Total synthesis of α-1 C-galactosylceramide, an immunostimulatory C-glycosphingolipid, and confirmation of the stereochemistry in the first-generation synthesis

Article abstract of DOI:10.1021/jo201450s

A nonisosteric α-C-glycoside analogue of KRN7000 (α-1C-GalCer, 1) was reported to induce a selective type of cytokine release in human invariant natural killer cells in vitro. We report here a very concise synthetic route to 1 and its analogue 1′. The key steps include olefin cross-metathesis, Sharpless asymmetric epoxidation, and epoxide opening by NaN₃/NH₄Cl. Inversion of configuration at the amide-bearing carbon in the phytosphingosine backbone constructed by epoxide opening in our previous synthesis of 1 was verified, indicating that remote group participation is not involved during the epoxide-opening reaction.

Full text of DOI:10.1021/jo201450s

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pubs.acs.org/joc
Total Synthesis of α-1C-Galactosylceramide, an Immunostimulatory
C-Glycosphingolipid, and Confirmation of the Stereochemistry in the
First-Generation Synthesis
Zheng Liu, Hoe-Sup Byun, and Robert Bittman*
Department of Chemistry and Biochemistry, Queens College of The City University of New York, Flushing, New York 11367-1597,
United States
S
* Supporting Information
ABSTRACT: A nonisosteric α-C-glycoside analogue of
KRN7000 (α-1C-GalCer, 1) was reported to induce a selective
type of cytokine release in human invariant natural killer cells
in vitro. We report here a very concise synthetic route to 1 and
its analogue 1′. The key steps include olefin cross-metathesis,
Sharpless asymmetric epoxidation, and epoxide opening by
NaN3/NH4Cl. Inversion of configuration at the amide-bearing
carbon in the phytosphingosine backbone constructed by
epoxide opening in our previous synthesis of 1 was verified,
indicating that remote group participation is not involved
during the epoxide-opening reaction.
the C-glycoside and the amino acid is shorter than three
carbons.5 To circumvent this limitation, we considered that the
internal alkene introduced into the linker region in previous
synthetic routes to C-glycosylpeptides, instead of being
hydrogenated, can be functionalized into the amino alcohol
moiety in 1. This approach led to our previous synthesis of 1 in
2006.
INTRODUCTION
■
(2′S,3′S,4′R)-2′-N-Hexacosanoylamino-3′,4′-dihydroxyoctadecyl-
α-C-D-galactopyranoside (α-1C-GalCer, 1, Chart 1),1 α-
Chart 1. Structures of KRN7000 (2) and C-Glycoside
Analogues 1 and 3
The synthesis requires construction of three contiguous
stereocenters in the phytosphingosine backbone; the key steps
in our previous route to 1 included Sharpless asymmetric
epoxidation (SAE)6 and an epoxide-opening reaction with
sodium azide under chelation-controlled conditions.1 However,
there are three problems in this synthetic route that still need to
be addressed. First, in the SAE reaction, an epimeric mixture
(1:1) of allylic propargylic alcohols was used;7 thus the
maximum yield of this step is 50%. Obviously, it would be
much more efficient if one could prepare the requisite allylic
propargylic alcohol epimer with a high diastereoisomeric purity
to participate in the SAE reaction. Second, the yield of the azido
diol product 5 formed by epoxide opening of 4 with NaN3/
NH4Cl was poor because 5 was transformed into bicyclic
triazole 6 (30%) via an intramolecular alkyne−azide cyclo-
addition8 (without catalysis by copper, Scheme 1). Attempts to
control the reaction time to maximize the yield of 5 prior to the
formation of 6 were unsuccessful because the Rf values of
reactant 4 and product 5 are nearly identical. An effort to
prevent the formation of 6 by lowering the temperature also
failed, leading to almost complete recovery of 4. Third, there is
an unresolved question9 concerning the stereochemical course
galactosylceramide (2),2 and α-C-galactosylceramide (3)3 are
synthetic glycolipids that bind to a cell surface protein, CD1d,
to activate invariant natural killer T (iNKT) cells. Stimulated
iNKT cells produce cytokines that regulate a wide range of
immune responses. An important challenge in the field of
synthetic glycosphingolipid research is the development of
ligands that selectively polarize the NKT cell response toward
the secretion of either Th1-type (such as interferon-γ, IFN-γ)
or Th2-type (such as IL-4 and IL-13) cytokines since secretion
of either type of cytokine (but not both types simultaneously)
may be useful in disease treatment.
In 2006, we reported that 1 induced higher ratios of IFN-
γ:IL-4 and IFN-γ:IL-13 than 2 and 3 in human iNKT cells.1
From the view of synthesis, 1 is structurally similar to unnatural
C-linked glycopeptides,4 which also feature a C-glycosidic bond
and are synthetically challenging when the carbon chain linking
Received: July 16, 2011
Published: September 28, 2011
© 2011 American Chemical Society
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immunology community. We also confirmed that the epoxide-
opening reaction of 4 with sodium azide proceeded with
inversion of configuration in the first-generation synthesis.
