1.56 (m, 2H), 1.38 (m, 2H), 0.94 (t, 3H, J = 7.3 Hz); 13
C
NMR (125 MHz, CDCl3) δ 166.7, 138.5, 132.9, 128.3, 128.1,
127.6, 118.2, 74.9, 72.6, 71.2, 39.1, 38.6, 35.9, 26.1, 18.1, 14.2; IR
(CH2Cl2) 696, 734, 920, 993, 1106, 1278, 1357, 1456, 1734, 2874,
2928, 2958, 3030, 3065 cm-1; [R]20D = þ131 (c 0.43, CH2Cl2);
HRMS (EI) calcd for C18H25 Br O3 (Mþ) 368.0987, found
368.0983.
Bromoacetic Acid 3-(Benzyloxy)-1-(2-oxopropyl)hexyl Ester (14).
A suspension of bromoacetyl bromide 13 (73.0 mg, 0.198 mmol,
1.00 equiv), PdCl2 (3.50 mg, 0.020 mmol, 0.100 equiv), and Cu-
(OAc)2 (7.30 mg, 0.0400 mmol, 0.200 equiv) in DMF/H2O (7:1, 2.00
(19) Yamaguchi, M.; Katsuki, T.; Saeki, H.; Hirata, K.; Inanaga, J. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(20) Krishna, P. R.; Dayaker, G. Tetrahedron Lett. 2007, 48, 7279.
4100 J. Org. Chem. Vol. 75, No. 12, 2010

Martinez-Solorio and Jennings
JOCArticle
mL) was placed under O2 balloon pressure and stirred at rt for 48 h.
The reaction was then diluted with Et2O (10.0 mL) and water (10.0
mL). The aqueous layer was extracted with Et2O(3ꢀ 10.0 mL), and
the combined organic extracts were dried over MgSO4, filtered, and
concentrated in vacuo. Flash chromatography (silica, 10% ethyl
acetate in hexanes) afforded ketone 14 as a yellow viscous oil
mixture was stirred for 8 h at -78 °C, at which time the reaction
was carefully quenched with a saturated NaHCO3 solution (50.0
mL) and then allowed to reach rt. The aqueous layer was extracted
with CH2Cl2 (3 ꢀ 50.0 mL), and the organic extracts were dried
over MgSO4, filtered, and concentrated in vacuo. Flash chroma-
tography (silica, 3% ethyl acetate in hexanes) afforded homo-
methallylic alcohol 18 as a clear viscous oil (4.35 g, 90% yield): Rf
at 10% ethyl acetate in hexanes 0.35; 1H NMR (500 MHz, CDCl3)
δ 7.31 (m, 5H), 4.82 (s, 1H), 4.76 (s, 1H), 4.57 and 4.52 (ABq, 2H,
J = 11.3 Hz), 4.06 (m, 1H), 3.74 (m, 1H), 2.69 (s, 1H), 2.17 (m,
2H), 1.75 (s, 3H), 1.65 (m, 3H), 1.51 (m, 1H), 1.38 (m, 2H), 0.94 (t,
3H, J = 7.3 Hz); 13C NMR (125 MHz, CDCl3) δ 142.8, 138.5,
128.3, 127.8, 127.6, 112.9, 76.8, 71.3, 65.9, 46.3, 40.1, 35.9, 22.4,
18.6, 14.2; IR (CH2Cl2) 700, 736, 891, 1071, 1201, 1376, 1454,
1650, 2869, 2931, 3034, 3070, 3458 cm-1; [R]20D=-88.7 (c 0.14,
CH2Cl2); HRMS (EI) calcd for C17H26O2 (Mþ) 262.1933, found
262.1937.
1
(51.0 mg, 70% yield): Rf at 10% ethyl acetate in hexanes 0.2; H
NMR (500 MHz, CDCl3), δ 7.33 (m, 4H), 7.27 (m, 1H), 5.49 (m,
1H), 4.55 and 4.39 (ABq, 2H, J = 11.3 Hz), 3.90 (m, 2H), 3.48 (m,
1H), 2.74 (m, 2H), 2.12 (s, 3H), 1.80 (m, 2H), 1.56 (m, 2H), 1.36 (m,
2H), 0.93 (t, 3H, J = 7.3 Hz); 13C NMR (125 MHz, CDCl3), δ
205.1, 166.7, 138.4, 128.4, 127.6, 74.9, 70.8, 70.2, 48.2, 40.9, 38.8,
35.7, 30.3, 18.1, 14.2; IR (CH2Cl2) 453, 696, 742, 977, 1073, 1183,
1293, 1357, 1411, 1453, 1723, 1742, 2870, 2958; [R]20D = -77.2 (c
0.3, CH2Cl2); HRMS (EI) calcd for C18H25 Br O4 (M - Hþ)
384.0936, found 384.0922.
