Total synthesis of (+)-mupirocin H from d-glucose

Article abstract of DOI:10.1021/jo200396q

Enantioselective total synthesis of mupirocin H is accomplished starting from d-glucose featuring strategic application of d-glucose derived chirality, diastereoselective Still-Barrish hydroboration, and further elaboration of carbon chain to furnish a phenyltetrazolyl sulfone intermediate, which on coupling with (2S,3S)-2-methyl-3-(triisopropylsilyloxy)butanal under Julia-Kocienski olefination conditions gave an advanced E-olefinic intermediate selectively. The E-olefin was transformed to the 4-hydroxynitrile, a prefinal substrate, which on acid-catalyzed oxidative lactonization furnished the target molecule mupirocin H in 19 steps from known compound 6 (longest linear sequence) with an overall yield of 4.96%.

Full text of DOI:10.1021/jo200396q

NOTE
pubs.acs.org/joc
Total Synthesis of (+)-Mupirocin H from D-Glucose†
Sandip P. Udawant‡ and Tushar Kanti Chakraborty*,§
‡CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India
§CSIR-Central Drug Research Institute, Lucknow 226001, India
S Supporting Information
b
ABSTRACT: Enantioselective total synthesis of mupirocin H is accomplished
starting from D-glucose featuring strategic application of D-glucose derived
chirality, diastereoselective StillÀBarrish hydroboration, and further elaboration
of carbon chain to furnish a phenyltetrazolyl sulfone intermediate, which on
coupling with (2S,3S)-2-methyl-3-(triisopropylsilyloxy)butanal under JuliaÀ
Kocienski olefination conditions gave an advanced E-olefinic intermediate
selectively. The E-olefin was transformed to the 4-hydroxynitrile, a prefinal
substrate, which on acid-catalyzed oxidative lactonization furnished the target
molecule mupirocin H in 19 steps from known compound 6 (longest linear
sequence) with an overall yield of 4.96%.
upirocin, a naturally occurring metabolite isolated from
Pseudomonas fluorescens (a soil isolate, NCIB 10586)
M
proved highly efficient in treatment of skin infections and one
of the most successful topical antibiotics for eradication of nasal
Staphylococcus aureus including methicillin-resistant Staphylococ-
cus aureus (MRSA).1 Mupirocin is a mixture of pseudomonic
acids2 with principal constituent pseudomonic acid A accounting
for 90%, and the other components present are pseudomonic
acids B, C, and D shown in Figure 1. Structural complexity
and important biological activities of these pseudomonic acids
attracted synthetic organic chemists resulting in many total
syntheses of these molecules.3 Studies on biosynthesis of pseu-
domonic acids from Pseudomonas fluorescens and its biosynthetic
gene cluster resulted in isolation of novel pseudomonic acid
analogues mupirocin W4 (1) and mupirocin H5 (2), among
which 1 has shown moderate bioactivity similar to those of earlier
reported pseudomonic acids. Despite excellent antibiotic proper-
ties of mupirocin, it is associated with poor metabolic stability
and poor bioavailability restricting it to be used as topical
antibiotic. Moreover emerging resistance to mupirocin is also a
matter of serious concern.6 In this scenario, development of
better alternatives to mupirocin is significant that led us to
perform total synthesis of mupirocin H. The versatility of the
present route lies in the fact that three out of its six chiral centers
are derived from D-glucose followed by late-stage introduction of
its trans double bond making this pathway useful for total
synthesis of many other structurally similar molecules like
pseudomonic acids and analogues, mupirocin W, antibiotic
thiomarinols,7 and their analogues for biological evaluations.
The common core for all these molecules, shown in red in
Figure 1, can be derived using the present strategy.
Figure 1. Chemical structures of pseudomonic acids, selected thiomar-
inols, and mupirocin W, H having a common core, shown in red, which
could be derived using the present strategy.
Our retrosynthetic analysis is illustrated in Scheme 1. We
planned to generate the γ-lactone functionality in the final step
of our synthesis by acid-catalyzed oxidative lactonization of
4-hydroxynitrile moiety 3, whose E-olefinic linkage suggested
Received: March 4, 2011
Published: June 27, 2011
r
2011 American Chemical Society
6331
dx.doi.org/10.1021/jo200396q J. Org. Chem. 2011, 76, 6331–6337
|

The Journal of Organic Chemistry
NOTE
Scheme 1. Retrosynthetic Analysis of Mupirocin H (2)
Scheme 2. Synthesis of Sulfone 4
disconnection of double bond to JuliaÀKocienski olefination
precursors, sulfone 4, and aldehyde 7. Further simplification of 4
via StillÀBarrish hydroboration, one-carbon homologation,
Mitsunobu reaction, and peroxide oxidation resulted in terminal
alkene precursor 5, which could easily be resourced from D-
glucose-derived known alcohol 6. On the other hand, aldehyde 7
was planned to be derived from another known alcohol 8.
To synthesize sulfone 4, as depicted in Scheme 2, we began
with D-glucose which was transformed into alcohol 6 using a
known procedure.8 This alcohol 6 was subjected to Swern
oxidiation9 conditions to give the corresponding keto intermedi-
ate which under one-carbon Wittig olefination10 conditions
afforded the olefin 9 in 72% yield. Treatment of 9 with 50%
aqueous TFA followed by LiBH4 reduction afforded triol 10,
which was subjected to selective TBDPS protection to give 11 in
75% yield over three steps. Compound 11 on treatment with 2,2-
dimethoxypropane in presence of CSA (cat.) gave the terminal
alkene 5, the StillÀBarrish hydroboration precursor, in 95%
yield. Thus, 5 on treatment with 9-borabicyclononane (9-BBN)
in dry THF at 0 °C followed by treatment with H2O2 and NaOH
gave 12 as a single diastereomer in 85% yield.11
In the course of the above hydroboration reaction, steric
bulkiness of the boron ligand in 9-BBN oriented the reagent to
such a face of the alkene 5, which ensured minimum interactions
with allylic hydroxyl (here protected as its acetonide) group of
alkene 5, thereby imparting maximum stability to that transition
state (TS). The above facial bias can be explained using the
Houk12 rationale for two possible TSs as depicted in Figure 2.13
As seen in TS-2, the allylic acetonide protected hydroxyl group of
alkene and the boron ligands are in eclipsed form generating
steric repulsive strain which is destabilizing this TS making it
nonfavored, whereas in TS-1 the allylic acetonide-protected
hydroxyl group of alkene and the boron ligands is in noneclipsed
form, making this TS more stable and favored, ultimately result-
ing in the formation of single diastereomer 12 in this reaction.
