Total synthesis of (-)-4,8,10-tridesmethyl telithromycin

Article abstract of DOI:10.1021/jo201319b

Novel sources of antibiotics are required to address the serious problem of antibiotic resistance. Telithromycin (2) is a third-generation macrolide antibiotic prepared from erythromycin (1) and used clinically since 2004. Herein we report the details of

Full text of DOI:10.1021/jo201319b

ARTICLE
pubs.acs.org/joc
Total Synthesis of (ꢀ)-4,8,10-Tridesmethyl Telithromycin
Venkata Velvadapu, Tapas Paul, Bharat Wagh, Ian Glassford, Charles DeBrosse, and Rodrigo B. Andrade*
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States
S Supporting Information
b
ABSTRACT: Novel sources of antibiotics are required to address the serious
problem of antibiotic resistance. Telithromycin (2) is a third-generation macrolide
antibiotic prepared from erythromycin (1) and used clinically since 2004. Herein we
report the details of our efforts that ultimately led to the total synthesis of (ꢀ)-4,8,10-
tridesmethyl telithromycin (3) wherein methyl groups have been replaced with
hydrogens. The synthesis of desmethyl macrolides has emerged as a novel strategy for
preparing bioactive antibiotics.
macroketolactone 5, we utilized two tactics employed in the
synthesis of the related ketolide, narbonolide: (1) the intramole-
cular NozakiꢀHiyamaꢀKishi (NHK) reaction employed by
Sherman and Fecik9 and (2) the intramolecular ring-closing
metathesis (RCM) strategy employed by Kang and co-workers.10
The NHK and RCM substrates could be accessed by an inter-
molecular Yamaguchi esterification,11 which then leads to frag-
ments 8, 9 and 10, the latter of which will be subjected to the
Evans aldol reaction to set stereocenters at C2 and C3.12 Finally,
the Sharpless asymmetric dihydroxylation (AD) reaction13 of
olefin 11, which is prepared via a JohnsonꢀClaisen orthoester
rearrangement, would establish the requisite configurations and
oxidation states at both C5 and C6.
2.2. Synthesis. The preparation of fragments 8 and 9 was
accomplished from aldehyde 15, which was synthesized from 12
(Scheme 2). Kinetic resolution of rac-12 via the Sharpless
asymmetric epoxidation protocol provided enantioenriched alco-
hol 13 in 32% yield (92% ee).14 Regioselective ring opening with
pivalic acid and Ti(O-iPr)4, acetonide formation, and treatment
with MeLi afforded alcohol 14 (59% over three steps).15 Swern
oxidation of 14 to aldehyde 1516 proceeded without incident. At
this point, 15 was subjected to the CoreyꢀFuchs alkynylation
protocol (59% yield from 14).17 Hydrostannation of the inter-
mediary alkyne with Bu3SnH and catalytic AIBN proceeded with
excellent stereocontrol to afford an (E)-vinyl stannane,18 which
was converted to vinyl iodide 16 with I2 in 80% over two steps.
Removal of the acetonide in 16 with 1 M HCl (aq) furnished
fragment 8 (72% yield). Access to fragment 9 was accomplished
by (1) Wittig methylenation of 15 and (2) removal of the
acetonide in 17 under acidic conditions in 53% yield from 14.16
1. INTRODUCTION
The incessant rise in antibiotic-resistant bacteria is a serious
public health issue.1,2 To address this need, we have initiated a
structure-based drug design program wherein desmethyl analo-
gues (i.e., CH3fH) of the third-generation macrolide antibiotic
telithromycin (2) are prepared via chemical synthesis (Figure 1).
Inspiration for desmethylation came from Steitz’s analysis of
X-ray crystal structures of 1 and 2 bound to the 50S ribosomal
subunits of H. marismortui, which explains how ribosomal point
mutations at critical residues (i.e., A2058G, E. coli numbering)
confer antibiotic resistance.3
Most modern macrolide antibiotics are semisynthetic analo-
gues of erythromycin A, of which clarithromycin, azithromycin,
and telithromycin are examples.4 As a part of our desmethyla-
tion approach to address antibiotic resistance, herein we report
the details of our synthetic efforts culminating in the total
synthesis of (ꢀ)-4,8,10-tridesmethyl telithromycin (3).5 We
have employed a de novo synthetic strategy to access this
simplified ketolide scaffold.
2. RESULTS AND DISCUSSION
2.1. Retrosynthesis. Our approach toward the synthesis of
(ꢀ)-4,8,10-tridesmethyl telithromycin (3) is shown in Scheme 1.
The retrosynthetic strategy employed was guided by prior art in
the field. Specifically, we envisioned the use of a sequential one-
pot carbamoylation/intramolecular aza-Michael method devel-
oped by Baker and co-workers at Abbott to install the C11ꢀC12
oxazolidinone with pendant butylarene to access 4 from 5.6 In
fact, thistactic was employed by Hoechst Marion Roussel (HMR)
with 6 in their synthesis of HMR-3647 (i.e., telithromycin).7
Glycosylation of a C5 hydroxyl acceptor derived from 5 would be
accomplished with known desosamine donor 7.8 To prepare
Received: July 8, 2011
Published: August 04, 2011
r
2011 American Chemical Society
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Figure 1. Structures of erythromycin (1), telithromycin (2), and novel analogue (ꢀ)-4,8,10-tridesmethyl telithromycin (3).
Scheme 1. Retrosynthesis of (ꢀ)-4,8,10-Tridesmethyl Telithromycin (3)
With fragments 8 and 9 in hand, attention was turned to the
preparation of fragment 10 (Scheme 1). To this end, commer-
cially available 3-benzyloxy-propanol (18) was oxidized using the
Swern protocol (Scheme 3). Addition of 2-propenyl MgBr and
subsequent JohnsonꢀClaisen orthoester rearrangement afforded
enoate 11 in 48% overall yield. Reduction of the ester and
protection of the newly formed alcohol as its tert-butyldimethyl-
silyl (TBS) ether provided 19 (78% yield over two steps).19
Sharpless dihydroxylation (AD mix-β) established the requisite
stereochemistry of the hydroxyls at C5 and C6 in 91% yield (er
>20:1).13 Selective protection of the secondary C5 alcohol with
TBSOTf and 2,6-lutidine followed by treatment with NaH and
MeI resulted in the formation of 24 as opposed to the desired
regioisomer 23 in 70% over two steps via a 1,4 silyl OfO
migration (Scheme 3).20 This migration came to light when we
succeeded in obtaining a single crystal X-ray structure of cyclized
product 35 (see Scheme 5). A survey of the literature revealed this
to be a common undesired pathway that attends the generation of
a nucleophilic alkoxide bearing a tethered trialkylsilyl ether.21
With the undesired regioisomer in hand, we pressed forward.
Hydrogenolysis of benzyl ether 24 afforded alcohol 25 in 80%
yield (Scheme 4). Swern oxidation of 25 to aldehyde 26 was
followed by the Evans aldol reaction with propionimide 27,
which set the stereochemistry at C2 and C3 positions in 78%
yield (dr >20:1) over two steps. Protection of the C3 hydroxyl in
28 with TBSOTf and removal of the auxiliary with LiOOH
delivered acid 30 in 85% yield over two steps. Chemoselective
Yamaguchi esterification of 30 and diol 8 afforded ester 31 in
74% yield.
To prepare the intramolecular NHK substrate 33, the
primary TBS ether of 31 was selectively removed under acidic
conditions in 85% yield (Scheme 5). Oxidation of alcohol 32
with the DessꢀMartin periodinane (DMP)22 and NaHCO3
proceeded smoothly to furnish 33 in 80% yield. The key step
was thus effected by adding excess CrCl2 and catalytic NiCl2 to
33 in degassed DMSO (0.0025 M) at rt for 16 h, affording a 50%
yield of 34 as a 1:1 mixture of diastereomeric allylic alcohols at
C9. Subsequent oxidation of 34 with DMP and pyridine
furnished macroketolactone 35, which fortunately was a solid.
Recrystallization of 35 from Et2O by slow evaporation resulted
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in crystals suitable for X-ray analysis. To our surprise, the
groups on C5 and C6 positions in regioisomeric 33 had been
transposed.
To rectify this issue, we revisited the methylation reaction
responsible for the attendant transposition. We reasoned that
employing a more reactive methylating agent (e.g., Meerwein’s
salt) would avoid the unwanted 1,4 OfO silyl migration enabled
by reactive metal alkoxide 21 (Scheme 3). In addition, we
recruited the TES protecting group to establish an orthogonal
set at C3 and C5 and offer recourse in the event a regioselective
glycosylation was unsuccessful (Scheme 6). To prepare substrate
36, we protected the secondary C5 hydroxyl as a TES ether under
standard conditions (90% yield). Methylation of 36 with
Me3OBF4 (i.e., Meerwein’s salt) and proton sponge in CH2Cl2
afforded desired regioisomer 38.23 Moreover, subjection to
rearrangement conditions (i.e., NaH and MeI) furnished the
expected, undesired regioisomer 37.