The retrosynthetic plan for the second-generation synthesis
of 1 is outlined in Scheme 3. As in our previous synthesis of 1,
Scheme 1. Opening of Epoxide 4 and Formation of Bicyclic
Triazole 6
Scheme 3. Retrosynthetic Plan to 1
we hypothesized that epoxy alcohol 9 might serve as a synthetic
precursor of 1 through four straightforward transformations: (i)
epoxide opening by azide anion, (ii) reduction of the resulting
azide to the corresponding amine, (iii) N-acylation with a fatty
acid, and (iv) global deprotection. A noteworthy modification is
the absence of the alkyne moiety in the phytosphingosine
chain; thus, the azido diol resulting from the epoxide opening
of 9 in the new synthetic route would not undergo an
intramolecular azide−alkyne click reaction. In turn, 9 can be
obtained from an allylic alcohol via SAE, which can be
disconnected into the simpler synthons, allylic alcohol 11 and
α-C-allyl tetra-O-benzylglycoside 10, by olefin cross-metathesis
(CM).14 Because 11 can be prepared in high enantiomeric
purity,15 SAE will not suffer from the same problem of 50%
maximum yield as was encountered under the kinetic resolution
condition in our previous synthesis of 1.
of the azide-mediated epoxide opening of 4; in a synthetic route
to 3, Pu and Franck disclosed a “retention” phenomenon
during the opening of an α-hydroxy epoxide using Ti(O-
iPr)2(N3)2.10,11 Retention of configuration might occur via
remote group participation.12 Therefore, we decided to
investigate the possibility of intramolecular participation by
the 2′-O-benzyl group to form oxonium ion intermediate 7
(Scheme 2), which on attack by the azide ion would form
amino diol 8 with retention of configuration.
RESULTS AND DISCUSSION
■
Second-Generation Synthesis of 1 and 1′. Our new
synthesis commenced with the preparation of the chain partner
of CM, alkene 11, which was obtained in high yield (86%, two
steps) by Wittig methylenation of aldehyde 13 (synthesized
from 1-hexadecene (12) in four steps and 50% overall yield)15
followed by deprotection of the PMB group under acidic
conditions (Scheme 4). α-C-Allyl tetra-O-benzylgalactoside 10
has already been used as a valuable synthon in CM;16 it was
obtained in 91% yield by allylation of methyl 2,3,4,6-tetra-O-
benzyl-α-D-galactopyranoside with allyltrimethylsilane using a
literature procedure.17 Furthermore, Grubbs and co-workers
demonstrated the utility of α-C-allyl tetra-O-benzylglucoside,
the glucosyl counterpart of 10, in CM with alkenes.14 To our
delight, we found that refluxing allylic alcohol 11 with an excess
of galactosyl olefin 10 (3.0 equiv) in the presence of 10 mol %
(relative to 11) of Grubbs−Hoveyda second-generation catalyst
(15)18 led to formation of CM product 17 in 63% isolated
yield. The E configuration of the alkene moiety in 17 was
confirmed by the coupling constant of the vinylic protons (J =
15.4 Hz). Several attempts to improve the yield of 17 were
unsuccessful. For example, we found that CM between 10 and
PMB-protected allylic alcohol 14 in a 1:3 molar ratio with 25
mol % (relative to 10) of Grubbs second-generation catalyst
(G2) afforded the desired heterodimer 16 in only 34% yield,
along with the homodimer of 10 in ∼28% yield. Reaction of 11
with 10 in a 4:1 molar ratio and 17 mol % of G2 catalyst
(relative to 10) at 45 °C for 21 h provided the desired product
17 in only 38% yield; changing the catalyst from G2 to 15
Scheme 2. Possible Mechanism of Retention in the Opening
of Epoxide 4
Given the importance of the absolute configuration of the
amide-bearing carbon of the phytosphingosine backbone of
glycosphingolipid antigens,10,13 clarification of this stereo-
chemical problem is necessary in the investigation of
structure−activity relationships. Herein, we report the develop-
ment of a more concise and practical route to 1, which will
allow us to make a larger quantity of analogue 1 available to the
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Scheme 4. Synthesis of 1 and 1′
improved the yield of 17 to 52%. Increasing the ratio of 11/10
did not improve the yield.
Confirmation of the Stereochemistry in the First-
Generation Synthesis of 1. The stereochemistry of the
phytosphingosine backbone in 2 strongly affects its bioactivity;
inversion of the configuration of the amide-bearing carbon
gives an analogue that failed to activate iNKT cells to produce
cytokines.13a To investigate the relative configurations in the
phytosphingosine backbone of 1, we initially attempted to
analyze the coupling constants in bicyclic triazole 21 prepared
SAE of 17 provided epoxy alcohol 9 in 77% yield. The
diastereoisomeric purity of 9 was determined to be high (dr
>20:1) by preparing the corresponding (S)-MTPA ester
derivative.19 Epoxide opening of 9 under Sharpless conditions20
(20 equiv of NaN3, 10 equiv of NH4Cl, methoxyethanol/H2O,
110 °C, 20 h) delivered a mixture of azido diol 18 and its C-3
azide regioismer in a ratio of 3:1 and a combined 73% yield,21
whereas at the temperature of refluxing MeOH/H2O, there was
almost complete recovery of reactant 9. Microwave-assisted
opening of epoxide 9 afforded 18 in about the same yield
(71%) but within a much shorter time period (1 h). Unlike the
epoxide-opening reaction of 4 in our previous synthesis,1
reactant 9 and product 18 have different Rf values (hexane/
EtOAc 3:1); thus the reaction can be monitored by TLC. Azide
18 was smoothly converted to the corresponding amine with
1,3-propanedithiol as the reducing agent,22 and in situ N-
acylation with p-nitrophenyl hexacosanoate (19a) afforded
amide 20a (72%, two steps). Because Wong and co-workers23
reported that introduction of a terminal phenyl group into the
amide chain of 2 led to an enhanced production of IFN-γ, we
also prepared amide 20b (49%, two steps) by N-acylation with
p-nitrophenyl 8-phenyloctanoate (19b). The target compounds
1 and 1′ were obtained by BF3·OEt2/EtSH24-mediated
deprotection of the O-benzyl groups in almost quantitative
yield (95 and 92%, respectively). The new route consists of
only six steps from α-C-allyl tetra-O-benzylglycoside 10 and
proceeded in an overall yield of 24% (compared with nine steps
and 11% overall yield in our previous synthesis).1
3
3
from diol 6. As shown in Scheme 5, J3,4 and J2,3 in 21, which
Scheme 5. Synthesis of 21 from 6
should have syn and anti relations, respectively, under the
scenario of inversion, surprisingly have almost the same
3
coupling constants (3J3,4 = 5.8 Hz and J2,3 = 5.6 Hz), and H-
3 displays a triplet-like signal.25 The flexibility of five-membered
rings makes the NMR coupling constants of vicinal protons of
little value in the assignment of relative configurations, and,
indeed, 3Jsyn can be larger or smaller than 3Janti
evidence of J values in 21 alone is unclear with respect to the
.