6-[2-(Benzyloxy)pentyl]-4-hydroxy-4-methyltetrahydropyran-
2-one (16). To a stirred solution of ketone 14 (720 mg, 1.87
mmol, 1.00 equiv) in deoxygenated THF (18.7 mL) at -78 °C
under Ar was added a SmI2 solution (0.100 M solution in THF,
9.34 mmol, 93.5 mL, 5.00 equiv) dropwise. The dark blue
mixture was allowed to stir at -78 °C for 6 h, at which time
the reaction was quenched with a saturated aqueous solution of
NH4Cl (150 mL) at 0 °C. The aqueous layer was extracted with
EtOAc (3 ꢀ 75.0 mL). The combined organic extracts were dried
over Na2SO4, filtered, and concentrated in vacuo. Flash chro-
matography (silica, 30% ethyl acetate in hexanes) afforded
β-hydroxy lactone 16 as a white crystalline solid (530 mg, 95%
Acrylic Acid 1(R)-[2(R)-(Benzyloxy)pentyl]-3-methylbut-3-enyl
Ester (19). To a stirred solution of homomethallylic alcohol 18
(8.74 g, 33.3 mmol, 1.00 equiv) in CH2Cl2 (166 mL) were added
DMAP (814 mg, 6.66 mmol, 0.200 equiv), DIPEA (29.0 mL,
166 mmol, 5.00 equiv), and acryloyl chloride (8.01 mL, 99.9 mmol,
3.00 equiv) at 0 °C under Ar. The reaction mixture was stirred for
18 h at rt, at which time the reaction temperature was lowered to
0 °C and carefully quenched with a saturated NaHCO3 solution
(200 mL) and then allowed to reach rt. The aqueous layer was
extracted with Et2O (3 ꢀ 150 mL), and the organic extracts were
dried over Na2SO4, filtered, and concentrated in vacuo. Flash
chromatography (silica, 1% ethyl acetate in hexanes) afforded
acrylate ester 19 as a clear viscous oil (9.77 g, 93% yield): Rf at 1%
ethyl acetate in hexanes 0.3; 1H NMR (500 MHz, CDCl3) δ 7.33
(m, 4H), 7.25 (m, 1H), 6.36 (dd, 1H, J = 1.3, 17.4 Hz), 6.08 (dd,
1H, J = 10.4, 17.3 Hz), 5.77 (dd, 1H, J = 1.7, 10.4 Hz), 5.41 (m,
1H), 4.81 (s, 1H), 4.72 (s, 1H), 4.49 and 4.41 (ABq, 2H, J = 11.1
Hz), 3.44 (m, 1H), 2.36 (m, 1H), 2.24 (m, 1H), 1.75 (m, 5H), 1.53
(m, 2H), 1.37 (m, 2H), 0.92 (t, 3H, J = 7.3 Hz); 13C NMR (125
MHz, CDCl3) δ 165.6, 141.5, 138.6, 130.2, 128.8, 128.2, 127.9,
127.7, 127.4, 112.5, 75.5, 71.5, 69.8, 43.6, 39.2, 36.3, 22.4,
18.2, 14.2; IR (CH2Cl2) 700, 741, 813, 901, 988, 1066, 1190,
1268, 1299, 1407, 1459, 1634, 1727, 2874, 2925, 2967, 3034, 3076
1
yield): Rf at 50% ethyl acetate in hexanes 0.4; H NMR (500
MHz, CDCl3), δ 7.33 (m, 4H), 7.27 (m, 1H), 4.86 (m, 1H), 4.62
and 4.49 (ABq, 2H, J = 11.3 Hz), 3.82 (m, 1H), 2.61 (d, 1H, J =
17.4 Hz), 2.42 (d, 1H, J = 17.4 Hz), 1.86 (dt, 1H, J = 2.8, 14.1
Hz), 1.76 (m, 1H), 1.68 (m, 2H), 1.58 (m, 2H), 1.51 (m, 1H), 1.39
(m, 2H), 1.33 (s, 3H), 0.94 (t, 3H, J = 7.3 Hz); 13C NMR (125
MHz, CDCl3), δ 170.5, 138.7, 128.4, 127.9, 127.6, 75.1, 73.9,
71.9, 68.3, 44.1, 42.5, 41.3, 36.7, 30.3, 18.2, 14.3; IR (CH2Cl2)
457, 703, 738, 1057, 1122, 1267, 1376, 1453, 1723, 2870, 2928,
2962, 3053, 3410 cm-1; [R]20 = -155.1 (c 0.13, CH2Cl2);
D
HRMS (EI) calcd for C18H26O4 (M þ Hþ) 306.1831, found
306.1838.
6-[2-(Benzyloxy)pentyl]-4-methyl-5,6-dihydropyran-2-one (17).
To a stirred solution of β-hydroxy lactone 16 (65.0 mg, 0.213
mmol, 1.00 equiv) in CH2Cl2 (2.20 mL) under Ar at 0 °C were
added pyridine (0.350 mL, 4.24 mmol, 20.0 equiv) and SOCl2
(0.003 mL, 0.424 mmol, 2.00 equiv) dropwise. The reaction
mixture was allowed to stir for 2 h and then quenched with a
saturated solution of aqueous NaHCO3 (10.0 mL). The aqueous
layer was extracted with EtOAc (3 ꢀ 10.0 mL). The combined
organic extracts were dried over Na2SO4, filtered, and concen-
trated in vacuo. Flash chromatography (silica, 10% ethyl acetate
in hexanes) afforded lactenone 17 as a clear oil (32.0 mg, 52%
cm-1; [R]20 = -141.3 (c 0.22, CH2Cl2); HRMS (EI) calcd for
D
C20H28O3 (Mþ) 316.2038, found 316.2029.
6-[2-(Benzyloxy)pentyl]-4-methyl-5,6-dihydropyran-2-one (17).
To a refluxing solution of acrylate ester 19 (410 mg, 1.30 mmol,
1.00 equiv) in toluene (130 mL, 80 °C) under Ar was added
a solution of Grubbs’ second-generation catalyst 20 (165 mg,
0.194 mmol, 0.150 equiv) in toluene (19.5 mL) dropwise over a
period of 2 h. The reaction mixture was allowed to stir at 80 °C for
18 h at which time the reaction was concentrated in vacuo. Flash
chromatography (silica, 10% ethyl acetate in hexanes) afforded
lactenone 17 as a clear viscous oil (352 mg, 94% yield).
1
6-(2-Hydroxypentyl)-4-methyltetrahydropyran-2-one (8). To
a solution of lactenone 17 (90.0 mg, 0.312 mmol, 1.00 equiv)
in EtOH (1.60 mL) was added Pd/C (45.0 mg) in one portion.