Scheme 2. Synthesis of Fragments 8 and 9 from Aldehyde 15a
With correct regioisomer 38 in hand, we reiterated the sequence
employed in Schemes 4 and 5. Thus, removal of the benzyl ether in
38 afforded alcohol 39 in 85% yield (Scheme 7). Oxidation of 39
with the Swern protocol followed by the Evans aldol reaction
furnished41 in 78% yield (dr >20:1). Protection of the C3 hydroxyl
with TBSOTf and removal of the auxiliary with LiOOH resulted in
acid 43 in 85% yield over two steps. Yamaguchi esterification of 43
and 8 delivered ester 44 in 75% yield. Removal of the primary TBS
group with TBAF/AcOH (60% yield) and subsequent DMP
oxidation (78% yield) set the stage for the intramolecular NHK
on 46. In the event, a 50% yield of 47 was obtained. Oxidation of
the ∼1:1 diastereomeric mixture of allylic alcohols at C9 furnished
desired macroketolactone 48 in 80% yield.
a Reagents and conditions: (a) (ꢀ)-DIPT, Ti(Oi-Pr)4, t-BuOOH, 32%
(92% ee); (b) PivOH, Ti(Oi-Pr)4; (c) Me2C(OMe)2, PPTS; (d) MeLi,
59% over three steps; (e) (COCl)2, DMSO, Et3N; (f) CBr4, Ph3P,
CH2Cl2, 65% over two steps; (g) n-BuLi, THF, 90%; (h) cat. AIBN,
Bu3SnH, C6H6; (i) I2, CH2Cl2, 80% over two steps; (j) 1 N HCl (aq),
72%; (k) Ph3PdCH2; (l) 1 N HCl (aq), 53% over three steps from 14.
Scheme 3. Unexpected Synthesis of Regioisomeric Fragment 24a
a Reagents and conditions: (a) (COCl)2, DMSO, Et3N; (b) 2-propenyl MgBr, THF; (c) (MeO)3CCH3, EtCO2H, 48% over three steps; (d) LiAlH4,
Et2O; (e) TBSCl, imidazole, 78% over two steps; (f) AD mix-β, 91% (er >20:1); (g) TBSOTf, 2,6-lutidine; (h) NaH, MeI, 70% over two steps.
Scheme 4. Elaboration of 24 into Macrocyclization Precursor 31a
a Reagents and conditions: (a) H2, Pd/C, 80%; (b) (COCl)2, DMSO, Et3N; (c) 27, Bu2BOTf, Et3N, 78% (dr >20:1) over two steps; (d) TBSOTf, 2,6-
lutidine; (e) LiOOH, THF, H2O, 85% over two steps. (f) Cl3PhCOCl, Et3N, DMAP, 8, 74%.
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Scheme 5. Macrocyclization of 33 and X-ray Structure of Macroketolactone 35a
a Reagents and conditions: (a) CSA, MeOH, 85%; (b) DMP, NaHCO3, 80%; (c) CrCl2, cat. NiCl2, DMSO, 50%; (d) DMP, Pyridine, 82%.
Scheme 6. Synthesis of Both Regioisomeric Fragments 37 and 38 (Desired)
In parallel, we developed a scalable RCM route inspired by
Kang’s synthesis of narbonolide (Scheme 8).24 To this end, we
employed Yamaguchi’s method to couple acid 43 and diol 9 to
access ester 49 in 75% yield. Selective removal of the primary
TBS ether with TBAF/AcOH afforded alcohol 50 (65% yield).
Oxidation of 50 with DMP, treatment with vinyl MgBr, and
subsequent oxidation with DMP furnished RCM substrate 51 in
60% over three steps. The RCM reaction proceeded smoothly in
CH2Cl2 (0.01 M) at rt for 20 h with 20 mol % Grubbs second
generation catalyst to provide 48 in 60% yield.25
With macroketolactone 48 in hand, attention was directed at the
installation of the desosamine moiety onto the C5 hydroxyl. To this
end, the C5 TES ether was removed under various conditions (e.g.,
p-TsOH, PPTS, HF). Unfortunately, this was accompanied by
ketalization at the C9 position (Scheme 9) as a consequence of the
acidic conditions employed to remove the TES group
Treatment of 48 with TBAF (i.e., basic conditions) resulted in
the removal of both silyl groups, affording triol 54 in 70% yield
(Scheme 10). Studies by Martin26 and Toshima and Tatsuta27
both demonstrated the viability of regioselective glycosylations in
closely related erythronolide systems. Attempted regioselective
glycosylation of 54 at C5 in the presence of C3 with donor 7 under
the agency of AgOTf and 2,6-di-t-Bu-4-Me-pyridine (DTBMP)
led exclusively to the decomposition of starting material.
C3 position blocked, assuming the secondary C5 hydroxyl would
be more reactive than the hindered tertiary C12 hydroxyl. To test
this plan, the C9 ketone of 48 was first subjected to a Luche
reduction to give an inseparable 7:1 mixture of diastereomers
that was carried throughout the synthesis (Scheme 11).28 Treat-
ment with p-TsOH in methanol selectively removed the C5 TES
ether in the presence of the C3 TBS ether to afford triol 55.
Regioselective protection of the more reactive allylic C9 hydroxyl
with TESCl and imidazole furnished diol 56. Glycosylation of 56
with donor 7, AgOTf, and DTBMP resulted in the desosamine at
the C12 position, as opposed to the desired C5. This was
confirmed by (1) 2D NMR experiments, particularly an HMBC
correlation between the anomeric proton in desosamine with the
C12 carbon and (2) removal of C9 TES and oxidation of product
with DMP resulted in a triketo species (structure not shown).
We speculate that glycosylation at the more hindered C-12
hydroxyl is due to two factors. First, the C-12 hydroxyl in 56 is
allylic and therefore more nucleophilic (and less sterically
demanding) than Tatsuta’s C-12 substrate, which was flanked
by a 9,11-isopropylidene ketal.27 Second, conformational proper-
ties of macrolactone acceptor 56 may render C-5 more sterically
shielded. The unexpected glycosylation at the more hindered
position necessitated protection at this position as well
(Scheme 12). Accordingly, macroketolactone 48 was first re-
duced under Luche conditions. Silylation of both C9 and C12
hydroxyls with TESOTf and 2,6-lutidine and subsequent
Recourse at this point was made to a more conservative
strategy. Specifically, we chose to install desosamine with the
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Scheme 7. Intramolecular NozakiꢀHiyamaꢀKishi (NHK) Route to Macroketolactone 48a
a Reagents and conditions: (a) H2, Pd/C, 85%; (b) (COCl)2, DMSO, Et3N; (c) 27, Bu2BOTf, Et3N, dr >20:1, 78% over 2 steps; (d) TBSOTf, 2,6-
lutidine; (e) LiOOH, THF, H2O, 85% over two steps; (f) Cl3PhCOCl, Et3N, DMAP, 75%; (g) TBAF, AcOH, 60%; (h) DMP, NaHCO3, 78%; (i)
CrCl2, cat. NiCl2, DMSO, 50%; (j) DMP, 80%
Scheme 8. Alternate Ring-Closing Metathesis (RCM) Route to Macroketolactone 48a
a Reagents and conditions: (a) Cl3PhCOCl, Et3N, DMAP, 9, 78%; (b) TBAF, AcOH, 65%; (c) DessꢀMartin periodinane, NaHCO3; (d) vinyl MgBr,
THF; (e) DessꢀMartin periodinane, CH2Cl2, 60% over three steps; (f) 20 mol % Grubbs II cat., 60%.
treatment with p-TsOH selectively afforded 58 wherein only
the tertiary C12 hydroxyl remained protected (52% yield over
three steps). Regioselective silylation of the allylic C9 alcohol
with TESCl furnished 59. Glycosylation at the C5 position with
donor 7 was accomplished in 50% yield over two steps.
Fluoride-mediated cleavage of silyl ethers at C9, C12 with
TBAF followed by DMP oxidation at C9 afforded glycosylated
macroketolactone 62 (84% yield over two steps). The structure
of 62 was rigorously confirmed by 2D NMR experiments (see
Supporting Information).
The endgame for (ꢀ)-4,8,10-tridesmethyl telithromycin (3)
began with a sequence employed by HMR to prepare C11ꢀC12
oxazolidinones, originally developed by Baker and co-workers at
Abbott.6 Activation of the C12 alcohol in 62 with NaH and
carbonyldiimidazole (CDI) followed by treatment with butylamine
67 effected a tandem carbamoylation/intramolecular aza-Michael
sequence to stereoselectively afford oxazolidinone 63 in 35%
overall yield (Scheme 13). Removal of the C3 TBS ether with
tris(dimethylamino)sulfonium difluorotrimethylsilicate (TAS-F)
proceeded in 70% yield.29 Alternative fluoride-mediated methods
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Scheme 9. Selective Removal of C5 TES Group and Attendant Ketalization
Scheme 10. Unsuccessful Regioselective Glycosylation of Diol 54 with Donor 7a
a Reagents and conditions: (a) TBAF, 4 Å MS, THF, 70%; (b) 7, AgOTf, DTBMP.
Scheme 11. Unexpected Glycosylation of Tertiary C12 Hydroxyl in the Presence of Secondary C5 Hydroxyla
a Reagents and conditions: (a) NaBH4, CeCl3 7H2O, dr = 7:1; (b) p-TsOH, MeOH, 75%; (c) TESCl, imidazole; (d) 7, AgOTf, DTBMP, 42% over
3
two steps.
(e.g., TBAF, HF pyridine, HF) were all inferior. CoreyꢀKim
and Baker’s sequential one-pot carbamoylation/intramolecular aza-
Michael method with amine 6 were representative key steps.
Ultimately, we were able to prepare a total of 12.1 mg of analogue
3 in 42 steps (31 steps in the longest linear sequence), which was
active against several wild type and resistant bacterial strains.5
3
oxidation furnished the C3 ketone 4.30 Finally, methanolysis removed
the methyl carbonate from the C20 position of desosamine to deliver
(ꢀ)-4,8,10-tridesmethyl telithromycin (3) in 45% overall yield.
