D-glucosamine-derived synthons for assembly of l - Threo -sphingoid bases. Total synthesis of rhizochalinin C

Article abstract of DOI:10.1021/jo302355t

A five-step transformation of d-glucosamine, commencing with indium-mediated Barbier reaction without isolation of intermediates, into (R,R)-2-aminohex-5-ene-1,3-diol in 45-51% is described. The latter is a useful synthon for assembly of l-threo-sphingoid bases: long-chain aminoalkanols and aminoalkanediols with configurations antipodal to that found in mammalian D-erythro-sphingosine but prevalent among invertebrate-derived sphingolipids. The utility of the method is demonstrated by the first total synthesis of rhizochalinin C, the long-chain, two-headed sphingoid base aglycon of the natural product rhizochalin C from the marine sponge Rhizochalina incrustata.

Full text of DOI:10.1021/jo302355t

Article
pubs.acs.org/joc
D‑Glucosamine-Derived Synthons for Assembly of L-threo-Sphingoid
Bases. Total Synthesis of Rhizochalinin C
Jaeyoung Ko†,§ and Tadeusz F. Molinski*,§,‡
†Department of Chemistry and Biochemistry and ‡Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California,
San Diego, 9500 Gilman Drive, La Jolla, California 92093-0358, United States
§Material Science Medical Beauty Research Institute, Amorepacific Corporation R&D Center, Yongin 446-729, Republic of Korea
S
* Supporting Information
ABSTRACT: A five-step transformation of D-glucosamine,
commencing with indium-mediated Barbier reaction without
isolation of intermediates, into (R,R)-2-aminohex-5-ene-1,3-
diol in 45−51% is described. The latter is a useful synthon for
assembly of L-threo-sphingoid bases: long-chain aminoalkanols
and aminoalkanediols with configurations antipodal to that
found in mammalian D-erythro-sphingosine but prevalent
among invertebrate-derived sphingolipids. The utility of the
method is demonstrated by the first total synthesis of
rhizochalinin C, the long-chain, “two-headed” sphingoid base
aglycon of the natural product rhizochalin C from the marine
sponge Rhizochalina incrustata.
anti-inflammatory agents.8 Fingolimod (FTY720, 4), an
INTRODUCTION
■
analogue of myriocin from Mycelia sterilia9 and other fungal
Sphingosine (2-aminooctadec-4-ene-1,3-diol) and related mam-
species, is an anti-inflammatory agent and potent inhibitor of
malian sphingosines possess the (2S,3R) configuration (D-
SK2; in 2010, it was approved for treatment of multiple
erythro), but microbe- and invertebrate-derived sphingoid bases
sclerosis.10
exhibit broad stereochemical heterogeneity.1,2 L-threo-Sphin-
goid bases have been reported from marine sponges, algae, and
tunicates. “Two-headed” sphingolipids composed of C28−C30
chains functionalized at each terminus as aminoalkanols or
aminoalkanediols3 span almost the complete set of permuta-
tions (n = 16) of the four stereocenters. For example, the
Madagascan sponge Rhizochalina incrustata contains C28 α,ω-
bifunctionalized sphingoid bases (2R,3R,26R,27R)-rhizochalin
C (1b)3f (the 3-β-galactoside of rhizochalinin C, 1a) and the
pseudo-C2 symmetric rhizochalin (1c).3a The head groups of
the latter compounds are both L-threo, but oceanapiside (2b)
has a hetergeneous configuration: the 2-amino-1,3-diol head-
group is D-erythro while the “deoxy” headgroup is L-threo.
Monofunctionalized L-threo sphingoid bases from marine
organisms include halisphingosine A (3a)4 and its correspond-
ing 6-deoxy derivative 3b5 from two different species of
Haliclona and (2R,3R)- and (2R,3S)-aminotetradec-5,7-dien-3-
ols from Xestospongia sp.,6 while crucigasterins from the
tunicate Pseudodistoma crucigaster have the L-erythro-(2R,3S)-
configuration.2h
Modified sphingoid bases have attracted interest because of
their potent biological activity. The α,ω-bifunctionalized 2a,
and to a greater extent, the aglycon oceanin (2a), exhibit
significant antifungal activity against the pathogenic species
Candida albicans, fluconazole-resistant C. albicans, C. glabrata,
and other species.7 Selective inhibitors of D-sphingosine kinase
isoforms, SK1 and SK2, are attractive targets as anticancer and
Synthesis of sphinganine and related sphingoid bases has
been extensively reviewed.11 Approaches to D-erythro-2-amino-
Received: October 26, 2012
Published: December 10, 2012
© 2012 American Chemical Society
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alkanols and 2-aminoalkan-1,3-diols utilizing chiral pool starting
materials commonly begin with natural L-serine and L-alanine,
respectively; however, preparation of L-sphingoid bases require
more expensive D-amino acids. Here, we disclose an optimized
procedure for rapid diastereoselective access to L-threo-
sphingoid base synthons using a remarkable five-step, one-pot
conversion of unprotected D-glucosamine into useful D-serine
synthons based on In0-mediated allylation. The method was
successfully applied to 1a, the first synthesis of a member of the
family of two-headed sphingolipids.
Inexpensive D-glucosamine has been exploited for prepara-
tion for L-serine synthons through oxidative degradation to N-
Boc-L-serinal that refunctionalizes C-3 to a carboxaldehyde
(Figure 1).12 Conceptually, inverting the orientation of
Table 1. Barbier Reaction of N-Protected D-Glucosamine
a
with In0 and Allyl Bromide
entry
N-protecting group, PG
yield (%)
b
1
2
3
4
5
Boc
Cbz
tosyl
78
55
40
38
50
c
Pht
CF3(CO)
a
Conditions: 1−2 mmol of D-glucosamine, 4:1 THF/H2O, reflux, In0
powder (99.99%, 230−400 mesh, 4 equiv), allyl bromide (6 equiv).
Yields were calculated by 1H NMR integration of the allyl vinyl signals
b
and the N-Me signals of caffeine added as an internal standard. For
c
N-Boc-mannosamine 88%, ref 15b. Pht = phthalimido.
eoisomers threo-i and erythro-ii (Table 1) in varying
diastereomeric ratios that always favored threo-i under chelation
control, as noted earlier.15,20 The product yields were variable
(38−78%) with the best yield obtained with N-Boc-D-
glucosamine (entry 1, 78%). Reaction of N-tosyl-D-glucosamine
under similar conditions, but with replacement of the solvent
with THF/H2O mixtures of various ratios (1:4 to 4:1, not
shown), resulted in similar or lower yields (9−40%).