The reaction vessel was evacuated under vacuum and placed
under atmospheric H2 balloon pressure. The reaction mixture
was allowed to stir at rt for 48 h until complete consumption of
the starting material was observed via TLC analysis. The
reaction was filtered through a plug of Celite and concentrated
in vacuo. Flash chromatography (silica, 40% ethyl acetate in
hexanes) afforded lactone 8 as a clear viscous oil (60.0 mg, 100%
yield): Rf at 10% ethyl acetate in hexanes 0.2; H NMR (500
MHz, CDCl3), δ 7.29 (m, 4H), 7.24 (m, 1H), 5.75 (s, 1H), 4.59 and
4.43 (ABq, 2H, J = 11.3 Hz), 4.55 (m, 1H), 3.80 (m, 1H), 2.25 (m,
1H), 2.13 (m, 1H), 1.90 (s, 3H), 1.85 (m, 1H), 1.68 (m, 1H), 1.59
(m, 1H), 1.48 (m, 1H), 1.37 (m, 2H), 0.93 (t, 3H, J = 7.3 Hz); 13C
NMR (125 MHz, CDCl3), δ 165.1, 157.2, 138.6, 128.3, 127.8,
127.6, 116.4, 74.8, 74.2, 71.8, 40.5, 36.5, 35.2, 22.8, 18.1, 14.3; IR
(CH2Cl2) 691, 739, 849, 1020, 1066, 1150, 1250, 1307, 1389, 1452,
1723, 2874, 2952, 3031, 3505 cm-1; [R]20D =-10.8 (c 0.3,
CH2Cl2); HRMS (EI) calcd for C18H24O3 (Mþ) 288.1725, found
288.1723
1
yield): Rf at 35% ethyl acetate in hexanes 0.2; H NMR (500
MHz, CDCl3) δ 4.55 (m, 1H), 3.93 (m, 1H), 2.62 (m, 1H), 2.46 (s,
1H), 2.02 (m, 2H), 1.86 (m, 1H), 1.68 (ddd, 1H, J = 2.1, 9.7, 14.5
Hz), 1.55 (ddd, 1H, J = 2.6, 14.2, 17.1 Hz), 1.36 (m, 4H), 1.19
(m, 1H), 0.98 (d, 3H, J = 7.1 Hz), 0.88 (t, 3H, J = 7.3 Hz); 13C
NMR (125 MHz, CDCl3) δ 171.6, 77.4, 66.7, 43.5, 40.1, 37.8,
37.4, 26.6, 21.6, 18.6, 13.9; IR (CH2Cl2) 572, 634, 791, 931, 984,
6(R)-(Benzyloxy)-2-methylnon-1-en-4(R)-ol (18). To a solution
of aldehyde 9 (3.81 g, 18.5 mmol, 1.00 equiv) in CH2Cl2 (50 mL) at
-78 °C under Ar was added TiCl4 (1.00 M in CH2Cl2, 20.3 mL,
1.10 equiv) dropwise. The solution was allowed to stir for 0.5 h.
The methyl-allylating reagent, CH2C(CH3)CH2TMS (16.2 mL,
92.4 mmol, 5.00 equiv), was then added dropwise. The reaction
J. Org. Chem. Vol. 75, No. 12, 2010 4101

Martinez-Solorio and Jennings
JOCArticle
1025, 1092, 1233, 1380, 1458, 1729, 2874, 2958, 3432 cm-1;[R]20
=
(CH2Cl2) 622, 710, 823, 999, 1108, 1382, 1428, 1464, 1671, 2859,
2947, 3070; [R]20D = þ15.1 (c 0.2, CH2Cl2); HRMS (EI) calcd for
C26H38NO4Si (M - C4H9) 456.2570, found 456.2574.
D
-76.4 (c 1.23, CH2Cl2); HRMS (EI) calcd for C11H20O3 (M þ H)
201.1484, found 201.1484.
6-[2-(tert-Butyldiphenylsilanyloxy)pentyl]-4-methyltetrahydro-
pyran-2-one (21). To a solution of lactone 8 (4.20 g, 21.0 mmol,
1.00 equiv) in DMF (105 mL) under Ar at 0 °C were added
imidazole (4.30 g, 62.9 mmol, 3.00 equiv), DMAP (512 mg,
4.19 mmol, 0.200 equiv), and TBDPSCl (8.00 mL, 31.5 mmol,
1.50 equiv). The reaction mixture was allowed to stir at rt for 48 h
and quenched with H2O (200 mL), and the aqueous layer was
extracted with EtOAc (3 ꢀ 150 mL). The combined organic
extracts were dried over MgSO4, filtered, and concentrated in
vacuo. Flash chromatography (silica, 5% ethyl acetate in
hexanes) afforded the TBDPS-protected lactone 21 (8.76 g,
7(R)-(tert-Butyldiphenylsilanyloxy)-5(R)-methoxy-3(R)-methyl-
decanal (23). To a solution of compound 7 (1.05 g, 2.04 mmol,
1.00 equiv) in CH2Cl2 (13.6 mL) at -78 °C was added a solution of
DIBAL-H (1.00 M in toluene, 3.20 mL, 1.55 equiv) dropwise. The
resulting solution was stirred at -78 °C for 1 h and quenched
carefully with MeOH (3 mL). The reaction was poured into
CH2Cl2 (20.0 mL) and washed with 1 M HCl (50.0 mL). The
organic layer was dried over Na2SO4, filtered, and concentrated in
vacuo. Flash chromatography (silica, 5% ethyl acetate in hexanes)
afforded aldehyde 23 as a clear viscous oil (860 mg, 92% yield): Rf
at 20% ethyl acetate in hexanes 0.65; 1H NMR (500 MHz, CDCl3)
δ 9.67 (t, 1H, J = 2.1 Hz), 7.71 (m, 4H), 7.39 (m, 6H), 3.86 (m, 1H),
3.28 (m, 1H), 3.10 (s, 3H), 2.30 (m, 1H), 2.14 (m, 2H), 1.72 (m, 1H),
1.45 (m, 3H), 1.31 (m, 3H), 1.23 (m, 1H), 1.06 (s, 9H), 0.90 (d, 3H,
J = 7.1 Hz), 0.76 (t, 3H, J = 7.3 Hz); 13C NMR (125 MHz,
CDCl3) δ 202.4, 135.9, 134.5, 129.5, 127.4, 75.5, 70.5, 55.6, 51.2,
41.8, 41.3, 39.4, 26.9, 24.9, 19.9, 19.3, 17.7, 13.9; IR (CH2Cl2) 611,
1
95% yield): Rf at 5% ethyl acetate in hexanes 0.2; H NMR
(500 MHz, CDCl3) δ 7.70, (m, 4H), 7.38 (m, 6H), 4.23 (m, 1H),
4.12 (m, 1H), 4.46 (m, 1H), 1.92 (m, 1H), 1.84 (m, 1H), 1.69 (m,
3H), 1.43 (m, 2H), 1.26 (m, 3H), 1.06 (s, 9H), 0.94 (d, 3H, J = 6.3
Hz), 0.74 (t, 3H, J = 7.2 Hz); 13C NMR (125 MHz, CDCl3) δ
171.1, 135.8, 129.5, 127.4, 69.4, 43.3, 39.8, 37.6, 37.3, 27.0, 26.4,
21.7, 19.4, 17.6, 13.9; IR (CH2Cl2) 509, 619, 713, 739, 817, 931,
1072, 1114, 1239, 1380, 1426, 1468, 1739, 2865, 2958, 3073, 3442;
[R]20D = -66.2 (c 0.7, CH2Cl2); HRMS (EI) calcd for C23H29-
O3Si (M - C4H9) 381.1886, found 381.1890.