3. CONCLUSION
4. EXPERIMENTAL SECTION
In conclusion, we have prepared (ꢀ)-4,8,10-tridesmethyl teli-
thromycin (3), a desmethyl analogue of FDA-approved ketolide
antibiotic telithromycin (2), by total synthesis. Both the intramole-
cular NHK and RCM reactions were used to prepare the 14-
membered ring. Glycosylation using known desosamine donor 7
(R)-5-((R)-3-(Benzyloxy)-1-methoxypropyl)-2,2,3,3,5,10,
10,11,11-nonamethyl-4,9-dioxa-3,10-disiladodecane (24). To
a solution of diol 20 (2.5 g, 18.29 mmol) in CH2Cl2 (30 mL) at ꢀ20 °C
were added 2,6-lutidine (2.10 g, 19.59 mmol) and TBSOTf (2.07 g,
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Scheme 12. Synthesis of Macroketolactone 62a
a Reagents and conditions: (a) NaBH4, CeCl3 7H2O, dr = 7:1; (b) TESOTf, 2,6-lutidine; (c) p-TsOH, 52% over three steps; (d) TESCl, imidazole; (e)
3
7, AgOTf, DTBMP, 50% over two steps; (f) 1 M TBAF, THF, 95%; (g) DMP, CH2Cl2, 88%.
Scheme 13. Endgame for (ꢀ)-4,8,10-Tridesmethyl Telithromycin (3)a
a Reagents and conditions: (a) NaH, CDI, THF/DMF then 6, 35%; (b) TASF, DMF/H2O, 70%; (c) NCS, DMS, Et3N; (d) MeOH, 45% over two steps.
7.83 mmol). After 2 h, the reaction was quenched by adding satd aq
NaHCO3 (20 mL). The aqueous layer was extracted with CH2Cl2 (2 ꢁ
10 mL). The combined organic layers were washed with brine (20 mL),
dried (Na2SO4), and filtered. The solvent was evaporated under reduced
pressure, azeotropedwith toluene (20 mL), and dried under high vacuum.
The residue was dissolved in THF (130 mL), MeI (2.01 g, 32.65 mmol)
was added, and the solution was cooled to 0 °C. Sodium hydride (0.78 g,
32.65 mmol) was added slowly in portions. The reaction mixture was
warmed to rt and stirred for 16 h. The reaction mixture was quenched by
adding MeOH (30 mL) followed by H2O (50 mL) at 0 °C. The reaction
mixture was diluted with Et2O (150 mL), and the aqueous layer was
extracted with Et2O (2 ꢁ 50 mL). The combined organics were washed
with brine (50 mL), dried (Na2SO4), and filtered. The solvent was
concentratedunder reducedpressure, and theresiduewas purified byflash
chromatography eluting with EtOAc/hexanes (0.4:1) to afford 2.9 g
(70%) of24 as colorless oil. [R]23D +9.4° (c 1.8, CH2Cl2); IR(film) 2880,
7.27ꢀ7.17 (m, 5H), 4.45 (d, J = 11.6 Hz, 1H), 4.41 (d, J = 12.0 Hz,
1H), 3.53ꢀ3.47 (m, 4H), 3.33 (s, 3H), 3.08 (dd, J = 10.0, 2.2 Hz, 1H),
1.90ꢀ1.87 (m, 1H), 1.55ꢀ1.34 (m, 5H), 1.14 (s, 3H), 0.82 (s, 9H), 0.80
(s, 9H), 0.02 (s, 6H), ꢀ0.04 (s, 6H); 13C NMR(100 MHz)δ138.6, 128.3
(2), 127.5 (2), 127.4, 84.9, 78.4, 72.8, 67.8, 63.7, 60.7, 35.1, 30.8, 27.0, 26.1
(3C), 26.0 (3C), 24.0, 18.4, 18.3, ꢀ1.8, ꢀ1.9, ꢀ5.3 (2); HRMS (FAB)
calcd for C28H54O4Si2 + Na 533.3458, found 533.3442.
(3R,4R)-4,7-Bis((tert-butyldimethylsilyl)oxy)-3-methoxy-4-
methylheptan-1-ol (25). To a solution of ether 24 (2.9 g, 5.67 mmol)
in EtOH (56 mL) was added 10% Pd/C (0.6 g, 0.56 mmol) under an
atmosphere of H2. The reaction mixture was followed 4ꢀ8 h (TLC
control). The reaction mixture was filtered through a Celite plug, which
had been previously washed with EtOAc. The solvent was concentrated
under reduced pressure, and the residue was purified by flash chroma-
tography eluting with EtOAc/hexanes (0.8:1) to afford 1.9 g (80%) of 25
as a colorless oil. [R]23 +6.0° (c 6.8, CH2Cl2); IR (film) 3306, 2953,
D
1475, 1422, 1361, 1055, 733, 696 cmꢀ1
;
1H NMR (400 MHz) δ
2928, 2885, 1471, 1462, 1253, 1098, 1055, 831, 811, 770 cmꢀ1; 1H NMR
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(400 MHz) δ 3.78ꢀ3.72 (m, 2H), 3.57ꢀ3.52 (m, 2H), 3.48 (s, 3H), 3.20
(dd, J = 10.0, 2.8 Hz, 1H), 2.40 (bs, 1H), 1.82ꢀ1.76 (m, 1H), 1.65ꢀ1.39
(m, 5H), 1.21 (s, 3H), 0.87 (m, 9H), 0.84 (s, 9H), 0.95 (m, 6H), 0.02 (s,
6H); 13C NMR (100 MHz) δ 86.6, 78.6, 63.6, 61.0, 60.8, 35.4, 33.0, 26.9,
26.0 (3C), 25.9 (3C), 23.9, 18.3, 18.2, ꢀ1.8, ꢀ1.9, ꢀ5.4 (2C); HRMS
(FAB) calcd for C21H48O4Si2 + Na 443.2989, found 443.2973.
concentrated under reduced pressure, and the residue purified by flash
chromatography eluting with EtOAc/hexanes (0.4/1) to yield 1.11 g
(85%) of 30 as a colorless oil. [R]23D +5.4° (c 2.5, CH2Cl2); IR (film)
3538, 2953, 2928, 2886, 2856, 1709, 1471, 1462, 1252, 1097, 1053, 1003,
832, 803 cmꢀ1; 1H NMR (400 MHz) δ 4.35ꢀ4.32 (m, 1H), 3.60ꢀ3.52
(m, 2H), 3.50 (s, 3H), 2.98 (d, J = 9.6 Hz, 1H), 2.69ꢀ2.64 (m, 1H),
1.82ꢀ1.76 (m, 1H), 1.67ꢀ1.40 (m, 5H), 1.21 (s, 3H), 1.14 (d, J =
7.2 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 18H), 0.10 (s, 3H), 0.09 (s, 3H), 0.07
(s, 3H), 0.03 (s, 9H); 13C NMR (100 MHz) δ 180.1, 84.7, 78.8, 70.7,
63.5, 60.5, 43.4, 35.8, 35.8, 27.1, 26.1 (3C), 25.9 (3C), 25.8 (3C), 24.1,
18.3, 17.9, 9.5, ꢀ1.7, ꢀ1.8, ꢀ2.0, ꢀ4.2, ꢀ5.1, ꢀ5.3 (2C); HRMS (FAB)
calcd for C30H66O6Si3 + Na 629.4065, found 629.4047.
(2R,3S,5R,6R)-(3R,4S,E)-4-Hydroxy-6-iodo-4-methylhex-5-
en-3-yl 3,6,9-tris((tert-butyldimethylsilyl)oxy)-5-methoxy-2,
6-dimethylnonanoate (31). To a solution of acid 30 (0.22 g, 0.36
mmol) in THF (4 mL) at rt was added Et3N (0.04 g, 0.38 mmol) and
2,4,6-trichlorobenzoyl chloride (0.01 g, 0.40 mmol). The reaction
mixture was stirred for 3 h at rt, and the solids were filtered and washed
with hexanes (10 mL). The combined filtrates were concentrated under
reduced pressure, dried under vacuum, and dissolved in toluene (5 mL).
To this solution were added iododiol 8 (0.11 g, 0.43 mmol) in toluene
(2 mL) and DMAP (0.06 g, 0.49 mmol). After being stirred for 16 h at rt,
the reaction mixture was diluted with EtOAc (20 mL), washed with satd
aq NaHCO3 (10 mL), dried (Na2SO4), and filtered. The solvent was
evaporated under reduced pressure, and the residue was purified by flash
chromatography eluting with EtOAc/hexanes (0.4/1) to afford 0.24 g
(74%) of 31 as a colorless oil. [R]23D +11.2° (c 1.2, CH2Cl2); IR (film)
3445, 2951, 2936, 2909, 2877, 2857, 1729, 1461, 1251, 1192, 1095, 1004,
950, 836, 775 cmꢀ1; 1H NMR (400 MHz) δ 6.68 (d, J = 14.6 Hz, 1H),
6.43 (d, J = 14.6, 1H), 4.81 (dd, J = 10.4, 2.8 Hz, 1H), 4.14ꢀ4.10 (m,
1H), 3.58ꢀ3.50 (m, 2H), 3.50 (s, 3H), 3.25 (dd, J = 9.6, 3.2 Hz, 1H),
3.18 (bs, 1H), 2.74ꢀ2.61 (m,1H), 1.68ꢀ1.35 (m, 8H), 1.25 (s, 3H),
1.21 (d, J = 4.8 Hz, 3H), 1.17 (s, 3H), 0.90 (s, 9H), 0.89ꢀ0.86 (m, 21H),
0.11 (s, 6H), 0.07 (s, 3H), 0.06 (s, 3H), 0.02 (s, 6H); 13C NMR (100
MHz) δ 175.8, 148.0, 83.9, 80.2, 79.3, 77.7, 71.2, 63.4, 60.7, 44.3, 36.5,
35.2, 26.7, 26.2 (3C), 26.1, 25.9 (6C), 24.8, 23.5, 23.2, 18.4, 18.3, 18.0,
14.4, 10.7,-1.6, ꢀ1.7, ꢀ3.8, ꢀ4.5, ꢀ5.4 (2C); HRMS (FAB) calcd for
C37H77IO7Si3 + Na 867.3920, found 867.3934.