26 Therefore, our
3
configuration at C-2. Unfortunately, the fact that the key
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3
proton at C-2 position in 21 overlapped with the protons in the
galactose moiety rendered an NOE investigation impossible.
Therefore, we decided to explore the stereochemical
relationships of several model bicyclic triazole compounds
generated from epoxy alcohols through the same sequence of
reactions. The results are summarized in Table 1. It is
the same pattern of J values as 21. Therefore, participation of
the 2′-O-benzyl group in 4 appears not to be involved in the
epoxide opening of 4 with NaN3/NH4Cl.
However, we have still not excluded the possibility that
retention of configuration at the azide-bearing carbon may have
taken place via a mechanism similar to the Ti-catalyzed epoxide
opening/intramolecular delivery of azide from the Ti(IV)
complex as suggested by Tan et al.27 To the best of our
knowledge, only one example of retention of epoxide opening
has been reported with NaN3/NH4Cl,28 but the mechanism
involves neighboring group participation of the d electrons on
iron, which is not applicable in the present reaction. Therefore,
we carried out 2D NOESY experiments with 25 in order to
assign the relative configuration at the C-2 position. As shown
in Table 2, the NOE correlation of H-3 and H-1b is greater
a
3
Table 1. J Values in Bicyclic Triazoles
Table 2. Key NOE Correlations in Bicyclic Triazoles 25 and
a
32
cross-peak integrals
25
32
mixing time
proton pair 300 ms 500 ms 700 ms 300 ms 500 ms 700 ms
H-4/H-3
H-4/H-2
H-4/H-1a
H-4/H-1b
H-3/H-2
H-3/H-1a
H-3/H-1b
1.00
NO
NO
NO
0.34
0.05
0.41
1.00
0.06
NO
NO
0.33
0.13
0.39
1.00
NO
NO
NO
0.27
0.07
0.40
1.00
NO
NO
NO
0.28
0.25
0.42
1.00
0.11
NO
NO
0.31
0.22
0.37
1.00
NO
NO
NO
0.25
0.18
0.31
a
The integral of the H-4/H-3 cross-peak was used as the internal
calibrant (its integral was set to 1.00). NO, not observed.
than that of H-3 and H-2, indicating that H-3 and H-1a/H-1b
are on the same side of the bicyclic ring. Since the NOE
correlation of H-4 and H-3 is greater than that of H-3 and H-2,
we conclude that H-3 and H-4 have a syn relationship, and thus
H-2 and H-3 are anti. It is noteworthy that when a 500 ms
mixing time was used, a weak NOESY cross-peak between H-4
and H-2 is observed, whereas no cross-peak of H-4 and H-1a
(or H-4 and H-1b) is observed (see Supporting Information).
In order to determine the configuration at the C-2 position, we
conducted 2D NOESY experiments with different mixing times
(700, 500, and 300 ms). In this progression, the intensity of the
NOE signals should decrease with a decrease in mixing time,
and the artifacts tend to disappear as the mixing time
decreases.29 The H-2/H-4 cross-peak integrated intensity
disappeared in the spectra recorded with the 300 and 700 ms
mixing times (Table 2). Therefore, we consider the H-2/H-4
cross-peak at the 500 ms mixing time to be an artifact. Thus, we
conclude that H-2 is on the opposite side of the bicyclic ring to
H-3 and H-4.
a
See ref 31 for the preparation of 24, 25, 30, and 31; for the
preparation of the other compounds, see Schemes S5, S6, and S7 in
the Supporting Information.
reasonable that cis-epoxy alcohols 28 and 30 were converted
to bicyclic triazoles 29 and 31 with almost the same J2,3 (1.7,
1.5 Hz) and J3,4 (1.4, 1.3 Hz) values, which both have a anti
3
3
relationship. However, like their sugar counterpart 21, bicyclic
triazoles 23, 25, and 27, which were obtained from trans-epoxy
alcohols 22, 24, and 26, respectively, again show almost
identical J2,3 (5.8, 5.8, 5.5 Hz) and J3,4 (5.8, 4.4, 5.8 Hz)
values, which are anti and syn relations, respectively.
In order to avoid the possibility of remote-group
participation in the epoxide-opening reaction, we prepared 2′-
deoxy epoxide 26, which does not contain a 2′-O-benzyl group.
The bicyclic triazole derivative 27 obtained from 26 exhibited
3
3
In view of the high degree of flexibility of five-membered
rings26 and the small difference in the 3J values between 25 and
21 (or 23), we also carried out 2D NOESY experiments with
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MHz, CDCl3) δ 0.88 (t, J = 7.0 Hz, 3H), 1.20−1.50 (m, 24H), 1.57−
1.67 (m, 2H), 3.68 (q, J = 6.9 Hz, 1H), 3.80 (s, 3H), 4.28 (d, J = 11.4
Hz, 1H), 4.52 (d, J = 11.4 Hz, 1H), 5.16−5.23 (m, 2H), 5.72 (ddd, J =
7.9, 10.3, 17.4 Hz, 1H), 6.85−6.89 (m, 2H), 7.23−7.28 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 14.1, 22.7, 25.4, 29.4, 29.53, 29.58, 29.61,
29.65, 29.67, 29.69, 31.9, 35.5, 55.2, 69.6, 80.3, 113.7, 116.9, 129.3,
130.9, 139.3, 159.0; ESI-HRMS [M + NH4]+ calcd for m/z
C25H46NO2 1 392.3523, found 392.3523. Data for 11: [α]D −7.0 (c
0.6, THF); H NMR (500 MHz, CDCl3) δ 0.88 (t, J = 7.0 Hz, 3H),
1.20−1.42 (m, 24H), 1.46−1.59 (m, 2H), 4.09 (q, J = 6.4 Hz, 1H),
5.09 (dt, J = 10.4, 1.4 Hz, 1H), 5.21 (dt, J = 17.1, 1.4 Hz, 1H), 5.86
(ddd, J = 6.3, 10.4, 17.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
14.1, 22.7, 25.3, 29.3, 29.54, 29.57, 29.64, 29.66, 29.67, 31.9, 37.0, 73.2,
114.5, 141.3; ESI-HRMS [M + Na]+ calcd for m/z C17H34NaO+
277.2502, found 277.2501.