The diastereoselection observed in the StillÀBarrish hydrobora-
tion is widely documented, and many examples of such hydro-
boration are reported.14
Figure 2. Transition states for hydroboration of alkene 5.
The alcohol 12 was tosylated with TsCl and triethylamine to
give a tosylate, which on heating with an excess of NaCN and
catalytic amount of NaI in DMSO produced 13 in 80% yield.
Intermediate 13 on reaction with DIBAL-H at À78 °C formed
intermediate aldehyde,15 which on reduction with NaBH4 gave
the alcohol 14 in 89% yield. Mitsunobu reaction of 14 and
1-phenyl-1-1H-tetrazole-5-thiol (PT-SH) formed sulfide 15 in
86% yield, which on oxidation with H2O2 and ammonium
molybdate afforded the sulfone 4 in 82% yield.
Synthesis of the aldehyde 7, depicted in Scheme 3, was started
from the known compound 8, which was prepared from
(E)-4-(benzyloxy)but-2-en-1-ol by employing the Sharpless asym-
metric epoxidation reaction, followed by dimethylcopper lithium
6332
dx.doi.org/10.1021/jo200396q |J. Org. Chem. 2011, 76, 6331–6337

The Journal of Organic Chemistry
NOTE
Scheme 3. Synthesis of Aldehyde 7
Scheme 4. JuliaÀKocienski Coupling between Sulfone 4 and
Aldehyde 7 and Completion of Synthesis
mediated regioselective epoxide opening.16 The diol 8 on selec-
tive protection of a primary hydroxyl group as TBDMS ether
followed by protection of secondary hydroxyl group as a TIPS
ether gave the fully protected compound 17 in 90% overall yield
in two steps. Compound 17 on hydrogenation in presence of
PdÀC in ethyl acetate gave 18 in 91% yield. Here we sought the
removal of the free hydroxyl group of 18. Hence, it was converted
to tosyl derivative, which on treatment with LiEt3BH (Super-
hydride) in dry THF gave 19 in 86% yield.17 Compound 19 on
treatment with HFÀpyridine complex in THF gave the alcohol
20, which on DessÀMartin periodinane oxidation18 furnished
aldehyde 7.
’ EXPERIMENTAL SECTION
(3aR,5R,6R,6aR)-6-(Benzyloxy)-2,2-dimethyl-5-(prop-1-en-
2-yl)tetrahydrofuro[2,3-d][1,3]dioxole (9). (R)-1-((3aR,5R,6R,6aR)-
6-(Benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)ethanol
(6) was prepared from D-glucose using a known procedure.8 Alcohol 6(8.0g,
27.37 mmol) was subjected to Swern oxidation reaction using same proce-
dure as described in our previous work24 to give the corresponding ketone.
The ketone (Rf = 0.60, 30% EtOAc in PE), thus obtained, was directly used
after flash chromatography for the next reaction.
With sulfone 4 and aldehyde 7 in hand, the stage was set for
the crucial JuliaÀKocienski olefination.19 Accordingly, 4 was
treated with KHMDS in dry THF at À78 °C, followed by slow
addition of 7 over 10 min period, and the same temperature was
maintained for 1.5 h. It was then warmed to rt and further stirred
for 12 h to furnish the E-olefinic compound 21 in 76% yield (with
trace amounts of Z-isomer which was separated by simple
column chromatography). Compound 21 was then treated with
3 N KOH in MeOH solution under refluxing conditions to give
the TBDPS-deprotected compound20 22 in 84% yield, which on
LiÀliquid ammonia mediated benzyl deprotection21 afforded
diol 23 in 72% yield. The diol on selective monotosylation22 gave
primary O-tosylate, which was heated with NaCN and catalytic
amount of NaI in DMSO to give our prefinal substrate 3 in 77%
yield. This compound with terminal 4-hydroxy-1-nitrile moiety
was proven to be ideal for our end game. Thus, it was heated with
5% concd HCl in MeOH solution23 generating the required γ-
lactone functionality with concomitant removal of diacetonide
and triisopropylsilyl (TIPS) protecting groups, all in one pot, to
give our target molecule mupirocin H in 64% yield (Scheme 4).
The 1H and 13C NMR spectra and specific rotation of synthetic
mupirocin H (2) were found to be in good agreement with the
reported values.5
To a suspension of methyltriphenylphophonium iodide (22.13 g,
54.74 mmol) in dry THF (150 mL) at 0 °C was added n-BuLi (1.6 M in
hexane, 34.21 mL, 54.74 mmol) slowly. After being stirred at the same
temparature for 10 min, the mixture was warmed to rt rapidly, stirred for
25 min, and then cooled to À50 °C, and to this was added slowly the
above ketone dissolved in dry THF (25 mL). The mixture was stirred at
the same temperature for 1 h, then gradually warmed to rt, and stirred
for 24 h. Water was added to the mixture, which was extracted with
EtOAc, washed with brine, dried (Na2SO4), and concentrated in vacuo.
Purification by column chromatography (SiO2, 8% EtOAc in PE)
yielded compound 9 as a colorless oil (5.72 g, 72%): Rf = 0.6 (SiO2,
30% EtOAc in PE); [R]24D = +60.5 (c 2.62, CHCl3); IR νmax 2924, 2857,
1
1726, 1513, 1454 cmÀ1; H NMR (500 MHz, CDCl3) δ 7.31À7.26
(m, 5H), 5.70 (d, J = 3.9 Hz, 1H), 5.12 (s, 1H), 4.94 (s, 1H), 4.70 (d, J =
11.6 Hz, 1H), 4.54 (d, J = 11.6 Hz, 1H), 4.52 (dd, J = 3.9, 3.8 Hz, 1H),
4.39 (d, J = 8.7 Hz, 1H), 3.52 (dd, J = 8.7, 3.9 Hz, 1H), 1.68 (s, 3H), 1.60
(s, 3H), 1.35 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 141.2, 137.4, 128.2,
127.7, 114.2, 112.6, 103.5, 81.1, 79.7, 77.4, 71.8, 26.6, 26.4, 17.4; MS m/z
308 [M + NH4]+; HRMS calcd for C17H22O4Na [M + Na]+ 313.1416,
found 313.1422.
(2S,3R,4R)-3-(Benzyloxy)-1-(tert-butyldiphenylsilyloxy)-5-
methylhex-5-ene-2,4-diol (11). Aqueous TFA (50%, 18.25 mL,
1 mL/mmol) was added to compound 9 (5.30 g, 18.25 mmol) at 0 °C,
and the resulting mixture was allowed to warm to rt and stirred for 3 h.
Then TFA was removed in vacuo, and the residue was dissolved in
DCM, washed with saturated aq NaHCO3 solution and brine, dried
(Na2SO4), and concentrated in vacuo. The lactol (Rf = 0.60, 50% EtOAc
in PE), thus obtained, was directly used after flash chromatography for
next reaction.