(R)-4-Benzyl-3-((2R,3S,5R,6R)-6,9-bis((tert-butyldimethyl-
silyl)oxy)-3-hydroxy-5-methoxy-2,6-dimethylnonanoyl)oxa-
zolidin-2-one (28). Toa solutionofoxalylchloride (0.61 g, 4.86 mmol)
in CH2Cl2 (30 mL) at ꢀ78 °C was added DMSO (0.79 g, 10.12 mmol)
dropwise. After 10 min of stirring, alcohol 25 (1.70 g, 4.05 mmol) in
CH2Cl2 (10 mL) was added via cannula, and the reaction mixture was
stirred at ꢀ78 °C for 45 min. Triethylamine (1.02 g, 10.12 mmol) was
added dropwise by cannula, and the reaction mixture was slowly warmed
to rt. After 2 h, the reaction was quenched with dropwise addition of H2O
(10mL). The organiclayer was separatedand washedwithbrine (10mL),
dried (Na2SO4), and concentrated under reduced pressure. The crude
product was dissolved in Et2O (50 mL), filtered through a plug of silica gel
using ether, concentrated, and dried under high vacuum. Thismaterialwas
used directly without further purification. To a solution of (R)-4-benzyl-3-
propionyl-2-oxazolidinone (27) (0.94 g, 4.05 mmol) in CH2Cl2 (20 mL)
were added dibutylborontriflate (5.30 mL of a 1.0 M solution in CH2Cl2,
5.26 mmol) and triethylamine (0.61 g, 6.07 mmol) dropwise at 0 °C. The
solution was cooled to ꢀ78 °C, and to this was added the aldehyde (1.70 g,
4.05 mmol) in CH2Cl2 (10 mL) at ꢀ78 °C. The resulting solution was
stirred for 20 min at ꢀ78 °C. After warming the solution to 0 °C, the
reaction mixture was stirred an additional hour. The reaction was
terminated by adding a pH 7 aq phosphate buffer solution (0.2 M aq
sodium hydrogen phosphate/0.1 M aq citric acid, 82:18, 8.0 mL) and
MeOH(24.2mL). Tothiscloudy solution was addeda solutionofMeOH
and 30% H2O2 (2:1, 24.2 mL), and the resulting solution was stirred for 1
h at 0 °C. The solution was concentrated and extracted with EtOAc (3 ꢁ
60 mL). The organic layer was washed with satd aq NaHCO3 (50 mL)
and brine (50 mL), dried (Na2SO4), and filtered. The solvent was
evaporated under reduced pressure, and the residue was purified by flash
chromatography eluting with EtOAc/hexanes (2:1) to afford 1.50 g
(78%) of 28 as colorless oil. [R]23 ꢀ39.2° (c 3.75, CH2Cl2); IR
D
(film) 3500, 2953, 2885, 2856, 1781, 1696, 1382, 1359, 1252, 1208,
1
1195, 1097, 1051, 1004, 832, 771, 700 cmꢀ1; H NMR (400 MHz) δ
(2R,3S,5R,6R)-(3R,4S,E)-4-Hydroxy-6-iodo-4-methylhex-5-
en-3-yl 3,6-bis((tert-butyldimethylsilyl)oxy)-9-hydroxy-5-meth-
oxy-2,6-dimethylnonanoate (32). To a solution of alcohol 31
(0.27 g, 0.32 mmol) in MeOH (7 mL) was added CSA (0.015 g, 0.065
mmol) at 0 °C. After stirring for 1 h, the reaction was quenched with
NaHCO3 (0.040 g). The mixture was concentrated under reduced
pressure, and the residue was purified by flash chromatography eluting
with EtOAc/hexanes (1/5) to afford 0.20 g (85%) of 32 as a colorless oil.
[R]23D +14.5° (c 0.9, CH2Cl2); IR (film) 3458, 2952, 2936, 2908, 2877,
1724, 1461, 1251, 1194, 1094, 1045, 1005, 836, 775, 735 cmꢀ1; 1H NMR
(400 MHz) δ 6.67 (d, J = 11.6 Hz, 1H), 6.42 (d, J = 11.6, 1H), 4.80 (dd,
J = 8.4, 2.0 Hz, 1H), 4.80 (dt, J = 5.6, 2.0 Hz, 1H), 3.59 (t, J = 4.4 Hz, 2H),
3.47 (s, 3H), 3.32ꢀ3.27 (m, 2H), 2.74ꢀ2.70 (m, 1H), 1.75ꢀ1.40 (m,
8H), 1.24 (s, 3H), 1.21 (d, J = 4.8 Hz, 3H), 1.21 (s, 3H), 0.90 (s, 9H),
0.88ꢀ0.85 (m, 12H), 0.11 (s, 3H), 0.10 (s, 3H), 0.08 (s,3H), 0.06 (s,
3H); 13C NMR (100 MHz) δ 175.8, 147.8, 84.3, 80.2, 78.9, 77.7, 77.4,
77.3, 63.3, 60.4, 44.6, 35.8, 34.9, 29.6, 26.2 (3C), 25.9 (3C), 24.5, 24.1,
23.2, 18.4, 18.0, 15.0, 10.6, ꢀ1.6, ꢀ1.7, ꢀ3.9, ꢀ4.5; HRMS (FAB) calcd
for C31H63IO7Si2 + Na 753.3055, found 753.3053.
7.30ꢀ7.14 (m, 5H), 4.65ꢀ4.60 (m, 1H), 4.17ꢀ4.10 (m, 2H), 4.07ꢀ4.04
(m, 1H), 3.82ꢀ3.79 (m, 2H), 3.63 (d, J = 1.2 Hz, 1H), 3.52 (t, J = 5.8 Hz,
2H), 3.46 (s, 3H), 3.25ꢀ3.20 (m, 2H), 2.71 (dd, J = 13.4, 9.4 Hz, 1H),
1.74ꢀ1.34 (m, 6H), 1.22 (d, J = 7.2 Hz, 3H), 1.19 (s, 3H), 0.83 (s, 9H),
0.80 (s, 9H), 0.05 (s, 6H), ꢀ0.01 (s, 6H); 13C NMR (100 MHz) δ 175.8,
153.1, 135.2, 129.4 (2C), 128.9 (2C), 127.3, 88.7, 78.7, 71.8, 66.0, 63.6,
60.7, 55.3, 43.0, 37.7, 36.3, 35.1, 34.2, 26.9, 26.0 (3C), 25.9 (3C), 24.1,
18.3, 11.4, ꢀ1.8, ꢀ1.8, ꢀ5.3; HRMS (FAB) calcd for C34H61NO7Si2 +
Na 674.3884, found 674.3868.
(2R,3S,5R,6R)-3,6,9-Tris((tert-butyldimethylsilyl)oxy)-5-meth-
oxy-2,6-dimethylnonanoic acid (30). To a stirred solution of aldol
28 (1.41 g, 2.16 mmol) in CH2Cl2 (15 mL) at 0 °C were added 2,6-
lutidine (0.41 g, 3.89 mmol) and TBSOTf (0.85 g, 3.24 mmol). The
reaction mixture was stirred for 15 min at 0 °C and quenched with satd
aq NaHCO3 (10 mL). The organic layer was separated, washed with
brine (10 mL), dried (Na2SO4), and filtered. The solvent was concen-
trated under reduced pressure, and the crude product dissolved in THF/
H2O (4:1, 31 mL). To this were added 30% aq H2O2 (1.14 mL, 10.07
mmol) and 0.8 M aq LiOH (4.6 mL, 3.65 mmol) at 0 °C. The reaction
was warmed to rt and stirred for 16 h. The reaction was quenched by
adding aq Na2SO3 (1.33 M, 10 mL) and aq NH4Cl solution (10 mL).