bicyclic triazole 32, which was prepared from epoxy alcohol 22
through the same sequence of transformations and straightfor-
ward manipulation of the protecting groups. As shown in Table
2, the pattern of NOE correlations of 32 is very similar to that
of 25. Again, we identified an artifact between H-4 and H-2 in
the 500 ms mixing time NOESY spectrum that was absent in
the other NOESY spectra.30 According to the analysis of NOE
correlations of 25 and 32 shown in Table 2, we conclude that
opening of trans-epoxy alcohols including 4 with NaN3/NH4Cl
proceeds with inversion of configuration and not with
retention.31
+
27
CONCLUSION
■
(4′R,2′E)-4′-(4″-Methoxybenzyloxy)]-2′-octadecenyl-
(2,3,4,6-tetra-O-benzyl)-α-C-D-galactopyranoside (16). A mix-
ture of 1017 (46 mg, 0.081 mmol) and 14 (82 mg, 0.219 mmol) was
dissolved in CH2Cl2 (5 mL). The solution was degassed by three
freeze−pump−thaw cycles. After Grubbs second-generation catalyst
(18 mg, 0.021 mmol) was added in one portion, the reaction mixture
was stirred at 45 °C for 27 h and was then reduced in volume to 1 mL
under reduced pressure. Purification by flash chromatography on silica
gel (PhMe/EtOAc 10:1, 8:1 to 6:1) provided 16 (25 mg, 34%) as a
In summary, we have achieved a concise total synthesis of 1 and
1′ in only six steps from α-C-allyl tetra-O-benzylglycoside 10
and allylic alcohol 11 and 24% overall yield, using CM with the
Grubbs−Hoveyda second-generation catalyst. The absence of
the alkyne group in the phytosphingosine chain of azido diol 18
circumvents the intramolecular azide−alkyne click reaction that
generated byproduct 6 in the first-generation synthesis, which
employed azido diol 5. Since the assignment of the relative
stereochemistry of the N3-bearing carbon in 5 from analysis of
the vicinal coupling constants (3J2,3 and 3J3,4) of bicyclic triazole
21 was inconclusive, we analyzed the configuration of model
compounds 25 and 32 using 2D NOESY with different mixing
times and verified that opening of epoxide 4 with NaN3 and
NH4Cl proceeds with inversion of configuration.
29
1
clear oil. Data for 16: [α]D +34.5 (c 1.35, CHCl3); H NMR (500
MHz, CDCl3) δ 0.88 (t, J = 7.0 Hz, 3H), 1.15−1.44 (m, 24H), 1.53−
1.64 (m, 2H), 2.32−2.50 (m, 2H), 3.56−3.62 (m, 1H), 3.65−3.70 (m,
1H), 3.71−3.85 (m, 6H), 3.98−4.07 (m, 3H), 4.21 (d, J = 11.5 Hz,
1H), 4.40−4.77 (m, 9H), 5.36 (dd, J = 8.3, 15.4 Hz, 1H), 5.49 (dt, J =
15.4, 6.9 Hz, 1H), 6.81−6.86 (m, 2H), 7.19−7.23 (m, 2H), 7.23−7.35
(m, 20H); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.7, 25.5, 29.4,
29.59, 29.65, 29.7, 31.9, 35.7, 55.2, 67.2, 69.1, 72.1, 72.9, 73.1, 73.2,
74.2, 76.3, 79.4, 113.6, 127.4, 127.5, 127.6, 127.8, 127.9, 128.26,
128.33, 128.4, 129.3, 130.1, 131.0, 133.4, 138.21, 138.24, 138.45,
EXPERIMENTAL SECTION
■
All reactions were carried out under a dry nitrogen atmosphere using
oven-dried glassware and magnetic stirring. The solvents were dried as
follows: THF was heated at reflux over sodium benzophenone ketyl;
toluene was heated at reflux over sodium; CH2Cl2 was dried over
CaH2. Anhydrous iPr2NEt, CH3CN, Et3N, and benzene were used
directly as purchased. Silica gel 60 F254 aluminum TLC plates of 0.2
mm thickness were used to monitor the reactions. The spots were
visualized with short wavelength ultraviolet light or by charring after
spraying with 15% H2SO4. Flash chromatography was carried out with
silica gel 60 (230−400 ASTM mesh). 1H NMR spectra were obtained
on 400 or 500 MHz spectrometers. Chemical shifts were referenced
138.51, 158.9; ESI-HRMS [M + NH4]+ calcd for m/z C60H82NO7
+
928.6086, found 928.6089.
(4′R,2′E)-4′-Hydroxy-2′-octadecenyl-(2,3,4,6-tetra-O-ben-
zyl)-α-C-D-galactopyranoside (17). A mixture of 1017 (160 mg,
0.283 mmol) and 11 (24 mg, 0.094 mmol) was dissolved in CH2Cl2 (5
mL). The solution was degassed by three freeze−pump−thaw cycles.