In summary, we have achieved the total synthesis of mupirocin
H using D-glucose as chiral pool material and StillÀBarrish
hydroboration and JuliaÀKocienski olefination as key steps.
Three chiral centers out of six were obtained from D-glucose.
The convergent strategy developed here can be utilized in the
total synthesis of other natural products of the same family like
pseudomonic acids, mupirocin W, and thiomarinols. Currently
we are working in this direction.
The lactol obtained above was dissolved in THF/MeOH (1:1,
60 mL) and cooled to 0 °C, and LiBH4 (0.795 g, 36.50 mmol) was
slowly added. The reaction mixture was then allowed to warm to rt,
6333
dx.doi.org/10.1021/jo200396q |J. Org. Chem. 2011, 76, 6331–6337

The Journal of Organic Chemistry
NOTE
stirred for 3 h, quenched slowly using saturated NH4Cl solution,
extracted with DCM, washed with brine, dried (Na2SO4), and concen-
trated in vacuo. The (2S,3R,4R)-3-(benzyloxy)-5-methylhex-5-ene-
1,2,4-triol (10) (Rf = 0.30, 60% EtOAc in PE), thus obtained, was
directly used after flash chromatography for next reaction.
solution of NH4Cl and extracted with EtOAc. The combined organic
layers were washed with water and brine, dried (Na2SO4), and con-
centrated in vacuo. The tosylate (Rf = 0.5, 10% EtOAc in PE), thus
obtained, was directly used after flash chromatography for the next
reaction.
Triol 10 was subjected to selective mono-TBDPS protection using
the same procedure as described in our previous work.25 Purification
by column chromatography (SiO2, 10% EtOAc in PE) afforded 11 as a
colorless oil (6.72 g, 75% over three steps): Rf = 0.4 (SiO2, 20% EtOAc in
PE); [R]24 = À6.44 (c 6.1, CHCl3); IR νmax 3565, 3421(br), 2929,
To a solution of above tosylate in dry DMSO (30 mL) were added
sodium cyanide (3.57 g, 72.88 mmol) followed by sodium iodide
(0.136 g, 0.911 mmol), and the reaction mixture was stirred at 90 °C for 2 h.
After being cooled to rt, the mixture was diluted with EtOAc, washed
with water and brine, dried (Na2SO4), and concentrated in vacuo.
Purification by column chromatography (SiO2, 5% EtOAc in PE) afforded
compound 13 as colorless oil (4.06 g, 80% over two steps): Rf = 0.6
(SiO2, 10% EtOAc in PE); [R]24D = +13.34 (c 3.45, CHCl3); IR νmax
2953, 2864, 2362, 2324, 1695, 1516 cmÀ1; 1H NMR δ 7.79À7.70 (m,
5H), 7.45À7.24 (m, 10H), 4.76 (d, J = 11.3 Hz, 1H), 4.60 (d, J = 10.6,
Hz, 1H), 4.00 (dd, J = 11.3, 3.0 Hz, 1H), 3.86 (dd, J = 11.3, 1.5 Hz, 1H),
3.71À3.56 (m, 3H), 2.34À2.20 (m, 3H), 1.40 (s, 6H), 1.18 (d, J = 6.8
Hz, 3H), 1.10 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 137.4, 135.9,
135.6, 134.7, 133.7, 133.1, 129.6, 128.6 128.2, 128.1, 127.6, 127.4, 119.7,
98.3, 74.6, 74.1, 70.7, 63.3, 31.1, 29.0, 26.8, 19.4, 19.1, 18.2, 17.4; MS m/z
575 [M + NH4]+; HRMS calcd for C34H43NO4SiNa [M + Na]+
580.2984, found 580.2980.
(R)-3-((4R,5R,6S)-5-(Benzyloxy)-6-((tert-butyldiphenylsily-
loxy)methyl)-2,2-dimethyl-1,3-dioxan-4-yl)butan-1-ol (14).
Nitrile 13 (3.90 g, 6.99 mmol) was converted to alcohol 14 using a
two-step protocol viz. DIBAL-H mediated conversion of nitrile to
aldehyde, followed by NaBH4 reduction using the same procedure as
described in our previous work.24 Purification by column chromatogra-
phy (SiO2, 18% EtOAc in PE) afforded compound 14 as a colorless oil
(3.5 g, 89%): Rf = 0.4 (SiO2, 20% EtOAc in PE); [R]24D = À3.4 (c 0.35,
CHCl3); IR νmax 3618, 2933, 2856, 1694, 1462 cmÀ1; 1H NMR (300
MHz, CDCl3) δ 7.80À7.71 (m, 5H), 7.44À7.22 (m, 10H), 4.70 and
4.64 (ABq, J = 10.6 Hz, 2H), 3.98 (dd, J = 11.3, 3.0 Hz, 1H), 3.86 (dd, J =
11.3, 1.5 Hz, 1H), 3.80À3.68 (m, 4H), 3.58 (m, 1H), 2.43 (bs, 1H), 2.19
(m, 1H), 1.81À1.62 (m, 2H), 1.43 (s, 6H), 1.10 (s, 9H), 1.04 (d, J =
6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 137.9, 135.9, 135.6, 133.8,
133.3, 129.5, 128.4, 127.9, 127.8, 127.5, 127.4, 98.3, 76.5, 74.3, 74.2, 71.0,
63.5, 59.8, 32.7, 29.9, 29.0, 26.8, 19.3, 19.2, 16.6; MS m/z 585 [M +
Na]+; HRMS calcd for C34H46O5SiNa [M + Na]+ 585.3012, found
585.3000.
1461 cmÀ1D
;
1H NMR (300 MHz, CDCl3) δ 7.67À7.64 (m, 5H),
7.46À7.33, (m, 6H), 7.28À7.23 (m, 2H), 7.17À7.14 (m, 2H), 5.10
(s, 1H), 4.97 (s, 1H), 4.60 (d, J = 11.3 Hz, 1H), 4.47 (d, J = 10.6 Hz, 1H),
4.31 (d, J = 6.0 Hz, 1H), 3.93À3.88 (m, 2H), 3.79 (dd, J = 11.3, 6.8 Hz,
1H), 3.63 (dd, J = 11.3, 5.3 Hz, 1H), 2.85 (bs, 1H), 1.80 (s, 3H), 1.08
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 144.3, 137.8, 135.5, 133.0,
132.8, 129.8, 128.3, 127.9, 127.8, 113.1, 79.7, 76.2, 73.6, 73.1, 64.7, 26.8,
19.2, 19.0; MS m/z 513 [M + Na]+; HRMS calcd for C30H38O4SiNa
[M + Na]+ 513.2437, found 513.2426.