Figure 1. Conversion of D-glucosamine by oxidative remodeling to N-
Boc-L-serinal (see ref 12) and D-serine synthons by Barbier allylation−
oxidation (this work). Locant numbering is based on D-glucosamine.
oxidative remodeling of D-glucosamine by alkylation at C-1
followed by periodate cleavage of the C-3−C-4 bond and
reductive workup would result in D-serine synthons.13 Organo-
indium compounds have found utility in homologation of
aldohexoses and ketoses, largely due to their compatibility with
water.14 Carbon−carbon bond formation at C-1 of D-glucos-
amine is conveniently carried out by Barbier-type allylation in
the aqueous solvents necessary to solubilize D-glucosamine.
Whitesides15 and Chan16b had previously shown that aldoses
and some ketoses undero Barbier allylation with allyl bromide
(refluxing THF) in the presence of Sn0; however, N-acetyl-D-
glucosamine and N-acetyl-D-mannosamine were inert under
these conditions.17 In contrast, N-acetyl-D-mannosamine was
allylated in high yield (90%) with In0 and the more reactive
ethyl α-bromomethacrylate in warm acidic ethanol (HCl, 55
°C) and subsequently converted to sialic acid (Neu5Ac).18
Paquette demonstrated Barbier allylation of N-acetyl-D-
mannosamine with allyl bromide (In0, 0.5 M NH4Cl, aq, 25
°C) with high threo selectivity (8.6:1), albeit in low yield
(31%).19 Amino acid derived N-Cbz-α-aminoaldehydes under-
go Barbier-type allylations under a variety of conditions in
yields up to 82%, or N-Boc-α-aminoaldehydes up to 90%, again
mostly with threo selectivity, but erythro selectivity with
Garner’s aldehyde.21 Critical evaluation of these reports
suggests that allylations of amino sugars under aqueous
conditions suffer from lower yields compared to aldohexoses
or succeed only with N-acyl-2-amino-2-deoxyhexoses which
limits their utility for sphingoid base synthesis.
We found, to our delight, that In0-mediated allylation of
unprotected D-glucosamine gave the best results (Table 2)
Table 2. Barbier Reaction of D-Glucosamine with In0 and
a
Allyl Bromide in Aqueous 1,4-Dioxane
entry
1,4-dioxane/H2O
threo/erythro
yield (%)
1
2
3
4
5
6
0:100
25:75
50:50
67:33
83:17
94:6
1.8:1
2.0:1
4.4:1
7.5:1
7.0:1
5.7:1
21
39
60
96
99
95
a
Conditions: 100 °C. PG = H. For other conditions, see the reaction
equation and footnote in Table 1.
approaching quantitative yields. Optimization of conditions
(Table 2, entry 4) resulted in excellent conversion of D-
glucosamine (1−2 mmol) to diastereomeric allylation products
(96% yield, dr (threo/erythro) = 7.5:1) in the presence of In0
powder (4 equiv) and excess allyl bromide (6 equiv) at reflux
(100 °C) in aqueous dioxane (1,4-dioxane−H2O 2:1).
Paquette and co-workers reported higher threo-product in
In0-mediated allylation of α-oxygenated-aldehydes upon
addition of metal salts, (Et)4NX and NH4Cl.22 In contrast,
we found higher amounts of erythro ii upon allylation of D-
glucosamine in the presence of metal salts, particularly MgCl2
(i:ii dr = 3.5:1, 94%, Table 3, entry 5), with comparable yields.
Scale-up of the five-step conversion of D-glucosamine (0.5−3
g) was optimized (Scheme 1) as follows. In0-mediated allylation
of D-glucosamine followed by sequential periodate cleavage
(NaIO4, H2O), reduction (NaBH4, MeOH), without isolation
of the intermediates from the aqueous milieu, and conversion
of the resulting 1,3-diols to acetonides (2,2-dimethoxypropane,
CH2Cl2, cat. CSA) gave threo-5a23 and erythro-5b (dr = 7.5:1).
Unlike allylation products i and ii, the latter compounds were
RESULTS AND DISCUSSION
■
In order to investigate methodology to improve the scope of
the In0-mediated allylation reaction of aldohexoses, we further
explored the Barbier allylation of D-glucosamine and its
derivatives under aqueous conditions (Table 1). Various N-
protected glucosamines (1−2 mmol) were reacted with allyl
bromide in the presence of powdered In0 (4:1 THF−H2O,
reflux) to yield mixtures of the 2-amino-1,3-hexenol diaster-
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Table 3. Effect of Added Salt on Barbier Reaction of D-
Glucosamine with In0 and Allyl Bromide in Aqueous 1,4-
a
Dioxane
entry
additive
LiCl
equiv
threo/
yield (%)
1
2
5.0
5.0
5.0
5.0
5.0
5.0
5.0
satd
satd
5.0
7.5:1
5.4:1
5.7:1
4.5:1
3.5:1
5.1:1
4.7:1
3.2:1
2.0:1
2.8:1
96
98
95
98
94
90
98
80
90
84
3
LiBr
4
KCl
5
MgCl2
(n-Bu)4NCl
(n-Bu)4NI
NaCl
6
7
8
9
NH4Cl
LiClO4
10
a
Conditions: solvent ratio, 2:1 dioxane/H2O, 100 °C. PG = H. For
other conditions, see the reaction equation and footnote in Table 1.
Scheme 1
Figure 2. Retrosynthesis of rhizochalinin C (1a).
Scheme 2. Elaboration of the Left-Hand Half of
Rhizochalinin C (1a)*
sufficiently nonpolar to allow recovery and separation by silica
chromatography (51% total yield, dr 7:1 over five steps).24 The
five-step conversion could be scaled up to 5.6 mmol of D-
glucosamine (51% overall yield of 5a) or to 17 mmol, albeit
with some loss in yield (45%) and only slight erosion of dr (7:1
5a:5b).
*
Major geometrical isomer is depicted (E/Z = 9.6:1).
The products 5a and 5b are useful synthons for preparation
of α,ω-dimeric sphingoid bases such as rhizhochalinin C (1a)
according to the retrosynthetic analysis depicted in Figure 2.
The allyl groups corresponding to left-hand and right-hand
halves of the target molecule can be conveniently coupled by
olefin cross-metathesis with suitable differentiation by chain
length and ω-functionalization for final unification of the two
halves by Horner−Emmons−Wadsworth reaction and global
deprotection−hydrogenation to give 1a. A convergent advant-
age arises by derivation of both halves of rhizochalinin C from
the allyl-substituted compounds 5a and 6a that are procured
from the same Barbier allylation of D-glucosamine followed by
differential protections of NH2 and OH groups.