700, 746, 819, 1113, 1422, 1454, 1733, 2709, 2859, 2941, 3070 cm-1
;
[R]20D = þ27.3 (c 1.01, CH2Cl2); HRMS (EI) calcd for C24H33-
O3Si (M - C4H9) 397.2199, found 397.2211.
10(R)-(tert-Butyldiphenylsilanyloxy)-8(R)-methoxy-6(S)-methyl-
tridec-1-en-4(R)-ol (6). To a stirred solution of (þ)-Ipc2Ballyl
(1.00 M solution in pentane, 0.320 mL, 1.20 equiv) in Et2O
(0.200 mL) at -78 °C under argon was added a solution of
aldehyde 23 (120 mg, 0.264 mmol, 1.00 equiv) in Et2O (1.30 mL)
dropwise. Thereaction mixturewas stirred for 2 h, atwhich time a
solution of 3 M NaOH (0.500 mL) and 30% aqueous H2O2 was
addedslowly at 0 °C. The mixture wasallowedtostirfor 12hat rt.
The aqueouslayerwas extractedwithEt2O (3ꢀ 10.0 mL), and the
combined extracts were dried over MgSO4, filtered, and concen-
trated in vacuo. Flash chromatography (silica, 5% ethyl acetate
in hexanes) afforded homoallylic alcohol 6 as a clear viscous oil
(110 mg, 84% yield): Rf at 5% ethyl acetate in hexanes 0.25; 1H
NMR (500 MHz, CDCl3) δ 7.69 (m, 4H), 7.39 (m, 6H), 5.82 (m,
1H), 5.14 (s, 1H), 5.12 (d, 1H, J = 3.6 Hz), 3.87 (m, 1H), 3.70 (m,
1H), 3.32 (m, 1H), 3.12 (s, 3H), 2.24 (m, 1H), 2.13 (m, 1H), 1.75
(m, 1H), 1.68 (m, 1H), 1.52 (m, 2H), 1.32 (m, 6H), 1.16 (m, 1H),
1.05 (s, 9H), 0.97 (m, 1H), 0.85 (d, 3H, J = 7.1 Hz), 0.72 (t, 3H,
J = 7.3 Hz); 13C NMR (125 MHz, CDCl3) δ 135.9, 134.9, 134.4,
129.4, 127.4, 117.9, 75.8, 70.5, 68.4, 55.8, 44.7, 42.7, 42.4, 42.0,
39.5, 26.1, 19.6, 19.4, 17.8, 14.1; IR (CH2Cl2) 619, 702, 827,
7-(tert-Butyldiphenylsilanyloxy)-5-hydroxy-3-methyldecanoic
Acid Methoxymethylamide (22). To a solution of MeO(NH)Me
3
HCl (116 mg, 1.19 mmol, 5.00 equiv) in CH2Cl2 (2.65 mL) at
-78 °C was added Me3Al (0.600 mL, 1.11 mmol, 5.10 equiv)
dropwise. The reaction mixture was allowed to warm to rt and
stirred to 2 h before the solution was recooled to 0 °C, and the
TBDPS-protected lactone 21 (95.0 mg, 0.217 mmol, 1.00 equiv)
was added dropwise as a solution in CH2Cl2 (1.45 mL). The
reaction mixture was allowed to stir for 18 h at rt before it was
carefully quenched at 0 °C with a 1 M solution of Rochelle’s salt
(10 mL). After 1 h, the mixture was extracted with ethyl acetate
(3 ꢀ 20.0 mL). The combined organic layers were dried over
Na2SO4 and concentrated in vacuo. Flash chromatography
(silica, 35% ethyl acetate in hexanes) afforded the hydroxy
Weinreb amide 22 (65.1 mg, 64% yield) along with the recovered
starting material 21 (30.4 mg): Rf at 35% ethyl acetate in hexanes
0.2; 1H NMR (500 MHz, CDCl3) δ 7.69, (m, 4H), 7.39 (m, 6H),
3.95 (m, 2H), 3.66 (s, 3H), 3.17 (s, 3H), 2.39 (m, 1H), 2.28 (m, 1H),
2.18(m,1H), 1.51(m,5H), 1.15(m, 2H), 1.06 (s, 10H), 0.91(d, 3H,
J = 6.7 Hz), 0.67 (t, 3H, J = 7.4 Hz); 13C NMR (125 MHz,
CDCl3) δ 135.9, 133.9, 133.6, 129.7, 127.5, 77.3, 76.7, 71.8, 66.0,
61.1, 45.1, 42.7, 38.5, 27.0, 26.5, 19.9, 19.2, 18.3, 13.9; IR (CH2Cl2)
615, 705, 737, 823, 906, 1008, 1110, 1386, 1427, 1466, 1650, 2859,
2935, 2957, 3434; [R]20D = þ26.1 (c 0.4, CH2Cl2).
901, 1114, 1380, 1432, 1473, 2219, 2932, 3067, 3453, 3693 cm-1
;
[R]20D = þ16.1 (c 0.062, CH2Cl2); HRMS (EI) calcd for C27H39-
O3Si (M - C4H9) 439.2668, found 439.2657.