The reaction mixture was then diluted with EtOAc (40 mL). The
organic layer was separated, and the aqueous layer was back-extracted
with EtOAc (2 ꢁ 20 mL). The combined organic layers were washed
with brine (20 mL), dried (Na2SO4), and filtered. The solvent was
(2R,3S,5R,6R)-(3R,4S,E)-4-Hydroxy-6-iodo-4-methylhex-5-
en-3-yl 3,6-bis((tert-butyldimethylsilyl)oxy)-5-methoxy-2,6-
dimethyl-9-oxononanoate (33). DessꢀMartin periodinane (0.53
g, 0.31 mmol) and NaHCO3 (0.13 g, 1.57 mmol) were suspended in
CH2Cl2 (3 mL). Alcohol 32 (0.23 g, 0.31 mmol) in CH2Cl2 (3 mL) was
added dropwise via cannula into the reaction mixture. After 1 h at rt, the
reaction mixture was added to a mixture of satd aq NaHCO3 (5 mL),
7523
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The Journal of Organic Chemistry
ARTICLE
satd aq Na2SO3 (5 mL), and H2O (10 mL). The mixture was extracted
with Et2O (2 ꢁ 20 mL). The combined organic layers were washed with
brine (10 mL), dried (Na2SO4), and filtered. The solvent was concen-
trated under reduced pressure, and the residue was purified by flash
chromatography eluting with EtOAc/hexanes (0.4/1) to afford 0.18 g
(80%) of 33 as a foam. [R]23D +14.9° (c 0.75, CH2Cl2); IR (film) 2962,
2886, 2853, 1736, 1695, 1461, 1401, 1250, 1190, 1094, 1050 cmꢀ1; 1H
NMR (400 MHz) δ 9.8 (s, 1H), 6.67 (d, J = 14.4 Hz, 1H), 6.43 (d, J =
14.4 Hz, 1H), 4.81 (dd, J = 10.4, 2.8 Hz, 1H), 4.11 (dt, J = 6.8, 3.2 Hz,
1H), 3.47 (s, 3H), 3.21 (d, J = 9.6 Hz, 2.4, 1H), 3.11 (bs, 1H), 1.85ꢀ1.50
(m, 8H), 1.25 (s, 3H), 1.21 (d, J = 7.2 Hz, 3H), 1.21 (s, 3H), 0.90 (s,
9H), 0.89ꢀ0.85 (m, 12H), 0.12 (s, 3H), 0.11 (s, 3H), 0.08 (s, 3H), 0.04
(s, 3H); 13C NMR (100 MHz) δ 202.1, 175.7, 148.0, 84.1, 80.2, 78.4,
77.7, 71.1, 60.7, 44.5, 38.7, 35.2, 31.4, 26.1 (3C), 25.9 (3C), 24.6, 23.5,
23.1, 18.4, 18.0, 14.6, 10.7, ꢀ1.6, ꢀ1.8, ꢀ3.9, ꢀ4.6; HRMS (FAB) calcd
for C31H61IO7Si2 + Na 751.2898, found 751.2892.
(3R,4S,6R,7R,13S,14R,E)-4,7-Bis((tert-butyldimethylsilyl)-
oxy)-14-ethyl-10,13-dihydroxy-6-methoxy-3,7,13-trimethy-
loxacyclotetradec-11-en-2-one (34). To a solution of aldehyde
33 (0.20 g, 0.27 mmol) in DMSO (125 mL) at rt were added CrCl2
(0.33 g, 2.75 mmol) and NiCl2 (0.004 mg, 0.027 mmol). The reaction
was stirred for 16 h and quenched by the addition of H2O (60 mL). The
mixture was diluted with EtOAc (500 mL), and the layers were
separated. The organic layer was washed with H2O (3 ꢁ 50 mL). The
combined aqueous layers were back-extracted with EtOAc (3 ꢁ
200 mL). The combined organic layers were washed with brine (200 mL),
dried (Na2SO4), and filtered. The solvent was concentrated under
reduced pressure, and the residue was purified by flash chromatography
eluting with EtOAc/hexanes (1/2) to afford 0.06 g (dr = 1:1 at C9)
(50%) of 34 as a foam. IR (film) 3465, 2953, 2909, 1731, 1461, 1251,
1095, 1252, 1118, 1093, 1067 cmꢀ1; 1H NMR (400 MHz) δ 6.85 (d, J =
16.4 Hz, 1H), 6.19 (d, J = 16.4 Hz, 1H), 4.83 (dd, J = 10.8, 1.2 Hz, 1H),
4.33 (t, J = 8.4 Hz, 1H), 3.76 (dd, J = 9.6, 3.2 Hz, 1H), 3.23 (dt, J = 12.8,
3.5 Hz, 1H), 3.12 (s, 3H), 2.83 (bs, 1H), 2.46ꢀ2.38 (m, 1H), 1.99ꢀ1.90
(m, 2H), 1.81ꢀ1.52 (m, 5H), 1.33 (s, 3H), 1.19 (d, J = 8.0 Hz, 3H), 1.18
(s, 3H), 0.94 (t, J = 8.2 Hz, 9H), 0.89 (s, 9H), 0.86 (t, J = 7.2 Hz, 3H),
0.60 (q, J = 7.8 Hz, 6H), 0.13 (s, 3H), 0.04 (s, 3H); 13C NMR (100
MHz) δ 204.1, 175.7, 151.8, 127.7, 80.1, 78.9, 74.1, 73.2, 71.2, 49.0, 48.3,
44.7, 34.6, 31.1, 26.2, 21.9, 21.0, 19.7, 18.4, 16.1, 10.3, 6.7, 5.1, ꢀ3.0,
ꢀ4.8; HRMS (FAB) calcd for C31H62O7Si2 + Na 625.3932, found
625.3925
(5R,6R)-5-(2-(bBenzyloxy)ethyl)-3,3-diethyl-6,11,11,12,12-
pentamethyl-4,10-dioxa-3,11-disilatridecan-6-ol (36). To a
solution of diol 20 (1.0 g, 2.61 mmol) in DMF (26 mL) at 0 °C were
added imidazole (0.25 g, 3.65 mmol) and TESCl (0.47 g, 3.13 mmol).
The reaction mixture was warmed to rt. After 1.5 h, the reaction was
quenched by with H2O (40 mL). The aqueous layer was extracted with
ether (4 ꢁ 50 mL). The combined organic layers were washed with H2O
(50 mL) and brine (50 mL), dried (Na2SO4), and filtered. The solvent
was concentrated under reduced pressure, and the residue was purified
by flash chromatography eluting with EtOAc/hexanes (1/5) to afford
1.16 g (90%) of 36 as a colorless oil. [R]23D +7.7° (c 8.3, CH2Cl2); IR
(film) 3443, 2956, 2930, 2893, 2883, 2857, 1733, 1658, 1461, 1262,
1
1126, 1095, 1066, 1053, 1001, 835 cmꢀ1; H NMR (400 MHz) δ
7.29ꢀ7.18 (m, 5H), 4.43 (s, 2H), 3.61 (dd, J = 7.2, 3.6 Hz, 1H), 3.54 (t,
J = 6.4 Hz, 2H), 3.50ꢀ3.47 (m, 1H), 2.47(s, 1H), 1.88ꢀ1.80 (m, 1H),
1.65ꢀ1.36 (m, 5H), 1.02(s, 3H), 0.88 (t, J = 6.4 Hz, 9H), 0.82 (s, 9H),
0.55 (q, J = 7.6 Hz, 6H), ꢀ0.02 (s, 6H); 13C NMR (100 MHz) δ 138.3,
128.3 (2), 127.6 (2), 127.5, 76.0, 74.1, 72.9, 67.3, 63.8, 34.9, 33.1, 26.8,
25.9 (3C), 21.8, 18.2, 6.9 (3C), 5.2 (3C), ꢀ5.3 (2C); HRMS (FAB)
calcd for C27H52O4Si2 + Na 519.3302 found 519.3286.
(R)-8-((R)-3-(Benzyloxy)-1-methoxypropyl)-10,10-diethyl-
2,2,3,3,8-pentamethyl-4,9-dioxa-3,10-disiladodecane (37).
To a solution of 36 (0.50 g, 1.00 mmol) in THF (10 mL) was added
MeI (2.01 g, 32.65 mmol), and the reaction mixture was cooled to 0 °C.
Sodium hydride (0.78 g, 32.65 mmol) was then added in small portions.
The reaction mixture was allowed to warm to rt and stirred for 16 h. The
reaction mixture was quenched by adding MeOH (3 mL) followed by
H2O (5 mL) at 0 °C. The reaction mixture was diluted with Et2O
(15 mL), and the aqueous layer was back-extracted with Et2O (2 ꢁ
5 mL). The combined organic layers were washed with brine (5 mL),
dried (Na2SO4), and filtered. The solvent was concentrated under
reduced pressure, and the residue was purified by flash chromatography
eluting with EtOAc/hexanes (0.4:1) to afford 0.4 g (78%) of 37 as a
colorless oil. [R]23D +8.4° (c 3.8, CH2Cl2); IR (film) 2880, 1475, 1422,
1361, 1055, 733, 696 cmꢀ1; 1H NMR (400 MHz) δ 7.35ꢀ7.26 (m, 5H),
4.54 (d, J = 12.0 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H), 3.61ꢀ3.55 (m, 4H),
3.42 (s, 3H), 3.17 (dd, J = 10.4, 2.4 Hz, 1H), 1.93ꢀ1.89 (m, 1H),
1.65ꢀ1.39 (m, 5H), 1.20 (s, 3H), 0.95 (t, J = 8 Hz, 9H), 0.89 (s, 9H),
0.59 (q, J = 8 Hz, 6H), 0.04 (s, 6H); 13C NMR (100 MHz) δ 138.6,
128.3 (2C), 127.6 (2C), 127.4, 84.6, 78.2, 72.8, 67.8, 63.7, 60.8, 35.4,
30.8, 27.0, 26.0 (3C), 24.2, 18.3, 7.2 (3C), 6.9 (3C), ꢀ5.3 (2C); HRMS
(FAB) calcd for C28H54O4Si2 + Na 533.3458, found 533.3455.
(8R,9R)-9-(2-(bBenzyloxy)ethyl)-11,11-diethyl-8-methoxy-
2,2,3,3,8-pentamethyl-4,10-dioxa-3,11-disilatridecane (38).