The left-hand half of rhizochalinin C was elaborated as
shown in Scheme 2. Compound 5a was subjected to olefin
cross-metathesis with tetradec-13-enyl acetate in the presence
of Grubbs II catalyst to provide, after methanolysis (NaOMe,
MeOH), primary alcohol 7 (51%, two steps) as an
inconsequential mixture of E/Z isomers (9.6:1) which was
carried forward as such.25 Oxidation of 7 (Dess−Martin
periodinane) to the corresponding aldehyde 8 (80%) followed
by addition of the anion derived from diethyl methylphosph-
onate (n-BuLi, −78 °C, THF)26 and Dess−-Martin oxidation
delivered the β-ketophosphonate 9 (64%, two steps).
The right-hand half of 1a was prepared as shown in Scheme
3. The multistep Barbier allylation−oxidation sequence
(Scheme 1) was repeated on D-glucosamine except for a
different N-protecting group ((Boc)2O, NaHCO3, aq) and
conversion of the 1,3-diol to a benzylidene acetal (benzalde-
hyde dimethyl acetal, CSA) to provide 6 in 35% yield over five
steps. Differential C−O bond cleavage of the benzylidene group
was achieved under two sets of conditions: reduction with in
situ generated alane (AlCl3, LiAlH4, CH2Cl2, 0 °C, 98%)27 or
DIBAL-H (toluene, 0 °C, 67%) to give 10.
The alcohol 10 was transformed into the phenylthio ether to
give 11 (n-Bu3P, (PhS)2, 88%) in preparation for later reductive
removal. Olefin cross-metathesis of 11 with 4-penten-1-yl
acetate (Grubbs II cat.,30 CH2Cl2, reflux) followed by
methanolysis (NaOMe, MeOH) gave primary alcohol 12 as
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1
(1a) as a single stereoisomer (87%). The H NMR, 13C NMR,
[α]D, and HRMS data of the synthetic 1a matched those of the
aglycon derived from natural rhizochalin C (1b). Finally, the
CD spectrum of the tetrabenzoyl derivative 16 (Figure 3)
Scheme 3. Elaboration of the Right-Hand Half of
Rhizochalinin C (1a)
†
Figure 3. CD spectra (CH3OH, 24 °C) of (a) naturally derived 16 and
(b) synthetic 16.
prepared from synthetic 1a (BzCl, pyridine) was identical in
sign and magnitude to that prepared in two steps from naturally
derived 1b,3b confirming the original assignment by deconvo-
lution of CD exciton coupling3c and demonstrating stereo-
chemical integrity (>95% ee) of the final synthetic product.
In conclusion, we have demonstrated a practical and versatile
preparation of D-threo-serine-related synthons in good yield by
a five-step conversion of D-glucosamine. The latter was
exploited for a bidirectional bond construction and convergent
assembly of rhizochalinin C (1a),3 the first total synthesis of a
member of the marine-derived “two-headed” sphingolipids.3f
The method should find utility in the synthesis of other L-threo
sphingoid bases; a subject of ongoing research in our
laboratories that will be reported in due course.
†
Major geometrical isomer is depicted (E/Z = 7:1).
an inconsequential mixture of geometrical isomers (E/Z = 7:1,
85%, two steps) which was carried forward without separation.
Reduction of 12 (Ra-Ni) delivered protected threo-2-amino-3-
alkanol 13 (88%). Oxidation of 13 to aldehyde 14 (Dess−
Martin, 85%) completed the right-hand half of 1a and set the
stage for coupling of the two segments.
Horner−Emmons−Wadsworth reaction of aldehyde 14 and
phosphonate 9 (Scheme 4) under Paterson conditions28
(Ba(OH)2, THF) gave the α,β-unsaturated ketone 15 as a
mixture of E/Z isomers (88%) but exclusively E at C-19, C-20.
Global deprotection of compound 15 (10 M HCl, MeOH, H2 2
atm, Pd−C) gave 1a·2HCl. Purification of the latter salt under
ammoniacal solvent (silica, flash chromatography, 9:4:1 CHCl3,
MeOH, NH4OH aq) afforded the free base rhizochalinin C
EXPERIMENTAL SECTION
■
General Experimental Procedures. General experimental
procedures are described in the Supporting Information and
elsewhere.29 13C NMR signal multiplicities (CH3, CH2, CH, Cq)
were determined from DEPT 90 and DEPT 135 experiments.
General Procedure for Indium-Mediated Allylation (Barbier
Reaction). A mixture of D-glucosamine or N-protected D-glucosamine
(1.16 mmol) and In0 powder (4 equiv) was suspended in solvent (15
Scheme 4. Coupling of Left-Hand and Right-Hand Halves and Global Deprotection To Give Rhizochalinin C (1a)*
*
Major geometrical isomer of 15 is depicted [C-5, C-6 E/Z = 9.6:1; C-23, C-24, E/Z = 7:1].
501
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mL, freshly purified THF, 1,4-dioxane, H2O, or mixtures thereof; see
Tables 1−3) at rt. Allyl bromide (6 equiv) was added, and the mixture
was heated to reflux and allowed to react until no starting material was
evident (TLC) or no change of product to starting material ratio could
be detected (1H NMR, internal calibration with added caffeine) (see
Tables 1−3). The heterogeneous mixture was cooled to room
temperature, the insoluble solid was removed by centrifugation, and
the supernatant was neutralized (pH 7−8) by addition of saturated
NaHCO3. Excess (Boc)2O was added, and the mixture subsequently
stirred at room temperature for 2 h, diluted with methanol, and filtered
with microfilter (0.45 μm). The filtrate was analyzed by HPLC
(reversed-phase C18, 22.5:77.5 CH3CN/H2O, ELSD detector).
removed under reduced pressure, the residue resuspended in methanol
(200 mL) and the insoluble solid removed by filtration. The filtrate
was cooled to 5 °C, sodium borohydride (1.6 g, 42 mmol) was added
slowly, and the solution was stirred for 3 h. After the mixture was
quenched by addition of H2O (50 mL), the volatiles were removed
under reduced pressure. Brine (200 mL) was added to the mixture
followed by extraction with EtOAc (200 mL × 2). The combined
organic extracts were dried with MgSO4 and concentrated under
reduced pressure, and the oily residue dissolved in dry CH2Cl2 (50
mL). Benzaldehyde dimethyl acetal (2.7 mL, 19 mmol) and a catalytic
amount of camphorsulfonic acid (10 mg) were added to the solution,
and the mixture was stirred at room temperature for 5 h. After the
completion of the reaction (TLC), the reaction mixture was quenched
by addition of triethylamine (4 mL) and concentrated under reduced
pressure. The residue was purified by flash chromatography (silica,
elution with 10% ether in hexanes) togive the pure compounds
(4R,5R)-6a and (4S,5R)-6b (total 1.5 g, 35%, five steps, dr = 7:1).