After Grubbs−Hoveyda second-generation catalyst (6 mg, 0.001
mmol) was added in one portion, the reaction mixture was stirred at
45 °C for 3 h and was then reduced in volume to 1 mL under reduced
pressure. Purification by flash chromatography on silica gel (PhMe/
EtOAc 8:1, 7:1 to 6:1) provided allylic alcohol 17 (47 mg, 63%) as a
1
on residual solvent peaks: CDCl3 (δ = 7.26 ppm for H NMR and
29
1
77.00 ppm for 13C NMR). Optical rotations were measured at rt in a
1.0 dm cell. High-resolution mass spectra were acquired by
electrospray ionization.
colorless wax: [α]D +24.9 (c 2.3, CHCl3); H NMR (500 MHz,
CDCl3) δ 0.88 (t, J = 7.0 Hz, 3H), 1.16−1.44 (m, 24H), 1.45−1.55
(m, 2H), 1.88 (s, 1H), 2.27−2.44 (m, 2H), 3.54 (dd, J = 3.6, 10.4 Hz,
1H), 3.72 (dd, J = 2.7, 7.2 Hz, 1H), 3.75−3.83 (m, 2H), 3.92−4.04
(m, 4H), 4.43−4.75 (m, 8H), 5.47 (dd, J = 6.5, 15.4 Hz, 1H), 5.52 (dt,
J = 6.3, 15.4 Hz, 1H), 7.23−7.35 (m, 20H); 13C NMR (125 MHz,
CDCl3) δ 14.1, 22.6, 25.4, 29.3, 29.57, 29.61, 29.65, 31.9, 36.9, 67.8,
70.8, 72.2, 72.96, 72.99, 73.2, 74.2, 76.3, 127.4, 127.53, 127.60, 127.71,
127.77, 127.82, 127.85, 127.90, 128.2, 128.3, 135.6, 138.0, 138.2,
(3R)-O-(4′-Methoxybenzyl)-1-heptadecen-3-ol (14) and (3R)-
1-Heptadecen-3-ol (11). To a stirred suspension of Ph3PCH3Br
(3.70 g, 10.4 mmol) in anhydrous THF (100 mL) was added n-BuLi
(4.10 mL, 2.5 M in hexane, 10.4 mmol) dropwise at −78 °C. The
mixture was stirred for 3 h at −78 °C. A solution of aldehyde 1315
(3.00 g, 7.97 mmol) in 20 mL of THF was added slowly. The mixture
was stirred overnight, during which time the temperature was
increased slowly from −78 °C to rt. Then 300 mL of hexane was
added. The mixture was passed through a pressed pad of Celite, which
was rinsed with hexane/EtOAc (300 mL, 10:1). The filtrate was
concentrated under reduced pressure to provide the crude PMB-
protected alkene 14, which was dissolved in CH2Cl2 (80 mL). TFA (9
mL, 0.12 mol) was added slowly at 0 °C. The reaction mixture was
stirred at rt for 10 min, and then the reaction was quenched by
dropwise addition of saturated aqueous NaHCO3 solution (caution:
CO2 is released). The resultant neutral biphasic mixture was
transferred to a separatory funnel. The aqueous phase was extracted
with CH2Cl2 (3 × 50 mL). The combined organic phases were washed
with brine, dried (Na2SO4), and concentrated under reduced pressure.
Purification of the residue by flash chromatography on silica gel
(hexane/EtOAc 15:1) provided allylic alcohol 11 (2.34 g, 86%, two
138.3, 138.5; ESI-HRMS [M + NH4]+ calcd for m/z C52H74NO6
+
808.5511, found 808.5505.
(2′R,3′R,4′S)-1-(2′,3′-Oxiran-4′-hydroxyoctadecyl)-(2,3,4,6-
tetra-O-benzyl)-α-C-D-galactopyranoside (9). A mixture of acti-
vated 4 Å molecular sieves (0.5 g), D-(−)-DIPT (85 mg, 0.35 mmol),
and CH2Cl2 (10 mL) was stirred at rt for 30 min. After the mixture
was cooled to −40 °C, Ti(O-iPr)4 (85 μL, 83 mg, 0.29 mmol) was
added. After the resultant mixture was allowed to stir at −40 °C for 1
h, a solution of 17 (230 mg, 0.291 mmol) in 3 mL of CH2Cl2 was
added dropwise. The reaction mixture was stirred at −40 °C for
another 30 min, and cumene hydroperoxide (215 μL, 1.16 mmol, 80%
technical grade) was added via syringe. The reaction mixture was
stored at −20 °C without stirring for 48 h, and then 10% aqueous D-
tartaric acid solution (1 mL) was added. The reaction mixture was
stirred vigorously at rt for 30 min and filtered through a pressed pad of
Celite. The organic layer was separated, and the aqueous layer was
28
1
steps). Data for 14: [α]D +19.5 (c 0.48, CHCl3); H NMR (500
8592
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Featured Article
extracted with CH2Cl2 (3 × 10 mL). The combined organic phases
were concentrated under reduced pressure. The residue was dissolved
in Et2O (10 mL), and 30% aqueous NaOH solution (1 mL) was
added. The biphasic mixture was stirred vigorously at 0 °C for 1 h. The
organic phase was separated, dried (MgSO4), and concentrated.
Purification of the residue by flash chromatography on silica gel
(hexane/EtOAc 3.5:1) afforded epoxy alcohol 9 (180 mg, 77%, dr
>20:1) as a colorless oil. The dr value was determined by analysis of
the corresponding (S)-MTPA esters:19 [α]D28 +41.6 (c 0.7, THF); 1H
NMR (500 MHz, CDCl3) δ 0.87 (t, J = 7.0 Hz, 3H), 1.16−1.57 (m,
26H), 1.67−1.79 (m, 2H), 2.65 (s, 1H), 2.68 (dd, J = 2.1, 5.8 Hz, 1H),
2.81−2.85 (m, 1H), 3.27−3.33 (m, 1H), 3.53 (dd, J = 3.4, 10.6 Hz,
1H), 3.56−3.60 (m, 1H), 3.68 (dd, J = 2.8, 5.9 Hz, 1H), 3.94 (dd, J =
2.9, 4.5 Hz, 1H), 3.99−4.15 (m, 3H), 4.42−4.68 (m, 8H), 7.18−7.34
(m, 20H); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.7, 25.1, 29.3,
29.60, 29.61, 29.63, 29.67, 31.9, 34.0, 54.8, 61.5, 66.6, 70.8, 72.5, 72.7,
73.0, 73.2, 73.4, 73.9, 75.4, 76.6, 127.5, 127.6, 127.7, 127.8, 127.9,
128.0, 128.2, 128.35, 128.36, 128.37, 128.39, 137.80, 138.84, 138.1,
138.3; ESI-HRMS [M + NH4]+ calcd for m/z C52H74NO7+ 824.5460,
found 824.5453.