(((4S,5R,6R)-5-(Benzyloxy)-2,2-dimethyl-6-(prop-1-en-
2-yl)-1,3-dioxan-4-yl)methoxy)(tert-butyl)diphenylsilane (5).
Diol 11 (6.50 g, 13.25 mmol) was protected to give 5 using the same
procedure as described in our previous work.24 Purification by column
chromatography (SiO2, 2 to 5% EtOAc in PE) afforded compound 5 as a
colorless oil (6.68 g, 95%): Rf = 0.4 (SiO2, 10% EtOAc in PE);
[R]24D = À41.0 (c 3.63, CHCl3); IR νmax 2932, 2859, 1462, 1381 cmÀ1
;
1H NMR (300 MHz, CDCl3) δ 7.80À7.70 (m, 5H), 7.44À7.33 (m, 6H),
7.31À7.20 (m, 4H), 5.24 (s, 1H), 5.08 (d, J = 1.5 Hz, 1H), 4.59
(d, J = 10.6 Hz, 1H), 4.50 (d, J = 9.8 Hz, 1H), 4.24 (d, J = 9.1 Hz, 1H),
3.98 (dd, J = 11.3, 3.8 Hz, 1H), 3.84 (dd, J = 11.3, 1.5 Hz, 1H), 3.78
(m, 1H), 3.69 (dd, J = 9.1, 9.1 Hz, 1H), 1.89 (s, 3H), 1.48 (s, 3H), 1.47
(s, 3H), 1.08 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 143.0, 137.9, 135.9,
135.6, 134.0, 133.4, 129.5, 128.3, 128.0, 127.8, 127.6, 127.4, 115.7, 98.2,
77.4, 74.0, 73.6, 71.4, 63.5, 29.3, 26.8, 19.4, 17.7; MS m/z 548 [M +
NH4]+; HRMS calcd for C33H42O4SiNa [M + Na]+ 553.2750, found
553.2740.
(R)-2-((4R,5R,6S)-5-(Benzyloxy)-6-((tert-butyldiphenylsily-
loxy)methyl)-2,2-dimethyl-1,3-dioxan-4-yl)propan-1-ol (12). A
solution of 9-BBN (0.5 M in THF, 67.8 mL, 33.9 mmol) was slowly added
dropwise at 0 °C to a solution of alkene (5) (6.0 g, 11.3 mmol) in dry THF
(30 mL). After the addition, the mixture was allowed to warm to rt, stirred
for 12 h, and then treated with EtOH (21.1 mL), aqueous NaOH (3 N,
14 mL), and 30% aqueous H2O2 (14 mL) and stirred at rt for 2 h. The
mixture was saturated with solid K2CO3 and extracted with Et2O. Com-
bined organic layers were washed with brine, dried (Na2SO4), filtered, and
concentrated in vacuo. Purification by column chromatography (SiO2, 10%
EtOAc in PE) afforded compound 12 as colorless oil (5.27 g, 85%): Rf = 0.5
(SiO2, 20% EtOAc in PE); [R]24D = À4.4 (c 3.96, CHCl3); IR νmax 3530,
5-((R)-3-((4R,5R,6S)-5-(Benzyloxy)-6-((tert-butyldiphenyl-
silyloxy)methyl)-2,2-dimethyl-1,3-dioxan-4-yl)butylthio)-
1-phenyl-1H-tetrazole (15). Triphenylphosphine (3.84 g, 14.65 mmol),
1-phenyl-1-1H-tetrazole-5-thiol (1.57 g, 8.79 mmol), and the alcohol 14
(3.30 g 5.86 mmol) were dissolved in dry THF (18 mL). This solution
was cooled to 0 °C, and diisopropyl azodicarboxylate (DIAD, 2.88 mL,
14.65 mmol) was slowly added and then the mixture allowed to warm to rt.
After 12 h of stirring, the reaction mixture was directly concentrated in vacuo.
Purification by column chromatography (SiO2, 12% EtOAc in PE) afforded
compound 15 as a colorless oil (3.64 g, 86%): Rf = 0.5 (SiO2, 20% EtOAc in
1
2931, 2865, 1427 cmÀ1; H NMR (300 MHz, CDCl3) δ 7.80À7.70
(m, 5H), 7.45À7.22 (m, 10H), 4.72 (d, J = 11.3 Hz, 1H), 4.59 (d, J = 10.6
Hz, 1H), 3.98 (dt, J = 11.3, 3.0 Hz 1H) 3.91À3.77 (m, 4H) 3.72 (m, 1H),
3.55 (dd, J = 10.6, 3.8 Hz, 1H), 2.64 (bs, 1H), 2.04 (m, 1H) 1.43 (s, 3H),
1.42 (s, 3H), 1.14 (d, J = 7.5 Hz, 3H), 1.10 (s, 9H); 13C NMR (75 Hz,
CDCl3) δ 137.6, 135.9, 135.6, 133.8, 133.2, 129.5, 128.5, 127.9, 127.6,
127.4, 98.5, 77.6, 74.4, 74.3, 71.5, 64.2, 63.4, 34.5, 29.3, 26.8, 19.4, 18.9, 14.8;
MS m/z 566 [M + NH4]+; HRMS calcd for C33H44O5SiNa [M + Na]+:
571.2855, found 571.2850.
PE);[R]24D =+31.0(c0.73, CHCl3);IRνmax 2930, 2858, 1795, 1499 cmÀ1
;
1H NMR (300 MHz, CDCl3) δ 7.71À7.61 (m, 5H), 7.44À7.38 (m, 5H),
7.35À7.23 (m, 5H), 7.22À7.11 (m, 5H), 4.58 and 4.52 (ABq, J = 10.9 Hz,
2H), 3.88 (dd, J = 11.5, 2.8 Hz, 1H), 3.76 (d, J = 11.5 Hz, 1H), 3.66À3.58
(m, 3H), 3.49 (m, 1H), 3.19 (m, 1H), 2.07À1.94 (m, 2H), 1.74 (m, 1H),
1.33 (s, 3H), 1.32 (s, 3H), 1.01 (d, J = 6.8 Hz, 3H), 0.98 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 154.3, 137.8, 135.9, 135.6, 133.8, 133.6, 133.3, 129.9,
129.6, 129.5, 128.4, 127.8, 127.6, 127.4, 123.7, 98.1, 76.4, 74.2, 70.8, 63.6, 32.2,
31.7, 29.4, 29.2, 26.8, 19.3, 19.2, 16.5; MS ESIMS (m/z) C41H50N4O4SSiNa
[M + Na]+ 745; HRMS calcd for C41H50N4O4SSiNa [M + Na]+ 745.3219,
found 745.3197.