(4R,5R)-6a: FTIR (ATR, neat) ν 1711, 1499, 1365, 1168 cm−1;
[α]D +3.2 (c 0.11, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.45−7.52
(m, 2H), 7.32−7.42 (m, 3H), 5.88 (m, 1H), 5.57 (s, 1H), 5.38 (d, J =
10.3 Hz, 1H), 5.10−5.18 (m, 2H), 4.17 (dd, J = 11.5, 1.7 Hz, 1H),
4.06 (dd, J = 11.5, 1.7 Hz, 1H), 3.98 (m, 1H), 3.70 (m, 1H), 2.41 (m,
1H), 2.32 (m, 1H), 1.46(s, 9H); 13C NMR (100 MHz, CDCl3) δ
155.8 (Cq), 138.1 (Cq), 133.4 (CH), 129.1 (CH), 128.4 (CH), 126.0
(CH), 118.1 (CH2), 101.6 (CH), 79.7 (Cq), 79.5 (CH), 72.2 (CH2),
46.9 (CH), 36.3 (CH2), 28.5 (CH3); HR-ESI-FT-MS m/z [M + Na]+
342.1674, calcd for C18H25NO4Na 342.1681.
Benzyl (4R,5R)-4-Allyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate
(5a and 5b). D-Glucosamine (3.00 g, 13.9 mmol) was suspended in
1,4-dioxane (135 mL) and distilled water (45 mL). Allyl bromide (4.8
mL, 56 mmol) and In0 powder (3.2 g, 28 mmol) were added, and the
mixture was heated at reflux for 20 h. The reaction mixture was cooled
to 10 °C and neutralized to pH 7−8 with 1 M NaOH solution prior to
addition of NaHCO3 (1.7 g, 21 mmol) and benzyl chloroformate (3
mL, 20.8 mmol) with continued stirring at room temperature for 24 h.
After the mixture was recooled to 5 °C, sodium periodate (8.9 g, 41.7
mmol) was added slowly portionwise and the mixture stirred
vigorously for 3 h at room temperature before removal of volatiles
under reduced pressure. The residue was suspended in methanol (200
mL), and insoluble material was removed by filtration. The filtrate was
cooled to 5 °C, and sodium borohydride (1.6 g, 41.7 mmol) was
slowly added followed by stirring for 3 h before quenching by addition
of water (50 mL). Volatiles were removed under reduced pressure, and
the mixture was diluted with brine (200 mL) and extracted with ethyl
acetate (200 mL × 2). The combined organic extracts were dried with
MgSO4 and concentrated under reduced pressure. The oily residue
was dissolved in acetone (50 mL) treated with excess 2,2-
dimethoxypropane (24 mL) and a catalytic amount of camphorsul-
fonic acid (60 mg), and then stirred at room temperature for 5 h. After
completion of the reaction was confirmed by TLC, the reaction was
quenched with triethylamine (9 mL) and the mixture concentrated
under reduced pressure. Purification of the residue by flash
chromatography (silica, 10% Et2O in hexanes) gave the two
diastereomers (4R,5R)-5a and (4S,5R)-5b (total 1.9 g, 45%, dr = 7:1).
(4R,5R)-5a: FTIR (ATR, neat) ν 1715, 1504, 1214, 1085 cm−1;
1
(4S, 5R)-6b: [α]D −22.3 (c 0.16, CHCl3); H NMR (500 MHz,
CDCl3) δ 7.45−7.52 (m, 2H), 7.30−7.40 (m, 3H), 5.95 (m, 1H), 5.43
(s, 1H), 5.10−5.17 (m, 2H), 4.29 (dd, J = 10.8, 4.3 Hz, 1H), 4.27 (br,
1H), 3.75 (m, 1H), 3.59 (m, 1H), 3.50 (dd, J = 10.8, 10.8 Hz, 1H),
2.53 (m, 1H), 2.42 (m, 1H), 1.47(s, 9H); 13C NMR (100 MHz,
CDCl3) δ 155.1 (Cq), 137.9 (Cq), 134.1 (CH), 129.0 (CH), 128.4
(CH), 126.2 (CH), 117.5 (CH2), 101.1 (CH), 80.6 (CH), 80.1 (Cq),
70.0 (CH2), 47.4 (CH), 36.7 (CH2), 28.5 (CH3); HR-ESI-FT-MS m/
z [M + Na]+ 342.1674, calcd for C18H25NO4Na 342.1681.
Benzyl (4R,5R)-4-((E)-15-Hydroxypentadec-2-enyl)-2,2-dimethyl-
1,3-dioxan-5-ylcarbamate (7). To a solution of 5a (709 mg, 2.32
mmol) in dry CH2Cl2 (20 mL) were added tetradec-13-enyl acetate
(3.6 g, 14 mmol) and Grubbs second-generation catalyst (90 mg, 0.10
mmol)30 under N2 at room temperature. After the reaction mixture
was stirred for 2 h under reflux, solvent was removed in vacuo to give a
dark-brown oil. To the stirred solution of dark brown oil in MeOH
(20 mL) at room temperature was added 1 M CH3ONa in methanol
(3.5 mL, 3.5 mmol), and after 2 h, methanol was removed under
reduced pressure. Water (20 mL) was added, the reaction mixture was
extracted with ethyl acetate (30 mL × 2), and the combined organic
extracts were dried with MgSO4 and concentrated under reduced
pressure. Flash chromatography of the residue (silica gel, 15% EtOAc−
hexane) gave alcohol 7 (580 mg, 51% for two steps) as a colorless oil
(E/Z = 9.6:1): FTIR (ATR, neat) ν 1715, 1506, 1215, 1083 cm−1; E-
isomer: 1H NMR (400 MHz, CDCl3) δ 7.28−7.40 (m, 5H), 5.55 (d, J
= 9.9 Hz, 1H), 5.47 (dt, J = 15.4, 6.6 Hz, 1H), 5.34 (dt, J = 15.4, 6.9
Hz, 1H), 5.11 (m, 2H), 4. 03 (dd, J = 11.7, 1.5 Hz, 1H), 3.90 (td, J =
6.9, 1.5 Hz, 1H), 3.72 (dd, J = 12.1, 1.5 Hz, 1H), 3.63 (t, J = 6.6 Hz,
2H), 3.58 (m, 1H), 2.13 (m, 2H), 1.96 (m, 2H), 1.72 (brs, 1H), 1.55
(m, 2H), 1.45 (s, 3H), 1.38 (s, 3H), 1.20−1.36 (m, 18H); 13C NMR
(100 MHz, CDCl3) δ 156.2 (Cq), 136.6 (Cq), 134.4 (CH), 128.7
(CH), 128.3 (CH), 128.2 (CH), 124.2 (CH), 99.3 (Cq), 71.7 (CH),
66.9 (CH2), 65.3 (CH2), 63.2 (CH2), 47.1 (CH), 35.2 (CH2), 33.0
(CH2), 32.8 (CH2), 29.8 (CH3), 29.75 (CH2), 29.73 (CH2), 29.70
(CH2), 29.6 (CH2), 29.56 (CH2), 29.52 (CH2), 29.3 (CH2), 25.9
(CH2), 18.7 (CH3); HR-ESI-FT-MS m/z [M + Na]+ 512.3344 calcd
for C29H47NO5Na 512.3351.