1H), 4.06−4.20 (m, 3H), 4.43−4.74 (m, 8H), 6.64 (d, J = 6.9 Hz,
1H), 7.22−7.36 (m, 20H); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.7,
25.7, 25.9, 29.3, 29.4, 29.5, 29.7, 31.9, 33.4, 36.5, 73.1, 73.2, 73.4,
127.5, 127.7, 127.9, 128.01, 128.03, 128.10, 128.37, 128.43, 128.49,
137.3, 137.90, 137.97, 138.3, 174.2; ESI-HRMS [M + Na]+ calcd for
+
m/z C78H123NNaO8 1224.9141, found 1224.9139.
To the other half of solution A (2 mL) were added p-nitrophenyl
ester 19b (46 mg, 0.135 mmol) and DMAP (0.5 mg, 4.0 μmol). After
the mixture was stirred at rt for 48 h, the solvent was removed under
reduced pressure. The residue was purified by flash chromatography
on silica gel (hexane/EtOAc 2:1) to provide amide 20b (15 mg, 49%,
1
based on the mixture of 18 and its C-3 regioisomer) as a wax: H
NMR (500 MHz, CDCl3) δ 0.88 (t, J = 7.1 Hz, 3H), 1.12−1.74 (m,
36H), 1.93−2.03 (m, 3H), 2.12−2.20 (m, 1H), 2.57 (t, J = 7.7 Hz,
2H), 3.32−3.43 (m, 3H), 3.62 (dd, J = 2.8, 7.5 Hz, 1H), 3.77−3.81
(m, 1H), 3.83 (t, J = 3.0 Hz, 1H), 3.89−3.97 (m, 1H), 4.06−4.19 (m,
3H), 4.43−4.74 (m, 8H), 6.63 (d, J = 6.9 Hz, 1H), 7.14−7.36 (m,
25H); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.7, 29.4, 29.67, 29.71,
31.9, 35.9, 72.1, 73.1, 73.3, 73.4, 74.1, 127.5, 127.7, 127.86, 127.88,
127.98, 128.00, 128.1, 128.2, 128.37, 128.42, 128.43, 128.49, 137.4,
137.9, 138.0, 138.3, 142.8, 174.1; ESI-HRMS [M + Na]+ calcd for m/z
(2′S,3′S,4′R)-1-(2′-Azido-3′,4′-dihydroxyoctadecyl)-(2,3,4,6-
tetra-O-benzyl)-α-C-D-galactopyranoside (18). Oil bath heating:
NH4Cl (50 mg, 0.935 mmol) and NaN3 (120 mg, 1.85 mmol) were
added to epoxy alcohol 9 (100 mg, 0.124 mmol) in 9 mL of
MeOCH2CH2OH/H2O (8/1). The reaction mixture was stirred at
110 °C for 20 h. The reaction mixture was allowed to cool to rt, and
the solvents were removed under reduced pressure. The residue was
extracted with EtOAc (3 × 10 mL). The combined organic phases
were dried (Na2SO4), filtered, and concentrated under reduced
pressure. Purification of the residue by flash chromatography on silica
gel (EtOAc/hexane 1:4) afforded a mixture of 18 and its C-3 azide
regioisomer (3:1, 77 mg, 73%). Microwave heating: To a solution of
epoxy alcohol 9 (10 mg, 0.0124 mmol) in 1.8 mL of
MeOCH2CH2OH/H2O (8/1) in a 10 mL microwave reaction test
tube were added NH4Cl (6.6 mg, 0.124 mmol) and NaN3 (16 mg,
0.248 mmol). The tube was placed in a microwave reactor. The
reaction was conducted at 140 °C for 1 h. The workup and purification
followed the above procedure to afford a mixture of 18 and its C-3
+
C66H91NNaO8 1048.6637, found 1048.6643.
(2′S,3′S,4′R)-2′-N-Hexacosanoylamino-3′,4′-dihydroxyocta-
decyl-α-C-D-galactopyranoside (1). A solution of 20a (12 mg, 10
μmol) in EtSH/BF3·OEt2 (3:1, 1.3 mL) was stirred at rt for 24 h. The
solvent was evaporated under reduced pressure, and the residue was
purified by flash chromatography on silica gel (CHCl3/MeOH 10:1)
and then was lyophilized with benzene to afford 1 (8 mg, 95%) as a
1
white powder: H NMR (500 MHz, C5D5N) δ 0.85−0.90 (m, 6H),
1.12−1.49 (m, 66H), 1.66−1.74 (m, 1H), 1.81−1.89 (m, 2H), 1.89−
2.02 (m, 2H), 2.29−2.39 (m, 1H), 2.45−2.58 (m, 2H), 2.80 (dt, J =
8.5, 14.7 Hz, 1H), 3.08 (dt, J = 4.3, 14.7 Hz, 1H), 4.25−4.30 (m, 1H),
4.36−4.40 (m, 1H), 4.42−4.48 (m, 2H), 4.52−4.57 (m, 1H), 4.69 (t, J
= 3.0 Hz, 1H), 4.71 (dd, J = 7.6, 11.1 Hz, 1H), 4.79 (dd, J = 4.8, 7.8
Hz, 1H), 5.01−5.06 (m, 1H), 5.32−5.38 (m, 1H), 8.62 (d, J = 8.5 Hz,
1H); 13C NMR (125 MHz, C5D5N) δ 14.8, 23.4, 27.0, 27.1, 30.1,
30.27, 30.34, 30.37, 30.40, 30.42, 30.5, 30.68, 30.9, 32.6, 34.8, 37.5,
51.7, 62.4, 70.3, 71.4, 72.9, 73.3, 73.8, 76.0, 78.7, 174.0; ESI-HRMS [M
+ Na+] calcd for m/z C50H99NNaO8 864.7263, found 864.7271.