11(R)-(tert-Butyldiphenylsilanyloxy)-5(S)-hydroxy-9(R)-meth-
oxy-7(S)-methyltetradec-2-enoic Acid Methyl Ester (24). To a
stirred solution of homoallylic alcohol 6 (100 mg, 0.201 mmol,
1.00 equiv) in benzene (1.00 mL) at rt under Ar were added
methylacrylate(0.0600mL, 0.403mmol, 3.00equiv) andGrubbs’
second-generation catalyst 20 (3.40 mg, 0.00400 mmol, 0.0200
equiv). The reaction mixture was allowed to stir at rt for 24 h at
which time the reaction was concentrated in vacuo. Flash chro-
matography (silica, 10% ethyl acetate in hexanes) afforded ester
24 as a clear viscous oil (100 mg, 90% yield): Rf at 15% ethyl
acetate in hexanes 0.2; 1H NMR (500 MHz, CDCl3) δ 7.69 (m,
4H), 7.38 (m, 6H), 6.98 (m, 1H), 5.89 (dt, 1H, J = 15.7 Hz), 3.82
(m, 2H), 3.73(s, 3H), 3.29(m, 1H), 3.11 (s, 3H), 2.32 (m, 2H), 1.86
(s, 1H), 1.71 (m, 2H), 1.31(m, 9H), 1.05 (s, 9H), 0.94 (m, 1H), 0.83
(d, 3H, J = 7.1 Hz), 0.73 (t, 3H, J = 7.3 Hz); 13C NMR (125
MHz, CDCl3) δ 166.7, 145.9, 135.9, 134.5, 129.5, 127.4, 123.2,
75.9, 70.6, 67.7, 55.9, 51.4, 44.8, 42.4, 41.8, 40.9, 40.4, 39.2, 27.1,
26.2, 20.9, 19.6, 17.8, 14.1; IR (CH2Cl2) 699, 820, 1040, 1108,
1427, 1654, 1722, 2858, 2935, 2958, 3439 cm-1; [R]20D = þ11.2
(c 0.14, CH2Cl2); HRMS (EI) calcd for C29H41O5Si (M - C4H9)
497.2723, found 497.2720.
7-(tert-Butyldiphenylsilanyloxy)-5-methoxy-3-methyldecanoicAcid
Methoxymethylamide (7). To a solution of hydroxy amide 22
(1.21 g, 2.40 mmol, 1.00 equiv) in CH2Cl2 (30.0 mL) protected
from light was added Me3OBF4 (1.25 g, 8.40 mmol, 3.50 equiv),
˚
proton sponge (2.57 g, 12.0 mmol, 5.00 equiv), and 4 A molecular
sieves (2.50 g) at rt under Ar. The reaction mixture was allowed to
stir for 8 h, at which time the reaction was transferred to a
separatory funnel, diluted with CH2Cl2 (70.0 mL), and washed
with a 1 M HCl solution (6 ꢀ 100 mL) and saturated NaHCO3
(100 mL). The combined organic layers were dried over Na2SO4,
filtered, and concentrated in vacuo. Flash chromatography
(silica, 10% ethyl acetate in hexanes) afforded methyl ether amide
7 as a yellow viscous oil (1.05 g, 88% yield): Rf at 10% ethyl
acetate in hexanes 0.25; 1H NMR (500 MHz, CDCl3) δ 7.69, (m,
4H), 7.37 (m, 6H), 3.88 (m, 1H), 3.65 (s, 3H), 3.36 (m, 1H), 3.17(s,
3H), 3.11 (s, 3H), 2.35 (m, 1H), 2.17 (m, 2H), 1.69 (m, 1H), 1.50
(m, 1H), 1.40 (m, 3H), 1.26 (m, 2H), 1.05 (s, 9H), 0.90 (d, 3H, J =
7.1 Hz), 0.71 (t, 3H, J = 7.3 Hz); 13C NMR (125 MHz, CDCl3) δ
135.9, 135.9, 134.9, 134.4, 129.4, 129.4, 127.4, 127.3, 75.5, 70.5,
61.0, 55.4, 41.9, 41.5, 39.5, 27.0, 26.6, 20.1, 19.4, 17.7, 13.9; IR
4102 J. Org. Chem. Vol. 75, No. 12, 2010

Martinez-Solorio and Jennings
JOCArticle
[6-[6-(tert-Butyldiphenylsilanyloxy)-4-methoxy-2-methylnonyl]-
2-phenyl-1,3-dioxan-4-yl]acetic Acid Methyl Ester (5). To a solu-
tion of ester 24 (100 mg, 0.180 mmol, 1.00 equiv) in THF (2.00 mL)
at 0 °C under Ar was added freshly distilled benzaldehyde
(0.0200 mL, 0.198 mmol, 1.10 equiv) followed by KO-t-Bu
(2.00 mg, 0.0180 mmol, 0.100 equiv). The addition of base and
benzaldehyde was repeated (three times for benzaldehyde and
eight times for KO-t-Bu) at 15-min intervals until consumption of
the starting material was complete as observed by TLC analysis.
The reaction was then quenched with a solution of pH 7 buffered
phosphate solution (5.00 mL). The aqueous layer was extracted
with Et2O (3 ꢀ 10.0 mL), and the combined organic extracts were
dried over Na2SO4, filtered, and concentrated in vacuo. Flash
chromatography (silica, 5% ethyl acetate in hexanes) afforded
benzylidene acetal 5 as a yellow viscous oil (95.0 mg, 80% yield):
yellow viscous oil (210 mg, 97% yield): Rf at 40% ethyl acetate
in hexanes 0.55; 1H NMR (500 MHz, CDCl3) δ 7.68 (t, 4H, J =
7.3 Hz), 7.37 (m, 6H), 4.66 (s, 3H), 4.13 (m, 1H), 3.86 (m, 1H),
3.35 (s, 3H), 3.31 (m, 1H), 3.11 (s, 3H), 2.68 (m, 2H), 1.99 (d, 1H,
J = 14.3 Hz), 1.90 (m, 1H), 1.68 (m, 3H), 1.47 (m, 1H), 1.38 (m,
2H), 1.27 (m, 4H), 1.04 (s, 9H), 0.94 (m, 2H), 0.87 (d, 3H, J = 6.3
Hz), 0.72 (t, 3H, J = 6.6 Hz); 13C NMR (125 MHz, CDCl3), δ
169.9, 135.9, 134.6, 129.4, 127.4, 95.1, 75.5, 73.8, 70.5, 68.0, 55.8,
55.6, 43.3, 41.9, 39.5, 36.4, 34.6, 27.0, 25.4, 19.4, 17.8, 13.9; IR
(CH2Cl2) 607, 700, 744, 817, 917, 1039, 1102, 1146, 1235, 1361,
1375, 1424, 1464, 1738, 2935, 2961, 3049, 3072 cm-1; [R]20
=
D
-19.1 (c 0.43, CH2Cl2); HRMS (EI) calcd for C30H43O6Si (M -
C4H9) 527.2829, found 527.2830.