(R)-3-((4R,5R,6S)-5-(Benzyloxy)-6-((tert-butyldiphenylsily-
loxy)methyl)-2,2-dimethyl-1,3-dioxan-4-yl)butanenitrile (13).
To a solution of 12 (5.0 g, 9.11 mmol) in DCM (30 mL) was added Et3N
(3.81 mL, 27.33 mmol) followed by TsCl (2.084 g, 10.93 mmol) at 0 °C.
After being stirred at the same temperature for 15 min, DMAP (0.111 g,
0.91 mmol) was added, and the reaction mixture was allowed to warm to
rt, then stirred for 12 h followed by quenching with saturated aqueous
5-((R)-3-((4R,5R,6S)-5-(Benzyloxy)-6-((tert-butyldiphenyl-
silyloxy)methyl)-2,2-dimethyl-1,3-dioxan-4-yl)butylsulfonyl)-
1-phenyl-1H-tetrazole (4). To a solution of compound 15 (3.40 g,
6334
dx.doi.org/10.1021/jo200396q |J. Org. Chem. 2011, 76, 6331–6337

The Journal of Organic Chemistry
NOTE
4.70 mmol) in absolute EtOH (15 mL) at 0 °C was added a premixed
synthesis of compound 13. The tosylate (Rf = 0.6, 10% EtOAc in PE), thus
obtained, was directly used after flash chromatography for next reaction.
A solution of the above tosylate in dry THF (75 mL) at 0 °C was
treated with lithium triethylborohydride (1.0 M in THF, 70.35 mL,
70.35 mmol) slowly. After being stirred for 5 h at the same temperature,
the reaction mixture was quenched with methanol (24 mL) and 1 N
NaOH (24 mL). The mixture was treated with 30% aqueous H2O2
(8 mL), stirred for 16 h at rt, and then concentrated in vacuo. The
residue was taken up in saturated aqueous NaHCO3 solution and
extracted with Et2O. The combined organic extracts were washed with
brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification
by column chromatography (SiO2, 1% EtOAc in PE) afforded pure 19
solution of(NH4)6Mo7O24 4H2O (1.89 g, 7.05 mmol) inH2O2 (30% aq,
3
9.6 mL, 94 mmol) using a glass pipet. The resulting yellow solution was
then removed from the ice bath and allowed to warm to rt. After 12 h,
saturated aqueous NaHCO3 solution was added to the reaction mixture
and the aqueous layer was extracted with Et2O. The combined organic
layers were washed with brine, dried (Na2SO4), and concentrated in
vacuo. Purification by column chromatography (SiO2, 15% EtOAc in PE)
afforded compound 4 as colorless oil (2.91 g, 82%): Rf = 0.4 (SiO2, 20%
EtOAc inPE); [R]24D = +20.3 (c 1.75, CHCl3); IR νmax 2991, 2933, 1462,
1
1384 cmÀ1 ; H NMR (300 MHz, CDCl3) δ 7.71À7.57 (m, 6H),
7.56À7.46 (m, 4H), 7.36À7.16 (m, 10H), 4.64 (d, J = 10.9 Hz, 1H), 4.54
(d, J = 10.9 Hz, 1H), 3.89 (dd, J = 11.3, 3.0 Hz, 1H), 3.83À3.73 (m, 2H),
3.66À3.56 (m, 3H), 3.48 (m, 1H), 2.07À1.95 (m, 2H), 1.88 (m, 1H),
1.33 (s, 6H), 0.99À1.01 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 153.4,
137.8, 135.9,135.6, 133.8, 133.2, 131.3, 129.6, 129.5, 128.5, 128.0, 127.6,
127.4, 125.0, 98.3, 76.1, 74.3, 71.1, 63.5, 54.2, 31.6, 29.2, 26.8, 22.6, 19.4,
19.1, 16.5; MS m/z 777 [M + Na]+; HRMS calcd for C41H54N5O6SiS
[M + NH4]+ 772.3564, found 772.3548.
(4.54 g, 86%) as a colorless oil: Rf = 0.6 (silica gel, 10% EtOAc in PE);
1
[R]24 = +3.0 (c 1.79, CHCl3); IR νmax 2993, 2862, 1464 cmÀ1; H
D
NMR (300 MHz, CDCl3) δ 4.08 (m, 1H), 4.52À4.42 (m, 2H), 1.86
(m, 1H), 1.07À1.06 (m, 24H), 0.88 (s, 9H), 0.84 (d, J = 6.8 Hz, 3H),
0.04À0.02 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 68.8, 65.6, 43.1,
25.9, 18.5, 18.2, 12.6, 10.8, À5.5, À5.4; MS m/z 375 [M + H]+; HRMS
calcd for C20H47O2Si2 [M + H]+ 375.3114, found 375.3125.
(2R,3R)-1-(Benzyloxy)-4-(tert-butyldimethylsilyloxy)-3-
methylbutan-2-ol (16). Compound 8 (5.50 g, 26.16 mmol), pre-
pared using a known procedure,16 was selectively protected as primary
TBDMS ether using the same procedure as described in our previous
work.26 Purification by column chromatography (SiO2, 10% EtOAc in
PE) afforded pure compound 16 as colorless oil (7.96 g, 94%): Rf = 0.6
(SiO2, 10% EtOAc in PE); [R]24D = À5.0 (c 2.28, CHCl3); IR νmax 3480
(br), 2929, 1531 cmÀ1; 1H NMR (300 MHz, CDCl3) δ 7.28À7.17 (m,
5H), 4.52 and 4.46 (ABq, J = 12.1 Hz, 2H), 3.68À3.62 (m, 2H),
3.56À3.39 (m, 4H), 1.80 (m, 1H), 0.80À0.83 (m, 12H), À0.02 (s, 6H);
13C NMR (75 MHz, CDCl3) δ 138.1, 128.3, 127.6, 127.5, 74.2, 73.3,
72.7, 66.7, 37.2, 25.7, 18.0, 13.3, À5.7; MS m/z 325 [M + H]+; HRMS
calcd for C18H33O3Si [M + H]+ 325.2198, found 325.2206.
(2R,3S)-2-Methyl-3-(triisopropylsilyloxy)butan-1-ol (20).
Compound 20 was synthesized from compound 19 (4.20 g, 11.21
mmol), following the same procedure as described in our previous
work.24 Purification by column chromatography (SiO2, 4% EtOAc in
PE) afforded the pure alcohol 20 (2.48 g, 85%) as a colorless oil.