To a solution of 36 (9.08 g, 18.29 mmol) in CH2Cl2 (90 mL) at 0 °C
were added proton sponge (11.74 g, 54.87 mmol) and Me3OBF4 (8.11 g,
54.87 mmol). The reaction mixture was warmed to rt and stirred for
16 h. The reaction mixture was concentrated and quenched with satd aq
NH4Cl (50 mL). The reaction mixture was diluted with Et2O (100 mL),
and the aqueous layer was back-extracted with Et2O (2 ꢁ 50 mL). The
combined organic layers were washed with 1 N aq HCl solution (60 mL),
satd aq NaHCO3 (80 mL), H2O (80 mL), and brine (50 mL), dried
(Na2SO4), and filtered. The solvent was concentrated under reduced
pressure, and the residue was purified by flash chromatography eluting
with EtOAc/hexanes (1/25) to afford 7.4 g (80%) of 38 as an oil.
[R]23D = +11.5° (c 2.6,CH2Cl2); IR (film) 1255, 1361, 1471, 2857, 2953,
3398, 1096, 899, 733, 696 cmꢀ1; 1H NMR (400 MHz) δ 7.27ꢀ7.20 (m,
5H), 4.45 (d, J = 12.0 Hz, 1H), 4.41 (d, J = 12.0 Hz, 1H), 3.74 (dd, J = 9.8,
2.2 Hz, 2H), 3.54ꢀ3.48 (m, 4H), 3.07 (s, 3H), 1.84ꢀ1.76 (m, 1H),
1.60ꢀ1.28 (m, 4H), 0.98 (s, 3H), 0.88ꢀ0.84 (m, 9H), 0.83 (s, 9H),
0.55ꢀ0.49 (m, 6H), ꢀ0.02 (s, 6H); 13C NMR (100 MHz) δ 138.6, 128.3
(2C), 127.6 (2C), 127.4, 78.8, 73.7, 72.9, 67.9, 63.5, 48.7, 32.7, 29.9, 26.0,
25.9 (3C), 18.2, 18.0, 7.1 (3C), 5.3 (3C), ꢀ5.3 (2C); HRMS (FAB) calcd
for C28H54O4Si2 + Na 533.3458, found 533.3445.
(3R,4S,6R,7R,13S,14R,E)-4,7-Bis((tert-butyldimethylsilyl)oxy)-
14-ethyl-13-hydroxy-6-methoxy-3,7,13-trimethyloxacyclo-
tetradec-11-ene-2,10-dione (35). DessꢀMartin periodinane
(0.07 g, 0.15 mmol) was added to alcohol 34 (0.03 g, 0.05 mmol) in
CH2Cl2 (5 mL) and pyridine (0.15 mL). After 1 h at rt, the reaction
mixture was added to a mixture of satd aq NaHCO3 (5 mL), satd aq
Na2SO3 (5 mL), and H2O (10 mL). The mixture was extracted with
Et2O (2 ꢁ 20 mL). The combined organic layers were washed with brine
(10 mL), dried (Na2SO4), and filtered. The solvent was concentrated
under reduced pressure, and the residue was purified by flash chroma-
tography eluting with EtOAc/hexanes (1.2/1) to afford 0.024 g (82%)
of 35 as a white solid (mp = 192ꢀ195 °C); [R]23 +6.7° (c 2.7,
D
CH2Cl2); IR (film) 3443, 2956, 2930, 2893, 2883, 2857, 1733, 1658,
1
1461, 1262, 1126, 1095, 1066, 1053, 1001, 835 cmꢀ1; H NMR (400
MHz) δ 7.08 (d, J = 16.4 Hz, 1H), 6.14 (d, J = 16.4 Hz, 1H), 4.77 (dd, J =
10.0, 2.8 Hz, 1H), 4.05 (dd, J = 10.0, 6.8 Hz, 1H), 3.46 (s, 3H),
3.40ꢀ3.31 (m, 2H), 3.02ꢀ2.95 (m, 1H), 2.52 (bs, 1H), 2.09ꢀ1.52 (m,
10H), 1.34 (s, 3H), 1.30 (s, 3H), 1.25 (d, J = 6.8 Hz, 3H), 0.95ꢀ0.89 (m,
12H), 0.80 (s, 3H), 0.07 (s, 3H), 0.07 (m, 6H), 0.05 (s, 3H); 13C NMR
(100 MHz) δ 203.7, 176.2, 152.5, 127.5, 86.6, 77.3, 76.6, 73.7, 71.7, 59.8,
45.4, 44.7, 34.8, 33.7, 32.7, 26.0 (6C), 25.5, 22.4, 21.5, 18.1, 17.4, 10.6,
ꢀ1.7, ꢀ1.8, ꢀ3.9, ꢀ4.6; HRMS (FAB) calcd for C31H60O7Si2 + Na
623.3775 found 623.3736.
7524
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The Journal of Organic Chemistry
ARTICLE
(2R,3S,5R,6R)-(3R,4S,E)-4-Hydroxy-6-iodo-4-methylhex-5-
en-3-yl 3,9-bis((tert-butyldimethylsilyl)oxy)-6-methoxy-2,6-
dimethyl-5-((triethylsilyl)oxy)nonanoate (44). To a solution of
acid 43 (0.60 g, 0.98 mmol) in THF (10 mL) at rt were added Et3N (0.1
g, 1.03 mmol) and 2,4,6-trichlorobenzoyl chloride (0.26 g, 1.08 mmol).
The reaction mixture was stirred for 3 h at rt, and the solids were filtered
and washed with hexanes (20 mL). The combined filtrates were
concentrated under reduced pressure, dried under vacuum, and dis-
solved in toluene (15 mL). To this solution were added diol 8 (0.26 g,
0.98 mmol) in toluene (5 mL) and DMAP (0.16 g, 1.33 mmol). After
stirring for 16 h at rt, the reaction mixture was diluted with EtOAc
(50 mL), washed with satd aq NaHCO3 (20 mL), dried (Na2SO4), and
filtered. The solvent was evaporated under reduced pressure, and the
residue was purified by flash chromatography eluting with EtOAc/
hexanes (1/5) to afford 0.28 g (78% yield) of 46 as a colorless oil. [R]23
D
+32.8° (c 0.7, CH2Cl2); IR (film) 2952, 2879, 2877, 1733, 1684, 1463,
1411, 1379, 1250, 1190, 1094, 1050 cmꢀ1; 1H NMR (400 MHz) δ 9.76
(m, 1H), 6.55 (d, J = 14.4 Hz, 1H), 6.41 (d, J = 14.4 Hz, 1H), 4.78 (dd,
J = 10.0, 3.2 Hz, 1H), 4.44 (dt, J = 8.8, 3.6 Hz, 1H), 3.59 (dd, J = 9.6, 2.4
Hz, 1H), 3.10 (s, 3H), 2.67 (dq, J = 4.8, 2.4 Hz, 1H), 2.53ꢀ2.35 (m, 3H),
1.99ꢀ1.91 (m, 1H), 1.77ꢀ1.47 (m, 6H), 1.24 (s, 3H), 1.17 (d, J = 7.2
Hz, 3H), 1.08 (s, 3H), 0.95 (t, J = 8.4 Hz, 9H), 0.87ꢀ0.85 (m, 12H),
0.66ꢀ0.55 (m, 6H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz) δ
202.1, 174.8, 147.6, 80.1, 78.6, 77.5, 77.2, 73.4, 69.8, 48.8, 43.3, 38.0,
37.6, 25.8 (3C), 25.6, 24.9, 22.7, 18.1, 17.7, 10.6, 10.2, 7.1 (3C), 5.4
(3C), ꢀ3.9, ꢀ4.6; HRMS (FAB) calcd for C31H61IO7Si2 + Na 751.2898
found 751.2892.
(3R,4S,6R,7R,13S,14R,E)-4-((tert-Butyldimethylsilyl)oxy)-14-
ethyl-10,13-dihydroxy-7-methoxy-3,7,13-trimethyl-6-((triethyl-
silyl)oxy)oxacyclotetradec-11-en-2-one (47). To a solution of
aldehyde 46 (0.28 g, 0.27 mmol) in DMSO (158 mL) at rt were added
CrCl2 (0.47 g, 3.84 mmol) and NiCl2 (0.005 mg, 0.038 mmol). The
reaction mixture was stirred for 16 h and then quenched by the addition
of H2O (90 mL). The mixture was diluted with EtOAc (600 mL), and
the layers were separated. The organic layer was washed with H2O (3 ꢁ
100 mL). The combined aqueous layers were back-extracted with
EtOAc (3 ꢁ 200 mL). The combined organic layers were washed with
brine (200 mL), dried (Na2SO4), and filtered. The solvent was
concentrated under reduced pressure, and the residue was purified by
flash chromatography eluting with EtOAc/hexanes (2/5) to afford
0.12 g (dr = 1:1 at C9) (50%) of 47 as a foam. IR (film) 3443, 2953,
2936, 2909, 2878, 1731, 1461, 1251, 1095, 1057, 1005, 972, 854, 831,
815, 774 cmꢀ1; 1H NMR (400 MHz) δ 5.75ꢀ5.60 (m, 2H), 4.81 (td, J =
10.6, 2.0 Hz, 1H), 4.30ꢀ4.12 (m, 1H), 4.07ꢀ3.98 (m, 1H), 3.14 (s, 3H),
2.69ꢀ2.46 (m, 2H), 2.19ꢀ1.73 (m, 2H), 1.53ꢀ133 (m, 4H), 1.29ꢀ1.26
(m, 3H), 1.21ꢀ1.16 (m, 3H), 1.12 ꢀ1.03 (m, 3H), 0.97ꢀ0.89 (m,
12H), 0.87ꢀ0.84 (s, 9H), 0.64ꢀ0.53 (m, 6H), 0.10ꢀ0.01 (m, 6H); 13C
NMR (100 MHz) δ 175.7, 175.3, 136.2, 133.7, 133.2, 132.4, 80.3, 79.6,
79.4, 79.3, 74.4, 73.9, 73.7, 73.4, 72.9, 72.6, 70.5, 70.3, 48.7, 48.3, 42.5,
40.4, 30.6, 30.5, 29.6, 27.5, 26.1, 25.8, 23.3, 22.1, 20.6, 19.1, 18.3, 18.0,
17.4, 15.5, 15.0, 10.6, 10.6, 7.1, 7.0, 5.3, 5.1, ꢀ3.4,-4.1,-4.8, ꢀ5.0; HRMS
(FAB) calcd for C31H62O7Si2 + Na 625.3932, found 625.3911.