[6-[6-Allyl-4-(methoxymethoxy)tetrahydropyran-2-yl]-3-methoxy-
5-methyl-1-propylhexyloxy]-tert-butyl-diphenylsilane (3). To a solu-
tion of lactone 25 (100 mg, 0.171 mmol, 1.00 equiv) in Et2O
(1.70 mL) was added allylmagnesium bromide (1.00 M solution
in Et2O, 0.550 mL, 3.10 equiv) at -78 °C under Ar. The reaction
mixture was stirred until the starting material had been con-
sumed as indicated by TLC analysis, quenched with a saturated
solution of NH4Cl (5 mL), and extracted with Et2O (3 ꢀ 10.0mL).
The combined organics were dried over Na2SO4, filtered, and
concentrated in vacuo and used directly in the next step without
further purification.
1
Rf at 20% ethyl acetate in hexanes 0.6; H NMR (500 MHz,
CDCl3) δ 7.70 (t, 4H, J = 6.9 Hz), 7.40 (m, 11H), 5.55 (m, 1H),
4.32 (m, 1H), 3.89 (m, 2H), 3.72 (s, 3H), 3.56 (m, 1H), 3.11 (s, 3H),
2.74 (m, 1H), 2.52, (m, 1H), 1.87 (m, 1H), 1.66 (m, 3H), 1.52 (m,
1H), 1.40 (m, 4H), 1.26 (m, 4H), 1.06 (s, 9H), 0.98 (m, 1H), 0.89
(d, 3H, J = 6.7 Hz), 0.72 (t, 3H, J = 6.9 Hz); 13C NMR (125
MHz, CDCl3) δ 171.2, 138.6, 134.4, 129.4, 128.1, 127.4, 126.1,
100.1, 75.6, 74.4, 73.2, 70.5, 55.7, 51.7, 43.4, 41.9, 40.8, 39.5, 37.1,
27.1, 25.4, 19.4, 17.7, 14.1; IR (CH2Cl2) 460, 517, 609, 700, 738,
818, 901, 1026, 1110, 1210, 1349, 1384, 1426, 1456, 1738, 2856,
The resultant crude hemiketal 26 (130 mg, 0.208 mmol, 1.00 equiv)
was dissolved in CH2Cl2 (2.10 mL) and cooled to -78 °C under
argon. To the solution were added Et3SiH (0.330 mL, 2.08 mmol,
10.0 equiv) and TFA (0.100 mL, 1.04 mmol, 5.00 equiv). The
temperature was allowed to warm to -40 °C and the reaction
mixture stirred for 0.5 h. The reaction was quenched with NaH-
CO3 (10.0 mL), and the aqueous layer was extracted with CH2Cl2
(3 ꢀ 10.0 mL), dried over Na2SO4, filtered, and concentrated in
vacuo. Flash chromatography (silica, 2% ethyl acetate in hexanes
then 10% ethyl acetate in hexanes) afforded β-C-glycoside 3 as a
yellow viscous oil (74.0 mg, 72% yield): Rf at 15% ethyl acetate in
hexanes 0.55; 1H NMR (500 MHz, CDCl3) δ 7.70 (t, 4H, J = 7.2
Hz), 7.39 (m, 6H), 5.85 (m, 1H), 5.07 (dd, 1H, J = 17.2 Hz), 4.99
(dd, 1H, J = 10.2 Hz), 4.67 (s, 2H), 4.02 (m, 1H), 3.90 (m, 1H),
3.73 (m, 2H), 3.38 (m, 1H), 3.37 (s, 3H), 3.11 (s, 3H), 2.28 (m, 1H),
2.12(m, 1H), 1.73(m, 4H), 1.36(m, 9H), 1.06(s, 9H), 0.96(m, 1H),
0.85 (d, 3H, J = 6.3 Hz), 0.70 (t, 3H, J = 6.6 Hz); 13C NMR (125
MHz, CDCl3) δ 135.9, 135.2, 134.8, 134.5, 129.4, 127.4, 116.3,
94.9, 75.6, 71.7, 70.5, 70.3, 69.8, 55.5, 55.3, 43.9, 41.9, 40.7, 39.6,
36.9, 36.1, 27.1, 25.8, 19.7, 19.4, 17.7, 13.9; IR (CH2Cl2) 611, 700,
740, 825, 847, 917, 1039, 1098, 1146, 1357, 1383, 1428, 1460, 2821,
2932, 2954, 3042, 3068 cm-1; [R]20 = -10.6 (c 0.6, CH2Cl2);
D
HRMS (EI) calcd for C36H47O6Si (M - C4H9) 603.3142, found
603.3129.
6-[6-(tert-Butyldiphenylsilanyloxy)-4-methoxy-2-methylnonyl]-
4-hydroxytetrahydropyran-2-one (4). A stirred solution of benzy-
lidene acetal 5 (780 mg, 1.18 mmol, 1.00 equiv) in HOAc (11.8 mL)
was hydrogenated over 10% Pd(OH)2 on carbon (780 mg) for 24 h
under H2 atatmospheric pressure. Once complete, the catalystwas
filtered off over a pad of Celite and the filtrate was concentrated
under vacuo to afford a mixture of lactone 4 and straight-chained
diol. The crude mixture was redissolved in HOAc (9.00 mL) and
H2O (3.00 mL) and refluxed (70 °C) for 4 h until complete
consumption of the diol was observed by TLC analysis. The
mixture was concentrated under reduced pressure and redissolved
in EtOAc (40.0 mL). The organic layer was then quenched at 0 °C
with a saturated solution of NaHCO3 (20.0 mL), and the aqueous
layer was extracted with EtOAc (3 ꢀ 30.0 mL), dried over
Na2SO4, filtered, and concentrated in vacuo. Flash chromatogra-
phy (silica, 40% ethyl acetate in hexanes) afforded lactone 4 as a
clear viscous oil (450 mg, 70% yield): Rf at 40% ethyl acetate
in hexanes 0.2; 1H NMR (500 MHz, CDCl3) δ 7.69 (t, 4H, J =
7.5 Hz), 7.39 (m, 6H), 4.74 (m, 1H), 4.34 (m, 1H), 3.85 (m, 1H),
3.30 (m, 1H), 3.11 (s, 3H), 2.70 (dd, 1H, J = 7.2, 15.8 Hz), 2.59,
(dd, 1H, J = 6.3, 15.7 Hz), 1.89 (m, 2H), 1.67 (m, 3H), 1.35 (m,
8H), 1.04 (s, 9H), 0.94 (m, 1H), 0.87 (d, 3H, J = 6.7 Hz), 0.72 (t,
3H, J = 6.5 Hz); 13C NMR (125 MHz, CDCl3), δ 170.7, 135.9,
134.3, 129.4, 127.4, 75.7, 73.6, 70.5, 62.5, 55.9, 43.2, 41.9, 39.4,
38.6, 36.4, 26.9, 25.3, 19.3, 17.8, 13.9; IR (CH2Cl2) 611, 698, 732,
819, 1076, 1105, 1253, 1385, 1427, 1461, 1714, 2855, 2931, 2957,
3047, 3071, 3425 cm-1; [R]20D = -9.8 (c 0.65, CH2Cl2); HRMS
(EI) calcd for C28H39O5Si (M - C4H9) 483.2567, found 483.2576.