Analytical data of 20 was matched with literature values.28
(((4S,5R,6R)-5-(Benzyloxy)-2,2-dimethyl-6-((2R,6R,7S,E)-
6-methyl-7-(triisopropylsilyloxy)oct-4-en-2-yl)-1,3-dioxan-4-yl)-
methoxy)(tert-butyl)diphenylsilane (21). Alcohol 20 (1.12 g,
4.30 mmol) was subjected to DessÀMartin oxidation using the same
procedure as described in our previous work.24 The (2S,3S)-2-methyl-
3-(triisopropylsilyloxy)butanal (7) (Rf = 0.6, 10% EtOAc in PE), thus
obtained, was directly used after flash chromatography for next
reaction.
A solution of sulfone 4 (2.70 g, 3.58 mmol) in dry THF (50 mL)
at À78 °C was treated with dropwise addition of potassium bis-
(trimethylsilyl)amide (KHMDS, 0.5 M in toluene, 14.32 mL, 7.16 mmol)
under nitrogen. The resulting yellow solution was stirred at À78 °C for
1 h, and then a solution of aldehyde 7 in dry THF (20 mL) was slowly
added via syringe over 10 min. The reaction mixture was stirred
at À78 °C for 1.5 h and then at rt for overnight. The cloudy white
reaction mixture was quenched with water, and extracted with EtOAc,
and the organic layer was washed with brine, dried (Na2SO4), filtered,
and concentrated in vacuo. Purification by column chromatography
(SiO2, 2% EtOAc in PE) afforded compound 21 as a colorless liquid
(2.14 g, 76%): Rf = 0.3 (SiO2, 5% EtOAc in PE); [R]24D = +9.43 (c 1.24,
CHCl3); IR νmax 2935, 2865, 1712, 1462 cmÀ1; 1H NMR (300 MHz,
CDCl3) δ 7.73À6.63 (m, 5H), 7.36À7.16 (m, 10H), 5.36À5.24
(m, 2H), 4.62 (d, J = 10.6 Hz, 1H), 4.54 (d, J = 11.3 Hz, 1H), 3.91
(dd, J = 11.3, 3.0 Hz, 1H), 3.87À3.75 (m, 2H), 3.71À3.57 (m, 3H),
2.27À2.17 (m, 2H), 1.93À1.80 (m, 2H), 1.34 (s, 6H), 1.01À0.96 (m,
33H), 0.93À0.90 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 138.0, 136.0,
135.6, 134.0, 133.3, 129.5, 129.2, 128.4, 127.8, 127.7, 127.6, 127.4, 98.1,
76.2, 74.3, 71.9, 71.3, 63.6, 44.1, 33.7, 33.4, 29.3, 26.8, 19.4, 19.3, 19.1,
18.1, 16.8, 14.1, 12.5; MS m/z 810 [M + Na]+; HRMS calcd for
C48H78NO5Si2 [M + NH4]+ 804.5418, found 804.5445.
((4S,5R,6R)-5-(Benzyloxy)-2,2-dimethyl-6-((2R,6R,7S,E)-6-
methyl-7-(triisopropylsilyloxy)oct-4-en-2-yl)-1,3-dioxan-4-
yl)methanol (22). Compound 21 (500 mg, 0.63 mmol) was treated
with 3 N KOH solution in MeOH (3 mL), and the resulting mixture was
refluxed at 70 °C for 12 h. The reaction mixture was then diluted
with EtOAc, washed with water and brine, dried (Na2SO4), filtered,
and concentrated in vacuo. Purification by column chromatography
(SiO2, 10% EtOAc in PE) afforded compound 22 as a colorless liquid
(289.3 mg, 84%): Rf = 0.3 (SiO2, 10% EtOAc in PE); [R]24D = +20.2
(6R,7R)-7-(Benzyloxymethyl)-9,9-diisopropyl-2,2,3,3,6,-
10-hexamethyl-4,8-dioxa-3,9-disilaundecane (17). Compound
16 (7.0 g, 21.57 mmol) was converted to TIPS ether 17 using the
same procedure as described in a previously published work27 with
TIPS-OTf and 2,6-lutidine. Purification by column chromatogra-
phy (SiO2, 1% EtOAc in PE) afforded compound 17 as a colorless liquid
(9.95 g, 96%): Rf = 0.5 (SiO2, in PE); [R]24D = À3.7 (c 0.9, CHCl3); IR
1
νmax 2932, 2862, 1725, 1464 cmÀ1; H NMR (300 MHz, CDCl3) δ
7.53À7.18 (m, 5H), 4.42 (s, 2H), 4.28 (m, 1H), 3.59 (m, 1H), 3.54À3.36
(m, 3H), 1.92 (m, 1H), 1.00À1.01 (m, 21H,), 0.81À0.86 (m, 12H),
0.03 to À0.06 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 138.5, 128.1, 127.6,
127.3, 73.1, 73.0, 72.8, 64.9, 40.7, 25.9, 18.1, 12.7, 12.4, À5.5; MS m/z 481
[M + H]+; HRMS calcd for C27H52O3Si2Na [M + Na]+ 503.3353, found
503.3365.
(2R,3R)-4-(tert-Butyldimethylsilyloxy)-3-methyl-2-(triiso-
propylsilyloxy)butan-1-ol (18). To a stirred solution of 17 (8.0 g,
16.64 mmol) in EtOAc (50 mL) was added catalytic PdÀC (10%), and
the mixture was hydrogenated overnight using a H2-filled balloon. It was
then filtered through a short pad of Celite, and the filter cake was washed
with EtOAc. The filtrate and washings were combined and concentrated
in vacuo. Purification by column chromatography (SiO2, 6% EtOAc in
PE) afforded compound 18 as a colorless liquid (5.91 g, 91%): Rf = 0.3
(SiO2, 10% EtOAc in PE); [R]24 = +16.4 (c 2.77, CHCl3); IR νmax
D
3496 (br), 2935, 2864, 1465 cmÀ1; 1H NMR (300 MHz, CDCl3) δ 3.98
(m, 1H), 3.68À3.53 (m, 4H), 3.01 (bs, 1H), 2.02, (m, 1H), 1.09À1.03
(m, 21H), 0.93 (d, J = 6.8 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 74.3, 64.8, 63.5, 40.0, 25.8, 18.1, 12.6, 11.9, À5.58,
À5.62; MS m/z 391 [M + H]+; HRMS calcd for C20H46O3Si2Na
[M + Na]+ 413.2883, found 413.2900.