1
[α]D −23 (c 0.083, CHCl3); H NMR (500 MHz, CDCl3) δ 7.30−
7.41 (m, 5H), 5.74−5.83 (m, 1H), 5.57 (dd, J = 9.7 Hz, 1H), 5.05−
5.15 (m, 4H), 4.06 (dd, J = 12.0, 1.7 Hz, 1H), 3.98 (dt, J = 6.9, 1.7 Hz,
1H), 3.77 (dd, J = 12.0, 1.7 Hz, 1H), 3.61 (m, 1H), 2.21 (m, 2H), 1.46
(s, 3H), 1.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.2 (Cq),
136.5 (Cq), 133.4 (CH), 128.6 (CH), 128.2 (CH), 128.1 (CH), 117.8
(CH2), 99.2 (Cq), 72.0 (CH), 66.9 (CH2), 65.2 (CH2), 47.2 (CH),
36.3 (CH2), 29.7 (CH3), 18.6 (CH3); HR-ESI-FT-MS m/z [M + Na]+
328.1516, calcd for C17H23NO4Na 328.1519.
(4S,5R)-5b: FTIR (ATR, neat) ν 1691, 1536, 1225, 1023 cm−1; [α]D
−21 (c 0.076, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.30−7.38 (m,
5H), 5.77−5.88 (m, 1H), 5.03−5.13 (m, 4H), 4.66 (br, 1H), 3.91−
3.94 (m, 1H), 3.55−3.67 (m, 3H), 2.38−2.42 (m, 1H), 2.25−2.29 (m,
1H), 1.42 (s, 3H), 1.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.8
(Cq), 136.3 (Cq), 133.1 (CH), 128.6 (CH), 128.3 (CH), 128.2 (CH),
117.1 (CH2), 98.9 (Cq), 72.2 (CH), 67.0 (CH2), 63.1 (CH2), 49.6
(CH), 37.1 (CH2), 28.1 (CH3), 19.9 (CH3); HR-ESI-FT-MS m/z [M
+ Na]+ 328.1517 calcd for C17H23NO4Na 328.1519.
tert-Butyl (5R)-4-Allyl-2-phenyl-1,3-dioxan-5-ylcarbamate (6a,
6b). D-Glucosamine (3g, 13.9 mmol) was suspended in 1,4-dioxane
(135 mL) and distilled water (45 mL). Allyl bromide (4.8 mL, 56
mmol) and In0 powder (3.2 g, 28 mmol) were added, and the mixture
was heated at reflux for 20 h. The reaction solution was cool to 10 °C
and adjusted to pH 7−8 with 1 M NaOH solution. NaHCO3 (1.7 g,
20.8 mmol) and di-tert-butyl bicarbonate (4.5 g, 21 mmol) were added
to the neutralized solution of allylated D-glucosamine at 5 °C. The
solution was stirred at room temperature for 24 h and then cooled to 5
°C prior to slow, portionwise addition of sodium periodate (8.9 g, 42
mmol). The mixture was stirred vigorously for 3 h at room
temperature, and after completion of reaction, the volatiles were
Benzyl (4R,5R)-2,2-Dimethyl-4-((E)-15-oxopentadec-2-enyl)-1,3-
dioxan-5-ylcarbamate (8). Dess−Martin periodinane (390 mg, 0.92
mmol) was added portionwise to a stirred, cooled (5 °C) solution of
compound 7 (300 mg, 0.61 mmol) in dry CH2Cl2 (10 mL), and after
2 h at 0 °C, the reaction was quenched by the addition of satd aqueous
NaHCO3 (10 mL). The reaction mixture was extracted with CH2Cl2
502
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The Journal of Organic Chemistry
Article
(15 mL × 2), and the combined organic extracts were dried with
MgSO4 and concentrated under reduced pressure. Separation of the
residue by flash chromatography (silica gel, 12% EtOAc−hexane) gave
aldehyde 8 (238 mg, 80%) as a colorless oil (E/Z = 9.6:1): FTIR
mixture was stirred for 1 h then extracted with CH2Cl2 (5 mL × 3).
The combined organic extracts were washed with brine (5 mL), dried
with MgSO4, and concentrated under reduced pressure. Purification of
the residue, as described above, gave 10 (62 mg, 67%) as a colorless
oil: FTIR (ATR, neat) ν 3441, 1692, 1496, 1164 cm−1; [α]D −4.1 (c
1
(ATR, neat) ν 1724, 1505, 1214, 1085 cm−1; H NMR (400 MHz,
1
CDCl3) E-isomer: δ 9.75 (t, J = 1.8 Hz, 1H), 7.29−7.39 (m, 5H), 5.54
(d, J = 9.9 Hz, 1H), 5.45 (dt, J = 15.5, 6.9 Hz, 1H), 5.36 (dt, J = 15.5,
6.9 Hz, 1H), 5.10 (m, 2H), 4.03 (dd, J = 12.0, 1.7 Hz, 1H), 3.90 (td, J
= 6.9, 1.7 Hz, 1H), 3.77 (dd, J = 12.0, 1.7 Hz, 1H), 3.59 (m, 1H), 2.40
(dt, J = 7.5, 1.7 Hz, 2H), 2.14 (dd, J = 6.9, 6.9 Hz, 2H), 1.96 (m, 2H),
1.60 (m, 2H), 1.44 (s, 3H), 1.37 (s, 3H), 1.23−1.37 (m, 16H). 13C
NMR (100 MHz, CDCl3) δ 203.1 (CH), 156.2 (Cq), 136.6 (Cq),
134.4 (CH), 128.7 (CH), 128.3 (CH), 128.2 (CH), 124.2 (CH), 99.3
(Cq), 71.7 (CH), 66.9 (CH2), 65.3 (CH2), 47.1 (CH), 44.1 (CH2),
35.2 (CH2), 32.8 (CH2), 29.8 (CH3), 29.75 (CH2), 29.73 (CH2), 29.6
(CH2), 29.57 (CH2), 29.55 (CH2), 29.51 (CH2), 29.3 (CH2), 22.2
(CH2), 18.7 (CH3); HR-ESI-FT-MS m/z [M + Na]+ 510.3191, calcd
for C29H45NO5Na 510.3190.