6-[6-(tert-Butyldiphenylsilanyloxy)-4-methoxy-2-methylnonyl]-
4-(methoxymethoxy)tetrahydropyran-2-one (25). To a stirred
solution of lactone 4 (200 mg, 0.370 mmol, 1.00 equiv) in CH2Cl2
(1.85 mL) at 0 °C under Ar were added DMAP (14.0 mg, 0.111
mmol, 0.300 equiv), DIPEA (0.390 mL, 2.22 mmol, 6.00 equiv),
and MOMCl (0.110 mL, 1.48 mmol, 4.00 equiv). The reaction
mixture was allowed to stir at rt for 18 h, at which time the
reaction was recooled to 0 °C and quenched with a solution of
saturated NaHCO3 (10.0 mL). The aqueous layer was extracted
with CH2Cl2 (3 ꢀ 10.0 mL), dried over Na2SO4, filtered, and
concentrated in vacuo. Flash chromatography (silica, 20% ethyl
acetate in hexanes) afforded MOM/TBDPS lactone 25 as a
2932, 3049, 3072, 3452 cm-1; [R]20 = þ24.8 (c 0.23, CH2Cl2);
D
HRMS (EI) calcd for C33H49O5Si (M - C4H9) 553.3349, found
553.3343.
[6-[6-(tert-Butyldiphenylsilanyloxy)-4-methoxy-2-methylnonyl]-
4-(methoxymethoxy)tetrahydropyran-2-yl]acetaldehyde (29).
A
solution of β-C-glycoside 3 (74.0 mg, 0.121 mmol, 1.00 equiv) in
CH2Cl2/MeOH(1:1, 2.00 mL) wascooledto-78 °C, andastream
of O3 was bubbled through the reaction mixture for 15 min until
the starting material had been consumed as indicated by TLC
analysis. The reaction was then quenched by the addition of SMe2
(0.0500 mL, 0.604 mmol, 5.00 equiv) and allowed to stir at rt for
4 h at which time the reaction was concentrated in vacuo. Flash
chromatography (silica, 15% ethyl acetate in hexanes) afforded
aldehyde 29 as a clear viscous oil (61.0 mg, 83% yield): Rf at 15%
ethyl acetate in hexanes 0.2; 1H NMR (500 MHz, CDCl3) δ 9.78
(t, 1H, J = 2.1 Hz), 7.69 (m, 4H), 7.38 (m, 6H), 4.68 (s, 2H), 4.25
(m, 1H), 4.03 (m, 1H), 3.89 (m, 1H), 3.82 (m, 1H), 3.35 (m, 5H),
3.09 (s, 3H), 2.52 (ddd, 1H, J = 2.4, 8.4, 16.1 Hz), 2.37 (ddd, 1H,
J = 2.2, 4.4, 16.0 Hz), 1.71 (m, 4H), 1.47 (m, 2H), 1.35 (m, 4H),
1.23 (m, 2H), 1.05 (s, 10H), 0.95 (m, 1H), 0.83 (d, 3H, J = 6.3 Hz),
0.69 (t, 3H, J = 7.3 Hz); 13C NMR (125 MHz, CDCl3) δ 201.6,
135.9, 134.8, 134.4, 129.4, 127.3, 94.9, 75.5, 70.5, 69.9, 69.7, 67.8,
55.6, 55.4, 49.6, 43.6, 42.1, 39.6, 36.7, 36.2, 27.1, 25.6, 19.6, 19.4,
J. Org. Chem. Vol. 75, No. 12, 2010 4103

Martinez-Solorio and Jennings
JOCArticle
17.7, 13.9; IR (CH2Cl2) 609, 701, 737, 821, 914, 1038, 1106,
1155, 1375, 1431, 1467, 1728, 2723, 2932, 3048, 3073, 3438
cm-1; [R]20D=þ28.1 (c 0.05, CH2Cl2); HRMS (EI) calcd for
C32H47O6Si (M - C4H9) 555.3142, found 555.3135.
Upon addition, stirring was continued for an additional 16 h. The
mixture was then allowed to cool to ambient temperature and
concentrated in vacuo. The crude product was filtered over a pad
short pad of silica using 60% ethyl acetate in hexanes and then
concentrated in vacuo. Flash chromatography (silica, 10% ethyl
acetate in hexanes) provided macrolactone 31 as a clear oil (27.0 mg,
87% yield): Rf at 10% ethyl acetate in hexanes 0.2; 1H NMR (500
MHz, CDCl3) δ 5.18 (m, 1H), 4.67 (s, 2H), 4.12 (m, 1H) 4.02 (t, 1H,
J = 2.9 Hz), 3.59 (m, 2H), 3.37 (s, 3H), 3.30 (s, 3H), 2.57 (dd, 1H,
J = 4.1, 14.5 Hz), 2.33 (dd, 1H, J = 10.9, 14.5 Hz), 1.71 (m, 5H),
1.40 (m, 8H), 1.22 (m, 1H), 1.13 (m, 1H), 0.97 (d, 3H, J = 6.6 Hz),
0.90 (t, 3H, J=7.2Hz);13CNMR(125MHz, CDCl3) δ171.0, 94.9,
75.6, 75.4, 72.9, 69.9, 69.6, 56.2, 55.4, 44.2, 42.5, 42.3, 40.2, 37.2, 36.9,
35.9, 31.3, 25.6, 18.9, 13.9; IR (CH2Cl2) 727, 793, 922, 984, 992, 1039,
1087, 1150, 1197, 1249, 1274, 1345, 1440, 1458, 1656, 1730, 2927,
3441 cm-1; [R]20D = -98.1 (c 0.1, CH2Cl2); HRMS (EI) calcd for
C19H33O6 (M - CH3) 357.2277, found 357.2290.