(1R,3S,4R,7R,8S,14R,E)-3-((tert-Butyldimethylsilyl)oxy)-7-
ethyl-8,11-dihydroxy-14-methoxy-4,8,14-trimethyl-6,15-di-
oxabicyclo[9.3.1]pentadec-9-en-5-one (53). To a solution of 48
(0.030 g, 0.05 mmol) in MeOH (7 mL) was added p-TsOH (2 mg, 0.01
mmol) at 0 °C. After 3 h at this temperature, the reaction was quenched
by adding satd aq NaHCO3 (5 mL). The reaction mixture was diluted
with EtOAc (20 mL), and the aqueous layer was back-extracted with
EtOAc (2 ꢁ 5 mL). The combined organic layers were washed with
brine (10 mL), dried (Na2SO4), and filtered. The solvent was concen-
trated under reduced pressure and purified directly by flash chromatog-
raphy eluting with hexanes/EtOAc (4:1) to afford 12 mg (52%) of 53 as
hexanes (0.4/1) to afford 0.68 g (75%) of 44 as a colorless oil. [R]23
D
+27.4° (c 0.7, CH2Cl2); IR (film) 3460, 2951, 2933, 2878, 1732, 1471,
1462, 1381, 1254, 1199, 1095, 1073, 1044, 1005, 949, 834, 774,
736 cmꢀ1; 1H NMR (400 MHz) δ 6.54 (d, J = 14.4 Hz, 1H), 6.41 (d,
J = 14.4, 1H), 4.78 (dd, J = 9.6, 3.2 Hz, 1H), 4.48 (dt, J = 9.6, 3.2 Hz, 1H),
3.60ꢀ3.55 (m, 3H), 3.10 (s, 3H), 2.67ꢀ2.62 (m, 1H), 2.33 (bs, 1H),
1.79ꢀ1.34 (m, 8H), 1.23 (s, 3H), 1.17 (d, J = 6.8 Hz, 3H), 1.02 (s, 3H),
0.94 (t, J = 8 Hz, 9H), 0.88ꢀ0.86 (m, 12H), 0.84 (s, 9H), 0.66ꢀ0.55 (m,
6H), 0.06 (s, 3H), 0.03 (s, 6H); 13C NMR (100 MHz) δ 175.0, 147.6,
80.0, 79.0, 77.6, 77.2, 73.6, 69.6, 63.2, 48.3, 42.7, 37.3, 29.4, 26.0, 25.9
(6C), 25.2, 22.6, 18.2, 18.0, 17.4, 10.6, 9.6, 7.2 (3C), 5.4 (3C), ꢀ3.8,
ꢀ4.6, ꢀ5.4 (2C); HRMS (FAB) calcd for C37H77IO7Si3 + Na 867.3920
found 867.3900.
(2R,3S,5R,6R)-(3R,4S,E)-4-Hydroxy-6-iodo-4-methylhex-5-
en-3-yl 3-((tert-butyldimethylsilyl)oxy)-9-hydroxy-6-meth-
oxy-2,6-dimethyl-5-((triethylsilyl)oxy)nonanoate (45). To a
solution of TBAF 3H2O (0.90 g, 2.86 mmol) in DMF (28 mL) was
3
added AcOH (0.70 g, 2.01 mmol). After 30 min of stirring, the solution
was added to 44 (0.68 g, 0.95 mmol), and the reaction mixture was
stirred for 20 h at rt. The reaction was quenched with H2O (20 mL), and
the aqueous layer was back-extracted with Et2O (4 ꢁ 60 mL). The
combined organic layers were washed with satd aq NaHCO3 (50 mL),
H2O (50 mL), and brine (50 mL), dried (Na2SO4), and filtered. The
solvent was concentrated under reduced pressure, and the residue was
purified by flash chromatography eluting with EtOAc/hexanes (1/5) to
afford 0.35 g (60%) of 45 as a colorless oil. [R]23 +30.8° (c 0.6,
D
CH2Cl2); IR (film) 3458, 2951, 2936, 2909, 2877, 1729, 1461, 1251,
1192, 1095, 1069, 1044, 1004, 950, 940, 836, 775 cmꢀ1; 1H NMR (400
MHz) δ 6.55 (d, J = 14.4 Hz, 1H), 6.41 (d, J = 14.4, 1H), 4.77 (dd, J =
10.0, 3.2 Hz, 1H), 4.45 (dt, J = 9.6, 3.2 Hz, 1H), 3.66 (dd, J = 10.4, 2.0 Hz,
1H), 3.62ꢀ3.58 (m, 2H), 3.14 (s, 3H), 2.67 (dq, J = 4.8, 2.4 Hz, 1H),
2.55 (bs, 1H), 2.03 (m, 1H), 1.82ꢀ1.42 (m, 8H), 1.23 (s, 3H), 1.18 (d,
J = 7.2 Hz, 3H), 1.05 (s, 3H), 0.94 (t, J = 8.0 Hz, 9H), 0.86ꢀ0.84 (m,
12H), 0.66ꢀ0.55 (m, 6H), 0.77 (s, 3H), 0.05 (s, 3H); 13C NMR (100
MHz) δ 175.0, 147.6, 80.1, 79.3, 77.5, 77.3,73.5, 69.8, 63.2, 48.6, 43.4,
37.7, 30.2, 26.2, 25.9 (3C), 24.9, 22.7, 18.1, 17.4, 10.6, 10.3, 7.1 (3C), 5.4
(3C), ꢀ3.9, ꢀ4.7; HRMS (FAB) calcd for C31H63IO7Si2 + Na 753.3055
found 753.3032.
a foam. [R]23 +10.7° (c 0.8, CH2Cl2); IR (film) 3441, 2954, 2934,
D
2882, 1729, 1461, 1374, 1264, 1178, 1145, 1072, 1006, 961, 834, 775,
702 cmꢀ1; 1H NMR (400 MHz) δ 6.07 (d, J = 16.4 Hz, 1H), 5.95 (d, J =
16.4 Hz, 1H), 4.85 (t, J = 3.6 Hz, 1H), 4.54 (dd, J = 11.2, 2.4 Hz, 1H),
4.29 (d, J = 9.6 Hz, 1H), 3.94ꢀ3.90 (m, 1H), 3.21 (s, 3H), 2.90ꢀ2.82
(m, 1H), 2.06ꢀ1.95 (m, 3H), 1.85ꢀ1.71 (m, 2H), 1.57ꢀ1.46 (m, 2H),
2.59 (bs, 2H), 1.30 (s, 3H), 1.27 (d, J = 6.8 Hz, 3H), 1.27 (s, 3H), 0.88 (t,
J = 7.2 Hz, 3H), 0.90 (s, 9H), 0.08 (s, 3H), 0.05 (s, 3H); 13C NMR (100
MHz) δ 175.4, 146.1, 136.3, 122.8, 102.9, 83.2, 74.7, 73.6, 71.7, 70.9,
49.1, 44.4, 31.3, 29.3, 25.9 (3C), 21.6, 21.2, 18.0, 16.4, 10.5, ꢀ4.1, ꢀ4.7;
HRMS (FAB) calcd for C25H46O7Si + K 525.2650, found 525.2667.
(3R,4S,6R,7R,13S,14R,E)-14-Ethyl-4,6,13-trihydroxy-7-meth-
oxy-3,7,13-trimethyloxacyclotetradec-11-ene-2,10-dione (54).
To a solution of 48 (34 mg, 0.05 mmol) in THF (2.2 mL) was added
(2R,3S,5R,6R)-(3R,4S,E)-4-Hydroxy-6-iodo-4-methylhex-5-
en-3-yl 3-((tert-butyldimethylsilyl)oxy)-6-methoxy-2,6-dimeth-
yl-9-oxo-5-((triethylsilyl)oxy)nonanoate (46). DessꢀMartin
periodinane (0.23 g, 0.54 mmol) and NaHCO3 (0.19 g, 2.25 mmol)
were suspended in CH2Cl2 (3 mL). Alcohol 45 (0.33 g, 0.45 mmol) in
CH2Cl2 (4 mL) was added dropwise via cannula into the reaction
mixture. After 1 h at rt, the reaction mixture was added to a mixture of
satd aq NaHCO3 (5 mL), satd aq Na2SO3 (5 mL), and H2O (10 mL).