+
1
azide regioisomer (3:1, 7.5 mg, 71%). Data for the mixture: H NMR
(2′S,3′S,4′R)-2′-N-8″-Phenyloctanoylamino-3′,4′-dihydroxy
octadecyl-α-C-D-galactopyranoside (1′). A solution of 20b (5 mg,
4.9 μmol) in EtSH/BF3·OEt2 (3:1, 1.3 mL) was stirred at rt for 24 h.
The solvent was evaporated under reduced pressure, and the residue
was purified by flash chromatography on silica gel (CHCl3/MeOH
10:1) and then was lyophilized with benzene to afford 1′ (3 mg, 92%)
as a white powder: 1H NMR (500 MHz, C5D5N) δ 0.87 (t, J = 6.9 Hz,
3H), 1.15−1.53 (m, 30H), 1.65−1.74 (m, 1H), 1.77−1.85 (m, 2H),
1.89−2.01 (m, 2H), 2.31−2.39 (m, 1H), 2.42−2.55 (m, 4H), 2.80 (dt,
J = 8.5, 14.7 Hz, 1H), 3.08 (dt, J = 4.5, 14.7 Hz, 1H), 4.26−4.30 (m,
1H), 4.35−4.40 (m, 1H), 4.42−4.49 (m, 2H), 4.52−4.57 (m, 1H),
4.69 (t, J = 3.1 Hz, 1H), 4.72 (dd, J = 7.6, 11.1 Hz, 1H), 4.79 (dd, J =
4.7, 7.8 Hz, 1H), 5.01−5.06 (m, 1H), 5.33−5.39 (m, 1H), 7.23−7.27
(m, 3H), 7.33−7.38 (m, 2H), 8.58 (d, J = 8.5 Hz, 1H); 13C NMR
(100 MHz, C5D5N) δ 14.8, 23.4, 26.9, 27.1, 29.9, 30.03, 30.08, 30.12,
30.39, 30.46, 30.49, 30.6, 30.9, 32.3, 32.6, 34.9, 36.6, 37.4, 51.7, 62.4,
70.2, 71.5, 72.9, 73.3, 73.8, 76.0, 78.7, 126.5, 129.2, 129.3, 143.7, 174.0;
ESI-HRMS [M + Na]+ m/z calcd for C38H67NNaO8+ 688.4759, found
688.4759.
(S,E)-1-(4′-Hydroxyoctadec-2′-en-5′-ynyl)-(2,3,4,6-tetra-O-
benzyl)-α-C-D-galactopyranoside (35a). A flame-dried 100 mL
round-bottom flask was charged with commercially available
ProPhenol ligand (R,R)-347 (123 mg, 0.192 mmol), 1-tetradecyne
(1.12 g, 5.76 mmol), and toluene (25 mL); see Scheme S1. After the
solution was degassed by two freeze−pump−thaw cycles and filled
with N2, a solution of Me2Zn in toluene (4.8 mL, 1.2 M, 5.76 mmol)
was added rapidly via syringe. The reaction mixture was stirred for 90
min at rt, and gas slowly evolved. A solution of α,β-unsaturated
aldehyde 331 (1.14 g, 1.92 mmol) in 10 mL of toluene, which was
degassed by two freeze−pump−thaw cycles, was added via syringe
over 10 s. The reaction mixture was sealed and cooled to 4 °C for 13
(500 MHz, CDCl3) δ 0.87 (t, J = 7.0 Hz, 3H), 1.15−1.34 (m, 24H),
1.35−1.50 (m, 2H), 1.92−1.99 (m, 1H), 2.18−2.26 (m, 1H), 3.32 (d,
J = 9.8 Hz, 1H), 3.50−3.57 (m, 1H), 3.59−3.66 (m, 2H), 3.69−3.75
(m, 1H), 3.77−3.85 (m, 2H), 3.90−4.02 (m, 2H), 4.40−4.83 (m, 9H),
7.19−7.39 (m, 20H); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.7, 25.9,
29.3, 29.61, 29.63, 29.7, 31.2, 31.9, 61.1, 70.5, 72.02, 72.05, 72.6, 73.16,
73.26, 73.45, 73.65, 74.4, 76.3, 127.6, 127.7, 127.82, 127.84, 128.0,
128.05, 128.15, 128.20, 128.34, 128.40, 128.43, 137.1, 137.9, 138.0,
138.3; ESI-HRMS [M + Na]+ calcd for m/z C52H71N3NaO7
+
872.5184, found 872.5187.