0.066, CHCl3); H NMR (500 MHz, CDCl3) δ 7.29−7.39 (m, 5H),
5.82 (m, 1H), 5.09−5.17 (m, 2H), 5.03 (d, J = 8.6 Hz, 1H), 4.67 (d, J
= 11.5 Hz, 1H), 4.45 (d, J = 11.5 Hz, 1H), 3.76 (m, 1H), 3.70 (m,
2H), 3.62 (m, 1H), 2.46 (m, 1H), 2.35 (m, 1H), 1.67 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 156.5 (Cq), 138.0 (Cq), 134.0 (CH),
128.6 (CH), 128.1 (CH), 128.0 (CH), 118.2 (CH2), 79.7 (Cq), 78.1
(CH), 72.4 (CH2), 64.0 (CH2), 54.0 (CH), 35.6 (CH2), 28.5 (CH3).
tert-Butyl (2S,3R)-3-(Benzyloxy)-1-(phenylthio)hex-5-en-2-ylcar-
bamate (11). Compound 10 (406 mg, 1.26 mmol) in THF (10
mL) was added to a solution of tri-n-butylphosphine (786 μL, 3.16
mmol) and phenyl disulfide (190 mg, 3.16 mmol) in THF (10 mL) at
0 °C. After the mixture was stirred at room temperature for 18 h, the
solvent was removed under reduced pressure to give the crude product
which was purified by flash chromatography (silica gel, 5% EtOAc−
hexane) to provide phenylthioether 11 (462 mg, 88%) as a colorless
oil: FTIR (ATR, neat) ν 1712, 1494, 1166 cm−1; [α]D −3.5 (c 0.14,
Benzyl (4R,5R)-4-((E)-16-(Diethoxyphosphoryl)-15-oxohexadec-2-
enyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (9). To a cooled
solution of diethyl methylphosphonate (242 mg, 1.54 mmol) in
THF (10 mL) was added n-butyllithium (2.21 M in hexane, 698 μL,
1.54 mmol) over 10 min at −78 °C followed, after 15 min, by a
solution of aldehyde 8 (251 mg, 0.51 mmol) in THF (10 mL). After
60 min at −78 °C, saturated aqueous NH4Cl was added, and the
mixture was extracted with EtOAc (×3). The combined organic layers
were washed with brine, dried over MgSO4, and concentrated under
reduced pressure. Flash chromatography of the residue (silica, 35%
EtOAc−hexane) gave the secondary alcohol (262 mg) as colorless oil
and starting material (38 mg, 15%). The secondary alcohol (262 mg,
0.41 mmol) was dissolved in dry CH2Cl2 (15 mL), cooled to 0 °C, and
treated portionwise with Dess−Martin periodinane (261 mg, 0.62
mmol) followed by stirring for 2 h at 0 °C. The reaction was quenched
by the addition of satd NaHCO3 solution (10 mL), the mixture
extracted with CH2Cl2 (15 mL × 2), and the combined organic
extracts were dried with MgSO4 and concentrated under reduced
pressure. Flash chromatography of the residue (silica gel, 50% EtOAc−
hexane) gave phosphonate 9 (210 mg, 64% for two steps) as colorless
oil (E/Z = 9.6:1): FTIR (ATR, neat) ν 1714, 1505, 1242, 1023, 970
1
CHCl3); H NMR (500 MHz, CDCl3) δ 7.23−7.42 (m, 9H), 7.13−
7.21 (m, 1H), 5.76 (m, 1H), 5.02−5.15 (m, 2H), 4.96 (d, J = 9.2 Hz,
1H), 4.64 (d, J = 11.5 Hz, 1H), 4.37 (d, J = 11.5 Hz, 1H), 3.87 (m,
2H), 3.16 (dd, J = 13.8, 5.7 Hz, 1H), 2.99 (dd, J = 13.2, 9.2 Hz, 1H),
2.46 (m, 1H), 2.28 (m, 1H), 1.45 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 155.5 (Cq), 138.2 (Cq), 136.1 (Cq), 134.0 (CH), 129.3
(CH), 129.1 (CH), 128.5 (CH), 128.1 (CH), 128.0 (CH), 126.2
(CH), 118.1 (CH2), 79.5 (Cq), 77.5 (CH), 72.5 (CH2), 52.1 (CH),
35.8 (CH2), 35.7 (CH2), 28.5 (CH3); HR-ESI-FT-MS m/z [M + Na]+
436.1919, calcd for C24H31NO3SNa 436.1917.
tert-Butyl (2S,3R,E)-3-(Benzyloxy)-9-hydroxy-1-(phenylthio)non-
5-en-2-ylcarbamate (12). Grubbs second-generation catalyst (45
mg, 0.05 mmol) was added to a solution of compound 11 (437 mg,
1.06 mmol) and 4-penten-1-yl acetate (1.50 mL, 10.6 mmol) in dry
CH2Cl2 (20 mL) under N2 at room temperature and the mixture
stirred for 4 h under reflux. Removal of the volatiles under reduced
pressure gave a dark brown oil which was taken up in MeOH (20 mL)
and treated wtih 1 M NaOMe in methanol (12.7 mL, 12.7 mmol).
After stirring the mixture for 2 h at room temperature, methanol was
removed under reduced pressure and the residue purified by flash
chromatography (silica gel, 20% EtOAc-hexane) to afford compound
12 as a colorless oil (E/Z = 7:1) (423 mg, 85% for two steps): FTIR
(ATR, neat) ν 3443, 1695, 1494, 1162 cm−1; [α]D −3.1 (c 0.093,
1
cm−1; E-isomer: H NMR (500 MHz, CDCl3) δ 7.29−7.40 (m, 5H),
5.52 (d, J = 9.7 Hz, 1H), 5.45 (dt, J = 14.9, 6.9 Hz, 1H), 5.35 (dt, J =
14.9, 6.9 Hz, 1H), 5.11 (m, 2H), 4.14 (m, 4H), 4.04 (dd, J = 12.0, 1.7
Hz, 1H), 3.90 (td, J = 6.9, 1.7 Hz, 1H), 3.77 (dd, J = 12.0. 1.7 Hz, 1H),
3.59 (m, 1H), 3.06 (d, J = 22.9 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H), 2.13
(m, 2H), 1.96 (m, 2H), 1.56 (m, 2H), 1.44(s, 3H), 1.38 (s, 3H), 1.33
(t, J = 6.9 Hz, 6H), 1.21−1.30 (m, 16H); 13C NMR (100 MHz,
CDCl3) δ 202.3 (d, JCP = 6.1 Hz, Cq), 156.2 (Cq), 136.5 (Cq), 134.3
(CH), 128.6 (CH), 128.2 (CH), 128.1 (CH), 124.1 (CH), 99.1 (Cq),
71.6 (CH), 66.8 (CH2), 65.2 (CH2), 62.5 (d, JCP = 6.1 Hz, CH2), 47.0
(CH), 44.1 (CH2), 41.7 (d, JCP = 127.4 Hz, CH2), 35.1 (CH2), 32.7
(CH2), 29.7 (CH3), 29.64 (CH2), 29.60 (CH2), 29.52 (CH2), 29.50
(CH2), 29.4 (CH2), 29.2 (CH2), 29.0 (CH2), 23.5 (CH2), 18.6 (CH3),
16.3 (d, JCP = 6.1 Hz, CH3); HR-ESI-FTMS m/z [M + H]+ 638.3815,
calcd for C34H57NO8P 638.3816.