(6R,7S)-9,9-Diisopropyl-2,2,3,3,6,7,10-heptamethyl-4,8-
dioxa-3,9-disilaundecane (19). Compound 18 (5.50 g, 14.07 mmol)
was subjected to tosylation following the same procedure as per the
6335
dx.doi.org/10.1021/jo200396q |J. Org. Chem. 2011, 76, 6331–6337

The Journal of Organic Chemistry
NOTE
(c 0.96, CHCl3); IR νmax 3619, 2931, 2866, 1741, 1461 cmÀ1; 1H NMR
(300 MHz, CDCl3) δ 7.37À7.27 (m, 5H), 5.42À5.28 (m, 2H), 4.61
(s, 2H), 3.90 (m, 1H), 3.83À3.65 (m, 4H), 3.48 (dd, J = 9.4, 9.3 Hz, 1H),
2.33À2.19 (m, 2H), 2.04 (m, 1H), 1.96À1.80 (m, 2H), 1.44 (s, 3H),
1.38 (s, 3H), 1.07À1.03 (m, 24H), 1.01À0.96 (m, 6H); 13C NMR (75
MHz, CDCl3) δ 137.7, 134.1, 129.0, 128.5, 128.0, 98.4, 76.4, 74.5, 73.7,
71.8, 71.3, 62.3, 44.1, 33.4, 33.3, 29.3, 19.4, 19.1, 18.2, 16.9, 14.2, 12.5;
MS m/z 571 [M + Na]+; HRMS calcd for C32H56O5Si Na [M + Na]+
571.3794, found 571.3774.
(dd, J = 15.1, 8.3 Hz, 1H), 4.58 (m, 1H), 4.44 (dd, J = 5.3, 3.0 Hz, 1H),
3.57 (dd, J = 6.8, 6.0 Hz, 1H), 3.49 (m, 1H), 2.93 (dd, J = 18.1, 7.6 Hz,
1H), 2.50 (dd, J = 18.1, 3.8 Hz, 1H), 2.36À2.21 (m, 2H), 2.06 (m, 1H),
1.89 (m, 1H), 1.18 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H), 0.98
(d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 176.2, 134.7, 129.6,
88.0, 75.1, 71.6, 68.4, 45.3, 38.3, 35.3, 34.6, 20.6, 17.0, 16.0; MS m/z 290
(100) [M + NH4]+; HRMS calcd for C14H24O5 Na [M + Na]+
295.1521, found 295.1522.
(4S,5R,6R)-4-(Hydroxymethyl)-2,2-dimethyl-6-((2R,6R,7S,
E)-6-methyl-7-(triisopropylsilyloxy)oct-4-en-2-yl)-1,3-diox-
an-5-ol (23). A solution of lithium in liquid ammonia was prepared by
stirring lithium (50 mg, 7.2 mmol, cleaned by successive dipping in
hexane and ether, and cut into small pieces) and liquid ammonia
(∼20 mL) at À78 °C for 0.5 h. To this dark blue LiÀNH3 solution was
added compound 22 (200 mg, 0.36 mmol) in dry THF (3 mL) via
cannula under nitrogen atmosphere. After being stirred at À78 °C for
0.5 h, the reaction was quenched by addition of excess solid NH4Cl and
diluted with ether, and ammonia was evaporated at rt. More ether was
added, and the mixture was filtered and concentrated in vacuo.
Purification by column chromatography (SiO2, 20% EtOAc in PE)
afforded compound 23 as a colorless liquid (120.3 mg, 72%): Rf = 0.3
(SiO2, 20% EtOAc in PE); [R]24D = +8.94 (c 2.13, CHCl3); IR νmax
3620, 3390, 2928, 2863, 1836, 1708, 1462 cmÀ1; 1H NMR (500 MHz,
CDCl3) δ 5.43À5.33 (m, 2H), 3.90 (m, 1H), 3.78 (d, J = 3.5 Hz, 2H),
3.66 (m, 1H), 3.60À3.54 (m, 2H), 2.35À2.21 (m, 3H), 2.03 (m, 1H),
1.93À1.86 (m, 2H), 1.45 (s, 3H), 1.37 (s, 3H), 1.05À1.03 (m, 24H),
0.99À0.96 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 134.2, 129.0, 98.5,
76.4, 73.5, 71.9, 64.9, 63.1, 44.1, 34.0, 33.8, 29.3, 19.4, 19.2, 18.2, 18.1,
16.4, 14.2, 12.5; MS m/z 481 [M + Na]+; HRMS calcd for C25H50O5Si
Na [M + Na]+ 481.3325, found 481.3348.
2-((4S,5S,6R)-5-Hydroxy-2,2-dimethyl-6-((2R,6R,7S,E)-6-
methyl-7-(triisopropylsilyloxy)oct-4-en-2-yl)-1,3-dioxan-4-
yl)acetonitrile (3). Compound 23 (100 mg, 0.22 mmol) was sub-
jected to the tosylation following the same procedure as per the
synthesis of compound 13, except for the initial addition of di-n-
butyltin oxide (5 mg, 0.02 mmol). The tosylate (Rf = 0.6, 20% EtOAc
in PE), thus obtained, was directly used after flash chromatography for
the next reaction.
The above tosylate was converted to nitrile 3 following the same
procedure as per the synthesis of compound 13. Purification by column
chromatography (SiO2, 12% EtOAc in PE) afforded compound 3
as a colorless oil (79.5 mg, 77%): Rf = 0.5 (SiO2, 20% EtOAc in PE);
[R]24D = +14.55 (c 1.45, CHCl3); IR νmax 3476 (br), 2935, 2866, 2263,
1491 cmÀ1; 1H NMR (300 MHz, CDCl3) δ 5.46À5.33 (m, 2H), 3.90,
(m, 1H), 3.81 (m, 1H), 3.55 (m, 1H), 3.41 (m, 1H), 2.77 (dd, J = 16.8,
3.8 Hz, 1H), 2.65 (dd, J = 16.8, 6.2 Hz, 1H), 2.30À2.22 (m, 2H),
1.97À1.87 (m, 2H), 1.65 (bs, 1H), 1.46 (s, 3H), 1.40 (s, 3H), 1.10À1.04
(m, 24 H), 1.01À0.97 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 134.4,
128.8, 117.3, 99.1, 76.6, 71.9, 70.1, 67.5, 44.1, 33.9, 33.7, 29.1, 21.6, 19.4,
19.2, 18.2, 16.6, 14.4, 12.6; MS m/z 490 [M + Na]+; HRMS calcd for
C26H49NO4Si Na [M + Na]+ 490.3328, found 490.3323.
’ ASSOCIATED CONTENT
Supporting Information. Copies of H and 13C NMR
1
S
b
for all the new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: chakraborty@cdri.res.in.
Notes
†CDRI Communication no. 8089.
’ ACKNOWLEDGMENT
S.P.U. thanks CSIR, India, for a research fellowship.
’ REFERENCES
(1) Cookson, B. D. J. Antimicrob. Chemother. 1998, 41, 11.