[6-(6-Hydroxy-4-methoxy-2-methylnonyl)-4-(methoxymethoxy)-
tetrahydropyran-2-yl]acetic Acid (30). To a solution of aldehyde 29
(60.0 mg, 0.0980 mmol, 1.00 equiv) in tert-butyl alcohol (1.20 mL)
and H2O (0.500 mL) cooled to 0 °C was added 2-methylbutene
(1.01 mL, 9.80 mmol, 100.0 equiv) in one portion. A freshly
prepared solution of NaClO2 (53.0 mg, 0.588 mmol, 6.00 equiv)
and NaH2PO4 (118 mg, 0.980 mmol, 10.0 equiv) in tert-butyl
alcohol (0.500 mL) and H2O (0.500 mL) was then added drop-
wise. The reaction mixture was then allowed to stir at rt for 5 h,
at which time the reaction was quenched by addition of a
saturated solution of NH4Cl(10.0 mL) and extractedwith EtOAc
(3 ꢀ10.0 mL). The combined organics were dried over Na2SO4,
filtered, and concentrated in vacuo. Flash chromatography
(silica, 25% ethyl acetate in hexanes and 1% acetic acid) afforded
the TBDPS acid as a yellow viscous oil (55 mg, 90% yield): Rf at
30% ethyl acetate in hexanes 0.25.
(-)-Neopeltolide Macrocyclic Core (2). To a stirred solution of
macrolactone 31 (12.0 mg, 0.0322 mmol, 1.00 equiv) in MeOH
(0.500 mL) at 0 °C was added concentrated HCl (0.0200 mL). The
reaction mixture was allowed to stir at rt for 24 h, at which time the
reaction was cooled to 0 °C and quenched with a saturated solution
of NaHCO3 (5.00 mL). The aqueous layer was extracted with
EtOAc (3 ꢀ 10.0 mL), dried over Na2SO4, filtered, and concen-
trated in vacuo. Flash chromatography (silica, 25% ethyl acetate in
hexanes) afforded (-)-neopeltolide core 2 as a clear viscous oil
(9.00 mg, 90% yield): Rf at 30% ethyl acetate in hexanes 0.3; 1H
NMR (500 MHz, CDCl3) δ 5.19 (m, 1H), 4.24 (t, 1H, J = 2.9 Hz),
4.19 (m, 1H), 3.68 (m, 1H), 3.59 (t, 1H, J = 9.8 Hz), 3.31 (s, 3H),
2.57 (m, 1H), 2.34 (m, 1H), 1.85 (1H), 1.65 (m, 2H), 1.51 (m, 5H),
1.37 (m, 4H), 1.24 (m, 2H), 0.97 (d, 3H, J = 7.1 Hz), 0.90 (t, 3H,
J=7.3Hz);13CNMR(125MHz, CDCl3) δ171.1, 75.6, 74.8, 72.8,
69.1, 64.9, 56.2, 44.2, 42.5, 42.3, 40.1, 39.4, 38.3, 36.9, 31.4, 25.7,
18.9, 13.9; IR (CH2Cl2) 734, 797, 988, 1032, 1079, 1164, 1197, 1274,
To a stirred solution of the TBDPS acid (55.0 mg, 0.088 mmol,
1.00 equiv) in THF (0.300 mL) at 0 °C was added TBAF (1.00 M
solution in THF, 0.900 mL, 10.0 equiv). The reaction mixture was
allowed to stir at rt for 72 h at which time the mixture was quenched
with H2O (5.00 mL) and extracted with EtOAc (3 ꢀ 10.0 mL). The
combined organics were dried over Na2SO4, filtered, and concen-
trated in vacuo. Flash chromatography (silica, 60% ethyl acetate in
hexanes and 1% acetic acid) afforded acid 30 as yellow viscous oil
(27.0 mg, 87% yield): Rf at 60% ethyl acetate in hexanes 0.2; 1H
NMR (500 MHz, CDCl3) δ 4.66 (s, 2H), 4.18 (m, 1H), 4.01 (m,
1H), 3.94 (m, 1H), 3.84 (t, 1H, J = 9.7 Hz), 3.53 (m, 1H), 3.36 (s,
3H), 3.34 (s, 3H), 2.43 (d, 2H, J = 6.2 Hz), 1.76 (m, 5H), 1.40 (m,
9H), 1.14 (m, 2H), 0.90 (m, 7H); 13C NMR (125 MHz, CDCl3) δ
174.4, 95.0, 78.2, 71.6, 69.8, 69.5, 68.9, 56.8, 55.3, 43.7, 41.3, 40.9,
40.1, 39.1, 36.9, 35.8, 27.3, 20.6, 18.8, 14.2; IR (CH2Cl2) 696, 734,
920, 993, 1106, 1278, 1357, 1456, 1734, 2874, 2928, 2958, 3030, 3065
1345, 1381, 1432, 1461, 1730, 2872, 2920, 3438 cm-1; [R]20
=
D
-48.4 (c 0.05, CH2Cl2); HRMS (EI) calcd for C18H32O5 (Mþ)
328.2250, found 328.2246.
cm-1; [R]20 = -72.3 (c 0.05, CH2Cl2); HRMS (EI) calcd for
D
C20H39O7 (M þ H) 391.2696, found 391.2701.
7-Methoxy-13-(methoxymethoxy)-9-methyl-5-propyl-4,15-
dioxabicyclo[9.3.1]pentadecan-3-one (31). To a stirred solution of
acid 30 (19.0 mg, 0.0487 mmol, 1.00 equiv) in THF (0.500 mL) at
0 °C under Ar was added Hunig’s base (0.0600 mL, 0.300 mmol,
6.00 equiv) followed by 2,4,6-trichlorobenzoyl chloride (0.0400 mL,
0.250 mmol, 5.00 equiv). The reaction mixture was stirred at rt for
4 h, after which time toluene was added (1.22 mL). This solution
was added over 8 h by syringe pump to a refluxing solution of
DMAP (150 mg, 1.22 mmol, 25.0 equiv) in toluene (38.0 mL).
Acknowledgment. Support for this project was provided
by the University of Alabama and the National Science
Foundation CAREER program under CHE-0845011.
Supporting Information Available: Additional experimental
procedures and full characterization data for all new com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
4104 J. Org. Chem. Vol. 75, No. 12, 2010