1
CHCl3); E-isomer: H NMR (500 MHz, CDCl3) δ 7.25−7.41 (m,
9H), 7.13−7.91 (m, 1H), 5.40 (dt, J = 14.9, 6.9 Hz, 1H), 5.23 (dt, J =
14.9, 7.5 Hz, 1H), 4.99 (d, J = 9.2 Hz, 1H), 4.63 (d, J = 11.5 Hz, 1H),
4.36 (d, J = 11.5 Hz, 1H), 3.85 (m, 2H), 3.47 (t, J = 6.3 Hz, 2H), 3.07
(dd, J = 13.2, 5.2 Hz, 1H), 2.88 (dd, J = 13.2, 9.2 Hz, 1H), 2.33 (m,
1H), 2.09 (m, 1H), 1.93 (m, 2H), 1.70 (br, 1H), 1.46 (m, 2H), 1.36(s,
9H); 13C NMR (100 MHz, CDCl3) δ 155.6 (Cq), 138.2 (Cq), 136.1
(Cq), 133.7 (CH), 129.1 (CH), 129.0 (CH), 128.6 (CH), 128.1 (CH),
127.9 (CH), 126.1 (CH), 125.6 (CH), 79.5 (Cq), 77.6 (CH), 72.3
(CH2), 62.3 (CH2), 52.5 (CH), 35.5 (CH2), 34.1 (CH2), 32.1 (CH2),
28.9 (CH2), 28.5 (CH3); HR-ESI-FT-MS m/z [M + Na]+ 494.2337,
calcd for C27H37NO4SNa 494.2336.
tert-Butyl (2R,3R)-3-(Benzyloxy)-1-hydroxyhex-5-en-2-ylcarba-
mate (10). Alane Method. To a cooled suspension of LiAlH4 (90
mg, 2.3 mmol) and 6a (163 mg, 0.51 mmol) in CH2Cl2−diethyl ether
(1:1, 5 mL) at 0 °C was added, dropwise, an ethereal solution of AlCl3
(182 μL, 4.1 M diethyl ether solution, 0.76 mmol) and the mixture
stirred at 25 °C for 2 h before quenching at 0 °C by dropwise addition
of EtOAc (2 mL), followed by H2O (10 mL). The resulting mixture
was extracted with EtOAc (10 mL × 3), and the combined organic
extracts were washed with brine (5 mL), dried with MgSO4, and
concentrated under reduced pressure. Flash chromatography of the
residue (silica, 17% EtOAc−hexane) gave the alcohol 10 (160 mg,
98%) as a colorless oil.
tert-Butyl (2R,3R,E)-3-(Benzyloxy)-9-hydroxynon-5-en-2-ylcarba-
mate (13). To a solution of compound 12 (200 mg, 0.42 mmol) in
methanol (3 mL) was added an excess of Raney 2800 nickel (washed
with methanol three times just prior to use). The reaction mixture was
stirred vigorously at room temperature for 2 h at which point TLC
analysis indicated completion of the reaction. The mixture was filtered
through Celite and the filtrate concentrated under reduced pressure to
a residue that was purified by flash chromatography (silica, 20%
EtOAc−hexane) to provide primary alcohol 13 as a colorless oil (135
mg, 88%, E/Z = 7:1): FTIR (ATR, neat) ν 3444, 1713, 1519, 1206,
1
DIBAL-H Method. To a cooled solution of 6a (92 mg, 0.29 mmol)
in dry CH2Cl2 (3 mL) was added DIBAL-H (575 μL, 1.5 M toluene
solution, 0.86 mmol) at 0 °C, and the reaction mixture was stirred for
2 h. A solution of Rochelle’s salt (3 mL, satd) was added, and the
1059 cm−1; E-isomer: H NMR (500 MHz, CDCl3) δ 7.28−7.38 (m,
5H), 5.53 (dt, J = 15.3, 6.6 Hz, 1H), 5.44 (dt, J = 15.5, 6.8 Hz, 1H),
4.79 (br, 1H), 4.64 (d, J = 11.5 Hz, 1H), 4.49 (d, J = 11.5 Hz, 1H),
3.83 (m, 1H), 3.64 (t, J = 6.4 Hz, 2H), 3.32 (m, 1H), 2.34 (m, 1H),
503
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2.21 (m, 1H), 2.10 (m, 2H), 1.81 (br, 1H), 1.64 (m, 2H), 1.44 (s, 9H),
1.16 (d, J = 6.6 Hz, 3H) 13C NMR (125 MHz, CDCl3) δ 155.6 (Cq),
138.4 (Cq), 133.1 (CH), 128.3 (CH), 127.8 (CH), 127.7 (CH), 126.2
(CH), 81.7 (CH), 78.9 (Cq), 72.4 (CH2), 62.3 (CH2), 47.8 (CH),
34.2 (CH2), 32.2 (CH2), 28.9 (CH2), 28.4 (CH3), 18.6 (CH3); HR-
FAB-MS m/z [M + H]+ 364.2491, calcd for C21H34NO4 364.2488
tert-Butyl (2R,3R,E)-3-(Benzyloxy)-9-oxonon-5-en-2-ylcarbamate
(14). To a cool solution of compound 13 (103 mg, 0.283 mmol) in dry
CH2Cl2 (mL) was added Dess−Martin periodinane (178 mg, 0.420
mmol) at 0 °C, and the reaction mixture was stirred for 2 h at 0 °C.
Saturated aqueous NaHCO3 (5 mL) was added, the reaction mixture
was extracted with CH2Cl2 (5 mL × 2), and the combined organic
extracts were dried with MgSO4 and concentrated under reduced
pressure. Purification of the residue by flash chromatography (silica
gel, 35% EtOAc−hexanes) gave the aldehyde 14 as a colorless oil (87
mg, 85%, E/Z = 7:1): FTIR (ATR, neat) ν 1713, 1505, 1169, 1060
(CH2, C-17), 43.4(CH2, C-19), 34.9 (CH2), 34.6 (CH2), 30.76
(CH2), 30.72 (CH2), 30.71 (CH2), 30.6 (CH2), 30.5 (CH2), 30.46
(CH2), 30.43 (CH2), 30.3 (CH2), 30.2 (CH2), 26.3 (CH2), 26.2
(CH2), 24.9 (CH2), 24.8 (CH2), 16.0 (CH2, C-28); ESI HRMS m/z
509.4288 [M + Na]+, calcd for C28H58N2O4Na 509.4289.