(2) (a) O’Hanlon, P. J.; Rogers, N. H.; Tyler, J. W. J. Chem. Soc.,
Perkin Trans. 1 1983, 2655. (b) Badder, A.; Garre, C. Corresp.-Bl. Sweiz.
Aerzte 1887, 17, 385.
(3) (a) Class, Y. J.; DeShong, P. Chem. Rev. 1995, 95, 1843 and
references cited therein. (b) McKay, C.; Simpson, T. J.; Willis, C. L.;
Forrest, A. K.; O’Hanlon, P. J. Chem. Commun. 2000, 1109.
(4) Cooper, S. M.; Cox, R. J.; Crosby, J.; Crump, M. P.; Hothersall,
J.; Laosripaiboon, W.; Simpson, T. J.; Thomas, C. M. Chem. Commun.
2005, 1179.
(5) Wu, J.; Cooper, S. M.; Cox, R. J.; Crosby, J.; Crump, M. P.;
Hothersall, J.; Simpson, T. J.; Thomas, C. M.; Willis, C. L. Chem. Commun.
2007, 2040.
(6) Thomas, C. M.; Hothersall, J.; Willis, C. L.; Simpson, T. J. Nat.
Rev.Microbiol. 2010, 8, 281.
(7) Shiozawa, H.; Kagasaki, T.; Torikata, A.; Tanaka, N.; Fujimoto,
K.; Hata, T.; Furukawa, Y.; Takahashi, S. J. Antibiot. 1995, 48, 907.
(8) (a) Whistler, R. L.; Bemiller, J. N. Methods Carbohydr. Chem.
1972, 6, 1230. (b) Stevens, J. D. Methods Carbohydr. Chem. 1972, 6, 123.
(c) Whistler, R. L.; Lake, W. C. Methods Carbohydr. Chem. 1972, 6, 286.
(d) Yamashita, M.; Nakatsukasa, Y.; Yoshida, H.; Ogata, T.; Inokawa, S.;
Hirotsu, K.; Clardy, J. Carbohydr. Res. 1979, 70, 247.
(9) (a) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978,
43, 2480. (b) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(10) Liang, D.; Schuda, A. D.; Fraser-Reid, B. Carbohydr. Res. 1987,
164, 229.
(11) Still, W. C.; Barrish, J. C. J. Am. Chem. Soc. 1983, 105, 2487.
(12) Houk, K. N.; Rondan, N. G.; Wu, U.; Metz, J. T.; Paddon-Row,
M. N. Tetrahedron 1984, 40, 2257.
(13) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. J. Am.
Chem. Soc. 1995, 117, 3448.
Mupirocin H (2). To the nitrile 3 (50 mg, 0.11 mmol) in methanol
(5 mL) was added concd HCl (0.25 mL). The resulting solution was
stirred at 65 °C for 3 h. After the reaction mixture was cooled to rt, 15 mL
each of DCM and half-saturated aqueous NaCl solution were added.
The organic layer was separated, and the aqueous layer was extracted
with DCM (3 Â 15 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo. Purification by column chroma-
tography (SiO2, 12% MeOH in chloroform) afforded mupirocin H (2)
as a colorless oil (18.8 mg, 64%): Rf = 0.3 (SiO2, 10% MeOH in
chloroform); [R]24D = +25.8 (c 0.64, CHCl3 (lit.5 [R]20D = +30.5, c 1.3,
CHCl3)); IR νmax 3375 (br), 2965, 2924, 1759, 1457 cmÀ1; 1H NMR
(CDCl3, 300 MHz) δ 5.59 (ddd, J = 15.1, 8.3, 6.8 Hz, 1H), 5.37
(14) (a) Paterson, I.; Chennon, J. A. Tetrahedron Lett. 1992, 33, 797.
(b) Evans, D. A.; Fitch, D. M. J. Org. Chem. 1997, 62, 454. (c) Sato, H.;
Kim, Y. S.; Shibasaki, M. Tetrahedron Lett. 1999, 40, 2973. (d) Phukan,
P.; Sasmal, S.; Maier, M. E. Eur. J. Org. Chem. 2003, 1733. (e) Loiseleur,
O.; Koch, G.; Wagner, T. Org. Process Res. Dev. 2004, 8, 597.
(f) Park, P. K.; O’Malley, S. J.; Schmidt, D. R.; Leighton, J. L. J. Am.
6336
dx.doi.org/10.1021/jo200396q |J. Org. Chem. 2011, 76, 6331–6337

The Journal of Organic Chemistry
NOTE
Chem. Soc. 2006, 128, 2796. (g) Parker, K. A.; Xie, Q. Org. Lett. 2008,
10, 1349.
(15) Matsuo, G.; Kawamura, K.; Hori, N.; Matsukara, H.; Nakata, T.
J. Am. Chem. Soc. 2004, 126, 14374.
(16) Chakraborty, T. K.; Das, S. Tetrahedron Lett. 2001, 42, 3387.
(17) (a) Nicolaou, K. C.; Bertinato, P.; Piscopio, A. D.; Chakraborty,
T. K.; Minowa, N. J. Chem. Soc., Chem. Commun. 1993, 619. (b) Nicolaou,
K. C.; Piscopio, A. D.; Bertinato, P.; Chakraborty, T. K.; Minowa, N.;
Koide, K. Chem.—Eur. J. 1995, 1, 318.
(18) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(19) (a) Bellingham, R.; Jarowicki, K.; Kocienski, P.; Martin, V.
Synthesis 1996, 285. (b) Gao, X.; Hall, D. G. J. Am. Chem. Soc. 2005,
127, 1628.
(20) Malik, A. A.; Cormier, R. J.; Sharts, C. M. Org. Prep. Proced. Int.
1986, 18, 345.
(21) Zakarian, A.; Batch, A.; Holton, R. A. J. Am. Chem. Soc. 2003,
125, 7822.
(22) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.;
Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447.
(23) Crimmins, M. T.; Macdougall, P. J.; Ellis, J. M. Org. Lett. 2006,
8, 4079.
(24) Chakraborty, T. K.; Chattopadhyay, A. K. J. Org. Chem. 2008,
73, 3578.
(25) Chakraborty, T. K.; Reddy, V. R.; Gajula, P. K. Tetrahedron
2008, 64, 5162.
(26) Chakraborty, T. K.; Samanta, R.; Kumar, P. K. Tetrahedron
2009, 65, 6925.
(27) Ghosh, S.; Kumar, S. U.; Shashidhar, J. J. Org. Chem. 2008,
73, 1582.
(28) Szpilman, A. M.; Cereghetti, D. M.; Wurtz, N. R.; Manthorpe,
J. M.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 4335.
6337
dx.doi.org/10.1021/jo200396q |J. Org. Chem. 2011, 76, 6331–6337