The mixture was extracted with Et2O (2 ꢁ 20 mL). The combined
organic layers were washed with brine (10 mL), dried (Na2SO4), and
filtered. The solvent was concentrated under reduced pressure, and the
residue was purified by flash chromatography eluting with EtOAc/
TBAF 3H2O (54 mg, 0.17 mmol) at 0 °C, and the mixture was allowed to
3
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dx.doi.org/10.1021/jo201319b |J. Org. Chem. 2011, 76, 7516–7527

The Journal of Organic Chemistry
ARTICLE
slowly warm to 10 °C and stirred for 6 h. The reaction mixture was
quenched by slowly adding satd aq NaHCO3 (3 mL). The mixture was
diluted with EtOAc (5 mL), and the aqueous layer was extracted with
EtOAc (2 ꢁ 5 mL). The combined organic layers were washed with brine
(10mL), dried(Na2SO4), and filtered. The solvent was concentrated under
reduced pressure, and the residue was purified by flash chromatography
eluting with EtOAc/hexanes (3:2) to afford 13 mg of 54 (70%) as a foam.
aluminum foil, warmed to rt, and stirred for an additional 20 h. The
reaction was quenched with Et3N (4.0 mL), filtered through Celite, and
eluted with EtOAc (50 mL). The filtrate was washed with satd aq
NaHCO3 (20 mL), dried (Na2SO4), filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
eluting with hexanes/EtOAc (3:2) to afford 42% of 57 as a foam (dr =
7:1 dr at C9 by 1H NMR). Major 9-(R) isomer: IR (film) 3441, 2956,
2878, 1727, 1462, 1372, 1265, 1178, 1093 cmꢀ1; 1H NMR (400 MHz) δ
5.80 (m, 1H), 5.48 (d, J = 16.4 Hz, 1H), 5.15 (dd, J = 10.0, 1.6 Hz, 1H),
4.55 (dd, J = 10.4, 7.6 Hz, 1H), 4.48 (d, J = 7.6 Hz, 1H), 3.96ꢀ3.93 (m,
2H), 3.77 (s, 3H), 3.72ꢀ3.68 (m, 1H), 3.47ꢀ3.43(m, 1H), 3.18 (s, 3H),
2.75ꢀ2.56 (m, 2H), 2.27 (m, 9H), 2.33ꢀ2.30 (m, 1H), 1.26 (s, 3H),
1.21 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 6.0 Hz, 3H), 1.04 (s, 3H), 0.95 (t, J =
8.0 Hz, 9H), 0.88 (s, 9H), 0.85 (t, J = 11.4 Hz, 3H), 0.62ꢀ0.52 (m, 6H),
0.12 (s, 3H), 0.10 (s, 3H); 13C NMR (100 MHz) δ 174.3, 153.3, 135.8,
131.2, 96.6, 79.7, 78.7, 77.8, 75.1, 73.9, 73.6, 73.0, 68.8, 63.0, 54.6, 49.1,
48.6, 40.6 (2C), 37.7, 31.7, 30.8, 29.6, 28.1, 25.8(3C), 22.9, 21.2, 20.6,
18.0, 15.6, 10.6, 6.9 (3C), 5.0 (3C), ꢀ4.2, ꢀ4.4; HRMS (FAB) calcd for
C41H79NO11Si2 + Na 840.5089, found 840.5081.
[R]23 +3.5° (c 0.9, CH2Cl2); IR (film) 3441, 2956, 2878, 1727, 1462,
D
1372, 1265, 1178, 1093 cmꢀ1; 1H NMR (400 MHz) δ 6.74 (d, J = 16.0 Hz,
1H), 6.19 (d, J = 16.0 Hz, 1H), 4.87 (dd, J = 10.8, 2.4 Hz, 1H), 4.00 (t, J =
8.8 Hz, 1H), 3.86 (dd, J = 10.8, 2.4 Hz, 1H), 3.72 (bs, 1H), 3.20 (s, 3H),
2.88 (bs, 1H), 2.65ꢀ2.53 (m, 3H), 2.31ꢀ2.23 (m, 1H), 12.95ꢀ1.84 (m,
2H), 1.74ꢀ1.46 (m, 5H), 1.33 (s, 3H), 1.30 (d, J = 6.8 Hz, 3H), 1.01 (s,
3H), 0.91 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz) δ 202.2, 175.9, 150.4,
128.3, 79.9, 78.7, 73.8, 73.2, 48.9, 46.8, 37.1, 33.5, 30.6, 22.0, 21.8, 20.8, 16.2,
14.1, 10.4; HRMS (FAB) calcd for C19H32O7 + Na 395.2046 found
395.2024.
(3R,4S,6R,7R,10R,13S,14R,E)-4-((tert-Butyldimethylsilyl)oxy)-
14-ethyl-6,10,13-trihydroxy-7-methoxy-3,7,13-trimethylox-
acyclotetradec-11-en-2-one (55). To a solution of 48 (0.075 g,
0.12 mmol) in MeOH (3 mL) at rt was added CeCl3 7H2O (53 mg,
’ ASSOCIATED CONTENT
3
0.14 mmol). The reaction mixture was cooled to ꢀ60 °C after which
NaBH4 (5.3 mg, 0.14 mmol) was added. After 30 min at this tempera-
ture, the reaction was quenched by adding satd aq NH4Cl (2 mL). Ethyl
acetate (10 mL) was added, and the aqueous layer was back-extracted
with EtOAc (2 ꢁ 5 mL). The combined organic layers were washed with
1 N HCl solution (5 mL), satd aq NaHCO3 (5 mL), H2O (5 mL), and
brine (5 mL), dried (Na2SO4), and filtered. The solvent was concen-
trated under reduced pressure, and the residue was dried under vacuum.
The residue was dissolved in MeOH (17 mL) and cooled to 0 °C after
which p-TsOH (4.5 mg, 0.024 mmol) was added. The reaction mixture
was stirred at 0 °C for 3 h after which the reaction was quenched by
adding NaHCO3 (10 mg). The mixture was concentrated and purified
directly by flash chromatography eluting with EtOAc/hexanes (2/5) to
afford 44 mg of 55 (75%) as a foam (dr = 7:1 dr at C9 by 1H NMR).
Major 9-(R) isomer: IR (film) 3441, 2956, 2878, 1727, 1462, 1372, 1265,
1178, 1093 cmꢀ1; 1H NMR (400 MHz) δ 5.90ꢀ5.84 (m, 1H), 5.71 (m,
1H), 4.87ꢀ4.84 (m, 1H), 4.13ꢀ4.04 (m, 2H), 3.75ꢀ3.73 (m, 1H), 3.20
(s, 3H), 2.80ꢀ2.70 (m, 2H), 2.52 (bs, 1H), 2.13 (bs, 1H), 2.02ꢀ1.96
(m, 1H), 1.83ꢀ1.42 (m, 5H), 1.30 (s, 3H), 1.22 (m, 1H), 1.26 (s, 3H),
1.22 (d, J = 6.4 Hz, 3H), 1.07 (s, 3H), 0.93 (t, J = 7.2 Hz, 3H), 0.87 (s,
9H), 0.10 (s, 6H); 13C NMR (100 MHz) δ 175.4, 133.7, 133.2, 81.5,
78.6, 73.9, 72.6, 72.1, 71.7, 49.4, 48.0, 37.2, 31.0, 29.6, 27.6, 25.8 (3C),
24.5, 23.5, 17.5, 15.1, 10.8, ꢀ4.6, ꢀ4.7; HRMS (FAB) calcd for
C25H48O7Si + Na 511.3067, found 511.3042.
(2S,3R,4R,6S)-2-(((2R,3S,6R,9R,10R,12S,13R,E)-12-((tert-Butyl-
dimethylsilyl)oxy)-2-ethyl-10-hydroxy-9-methoxy-3,9,13-tri-
methyl-14-oxo-6-((triethylsilyl)oxy)oxacyclotetradec-4-en-3-
yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl
Methyl Carbonate (57). To a solution of 55 (70 mg, 0.14 mmol) in
DMF (1.5 mL) and CH2Cl2 (1.5 mL) at rt were added imidazole (12
mg, 0.16 mmol) and DMAP (2 mg). The reaction mixture was cooled to
ꢀ78 °C, and TESCl (25 mg, 0.15 mmol) was added. After stirring for 3 h
at ꢀ78 °C the reaction was quenched by adding satd aq NH4Cl (3 mL).
The mixture was diluted with EtOAc (10 mL), and the aqueous layer was
back-extracted with EtOAc (2 ꢁ 5 mL). The combined organic layers
were washed with H2O (5 mL), dried (Na2SO4), and filtered. The
solvent was concentrated under reduced pressure and azeotroped with
toluene (5 mL), and the crude alcohol was taken to the next step. To a
suspension of freshly activated 4 Å molecular sieves (1.55 g) and AgOTf
(0.72 g, 2.82 mmol) in CH2Cl2/toluene (5 mL, 1:1) was added dropwise
by cannula a mixture of C5 alcohol (0.14 mmol), desosamine donor 7
(0.28 g, 0.85 mmol), and 2,6-di-tert-butyl-4-methylpyridine (0.18 g, 0.85
mmol) in CH2Cl2 (2.5 mL) at 0 °C. The reaction flask was wrapped with
S
Supporting Information. General experimental proce-
b
dures and NMR spectra (1H and 13C) for 24, 25, 28, 30ꢀ38,
44ꢀ47, 53ꢀ55, and 57; crystallographic details of 35; complete
structural assignments (2D NMR analysis) of 62. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: randrade@temple.edu.
’ ACKNOWLEDGMENT
We thank Dr. Richard Pederson (Materia, Inc.) for catalyst
support. Finally, this work was supported by the NIH (AI080968).
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