Rhizochalinin C Perbenzoate (16). Perbenzoate 16 was prepared
from synthetic 1a using the previously reported procedure.3f The CD,
1H NMR, and HMRS data for synthetic 16 were in excellent
agreement with those reported for natural-product-derived 16:3f CD,
1
see Figure 3; H NMR (500 MHz, CDCl3) δ 7.35−8.08 (m, 25H),
6.61 (d, J = 9.3 Hz, 1H), 6.36 (d, J = 9.0 Hz, 1H), 5.54 (dt, J = 8.0, 5.0
Hz, 1H), 5.21 (dt, J = 7.9, 5.1 Hz, 1H), 4.88 (m, 1H), 4.55(dd, J =
11.6, 5.9 Hz, 1H), 4.51 (m, 1H), 4.46 (dd, J = 11.6, 5.0 Hz, 1H), 2.36
(t, J = 7.3 Hz, 2H), 2.35 (t, J = 7.3 Hz, 2H), 1.15−1.96 (m, 38H), 1.28
(d, J = 6.7 Hz, 3H); ESI HRMS m/z 1029.5599 [M + Na]+, calcd for
C63H78N2O9Na 1029.5600.
1
cm−1; E-isomer: H NMR (700 MHz, CDCl3) δ 9.76 (s, 1H), 7.28−
7.38 (m, 5H), 5.49 (m, 2H), 4.76 (br, 1H), 4.62 (d, J = 11.4 Hz, 1H),
4.49 (d, J = 11.4 Hz, 1H), 3.81 (m, 1H), 3.31 (m, 1H), 2.50 (t, J = 7.0
Hz, 2H), 2.34 (m, 3H), 2.19 (m, 1H), 1.44 (s, 9H), 1.16 (d, J = 6.6
Hz, 3H) ; 13C NMR (175 MHz, CDCl3) δ 202.2 (CH), 155.5 (Cq),
138.3 (Cq), 131.1 (CH), 128.3 (CH), 127.8 (CH), 127.7 (CH), 127.1
(CH), 81.5 (CH), 78.9 (Cq), 72.4(CH2), 47.8 (CH), 43.2 (CH2), 34.2
(CH2), 28.4 (CH3), 25.1 (CH2), 18.6 (CH3); HR-FAB-MS m/z [M +
H]+ 362.2337, calcd for C21H32NO4 362.2331
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR NMR data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: +1 (858) 534-7115. Fax: +1 (858) 822-0386. E-mail:
tmolinski@ucsd.edu.
Notes
■
Compound 15. Ba(OH)2 monohydrate (20 mg, 0.11 mmol;
activated by heating under low pressure, 0.5 mmHg) was added to a
stirred solution of phosphonate 9 (85 mg, 0.13 mmol) in THF (2
mL). After 30 min, aldehyde 14 (48 mg, 0.13 mmol) in wet THF (4
mL, THF-H2O 40:1) was added and the mixture stirred at room
temperature for an additional 2 h. The mixture was diluted with H2O,
and the aqueous mixture was extracted with CH2Cl2 (×3). The
combined organic extracts were dried with MgSO4 and concentrated,
and the residue was purified by flash chromatography (silica, 35%
EtOAc−hexane) to provide enone 15 as a colorless oil (mixture of E/
Z isomers, 99 mg, 91%): FTIR (ATR, neat) ν 1714, 1505, 1169, 1085
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Y. Su and Anthony Mrse (UCSD) for assistance with
HRMS and NMR measurements, respectively, E. P. Stout for
measurement of CD spectra, and J. Olejniczak for preparation
of N-phthalimido-D-glucosamine. The purchase of the HPLC-
TOF mass spectrometer and the 500 MHz NMR spectrometer
was made possible with funds from the NIH Shared Instrument
Grant program (S10RR025636) and the NSF Chemical
Research Instrument Fund (CHE0741968), respectively. We
are grateful for funding support of this work from the NIH
(AI039978, AI100776).
1
cm−1; E/Z-isomers: H NMR (700 MHz, CDCl3) δ 7.24−7.42 (m,
10H), 6.81 (dt, J = 15.8, 6.6 Hz, 1H), 6.09 (d, J = 15.8 Hz, 1H), 5.53
(d, J = 9.7 Hz, 1H), 5.50 (m, 1H), 5.46 (m, 2H), 5.35 (dt, J = 15.4, 6.6
Hz, 1H), 5.12(m, 2H), 4.77 (d, J = 7.9 Hz, 1H), 4.62 (d, J = 11.4 Hz,
1H), 4.47 (d, J = 11.4 Hz, 1H), 4.02 (d, J = 11.9 Hz, 1H), 3.91 (m,
1H), 3.82 (m, 1H), 3.76 (d, J = 11.9 Hz, 1H), 3.59 (m, 1H), 3.30 (m,
1H), 2.51 (t, J = 7.0 Hz, 2H), 2.33 (m, 1H), 2.27 (m, 2H), 2.20 (m,
1H), 2.18 (m, 2H), 2.14 (m, 2H), 1.97 (m, 2H), 1.58 (m, 2H), 1.45 (s,
3H), 1.42 (s, 9H), 1.38 (s, 3H), 1.21−1.35 (m, 16H), 1.16 (d, J = 6.6
Hz, 3H) 13C NMR (175 MHz, CDCl3) δ 200.8 (Cq), 155.9 (Cq),
155.4 (Cq), 146.3 (CH), 138.2 (Cq), 136.3 (Cq), 134.2 (CH), 131.8
(CH), 130.5 (CH), 128.4 (CH), 128.3 (CH), 128.1 (CH), 128.0
(CH), 127.7 (CH), 127.6 (CH), 126.9 (CH), 123.9 (CH), 99.0 (Cq),
81.6 (CH), 78.8 (Cq), 72.3 (CH2), 71.5 (CH), 66.7 (CH2), 65.1
(CH2), 47.7 (CH), 46.8 (CH), 39.9 (CH2), 34.9 (CH2), 34.1 (CH2),
32.5 (CH2), 32.1 (CH2), 31.0 (CH2), 29.5 (CH3), 29.4 (CH2), 29.3
(CH2), 29.2 (CH2), 29.1 (CH2), 29.0 (CH2), 24.2 (CH2), 18.5 (CH3),
18.4 (CH3); HR-FAB-MS m/z [M + H]+ 845.5685, calcd for
C51H76N2O8 845.5680.
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1
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