(2′S,3′S,4′R)-2′-N-Hexacosanoylamino-3′,4′-dihydroxyocta-
decyl-(2,3,4,6-tetra-O-benzyl)-α-C-D-galactopyranoside (20a)
and (2′S,3′S,4′R)-2′-N-8″-Phenyloctanoylamino-3′,4′-dihy-
droxyoctadecyl-(2,3,4,6-tetra-O-benzyl)-α-C-D-galactopyrano-
side (20b). To a solution of azido diol 18 and its C-3 azide
regioisomer (3:1, 50 mg, 0.059 mmol) in MeOH (2 mL) were added
Et3N (200 μL, 1.44 mmol) and 1,3-propanedithiol (120 μL, 1.19
mmol). The solution was heated at reflux for 20 h and allowed to cool
to rt. The solvent was removed in vacuo to give a residue, which was
dissolved in anhydrous THF (4 mL, solution A). Solution A was
divided into two 10 mL round-bottom flasks, which were directly used
in the amidation reaction. p-Nitrophenyl ester 19a (46 mg, 0.089
mmol) and DMAP (0.5 mg, 4.0 μmol) were added to the first half of
solution A (2 mL). After the mixture was stirred at rt for 48 h, the
solvent was removed under reduced pressure. The residue was purified
by flash chromatography on silica gel (hexane/EtOAc 3:1 to 5:2) to
provide amide 20a (25 mg, 72%, based on the mixture of 18 and its C-
1
3 regioisomer) as a wax: H NMR (500 MHz, CDCl3) δ 0.85−0.90
(m, 6H), 1.12−1.80 (m, 72H), 1.94−2.07 (m, 3H), 2.11−2.21 (m,
1H), 3.32−3.38 (m, 2H), 3.39−3.44 (m, 1H), 3.62 (dd, J = 2.7, 7.5
Hz, 1H), 3.77−3.81 (m, 1H), 3.83 (t, J = 3.0 Hz, 1H), 3.90−3.96 (m,
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days without stirring. Then the reaction mixture was slowly quenched
with aqueous saturated NH4Cl solution and stirred vigorously for 15
min. The organic layer was separated, and the aqueous layer was
extracted with EtOAc (3 × 100 mL). The combined organic phases
were dried (Na2SO4), filtered, and concentrated under reduced
pressure. Purification of the residue by flash chromatography on silica
gel (hexane/EtOAc 7:2) provided a mixture of 35a and 35b in a ratio
of 3.5:1 (1.35 g, 89% combined yield). The ratio of 35a and 35b and
the absolute configuration of the OH-bearing carbon (C-4 position) in
35a and 35b were determined by analysis of the corresponding (S)-
reaction mixture was heated at reflux for 2 days. The reaction mixture
was allowed to cool to rt, and the solvents were removed under
reduced pressure. The residue was extracted with EtOAc (3 × 10 mL).
The combined organic phases were dried (Na2SO4), filtered, and
concentrated under reduced pressure. Purification of the residue by
flash chromatography on silica gel (EtOAc/hexane 1:3.5) afforded 5
1
(202 mg, 63%): Rf 0.80 (hexane/EtOAc 1:1). The H and 13C NMR
spectra matched the reported data;1 ESI-HRMS [M + Na]+ calcd for
+
m/z C52H67N3NaO7 868.4871, found 868.4876.
Bicyclic triazole 6 (120 mg, 35%) was obtained as a byproduct: Rf
0.25 (hexane/EtOAc 1:1); [α]D24 +29.1 (c 1.6, THF); 1H NMR (400
MHz, CDCl3) δ 0.88 (t, J = 7.1 Hz, 3H), 1.18−1.42 (m, 18H), 1.63−
1.77 (m, 2H), 2.00−2.11 (m, 1H), 2.74 (dd, J = 6.4, 8.5 Hz, 2H),
2.80−2.91 (m, 2H), 3.43 (dd, J = 2.2, 10.6 Hz, 1H), 3.71−3.79 (m,
2H), 3.89−3.92 (m, 1H), 3.97−4.04 (m, 1H), 4.06−4.13 (m, 1H),
4.22 (dt, J = 11.5, 2.5 Hz, 1H), 4.43−4.73 (m, 11H), 4.82 (dd, J = 2.2,
5.2 Hz, 1H), 7.22−7.39 (m, 20H); 13C NMR (100 MHz, CDCl3) δ
14.1, 22.7, 25.6, 27.3, 29.1, 29.34, 29.38, 29.41, 29.58, 29.63, 29.66,
31.9, 60.6, 63.7, 68.0, 72.1, 73.1, 73.2, 73.3, 73.4, 74.0, 76.2, 78.1,
127.6, 127.8, 127.87, 127.93, 128.0, 128.13, 128.18, 128.22, 128.39,
128.45, 128.52, 136.2, 137.1, 137.7, 138.0, 138.2, 143.7; ESI-HRMS
[M + Na]+ calcd for m/z C52H67N3NaO7+ 868.4871, found 868.4883.
(E)-2-{[(2′,3′,4′,6′-Tetra-O-benzyl)-α-C-D-galactopyranoside]-
methyl}-heptadec-2-en-4-ynal (36). Ti(O-iPr)4 (90 μL, 0.3
mmol) and TMSN3 (79 μL, 0.6 mmol) were added to anhydrous
benzene (5 mL), and the solution was heated at 80 °C under N2 for at
least 5 h; see Scheme S3. A solution of epoxides 4 and 4′ (ratio of
3.2:1, 160 mg, 0.2 mmol) in anhydrous benzene (5 mL) was added in
one portion. The mixture was stirred for 30 min at 80 °C and then was
cooled to rt. The solvent was removed under reduced pressure. Then
Et2O (20 mL) was added, followed by 10 mL of a 5% aqueous H2SO4
solution, and the solution was stirred at rt until two clear phases
appeared. The mixture was extracted with CH2Cl2 (3 × 30 mL). The
organic phase was dried over Na2SO4, filtered, and concentrated in
vacuo. Purification of the residue by flash chromatography on silica gel
and (R)-MTPA esters.19 Data for the major diastereoisomer 35a: H
1
NMR (400 MHz, CDCl3) δ 0.88 (t, J = 7.0 Hz, 3H), 1.17−1.43 (m,
18H), 1.43−1.56 (m, 2H), 2.00 (br s, 1H), 2.18 (dt, J = 1.9, 7.2 Hz,
2H), 2.30−2.47 (m, 2H), 3.58 (dd, J = 4.0, 10.6 Hz, 1H), 3.70 (dd, J =
2.6, 7.0 Hz, 1H), 3.73−3.87 (m, 2H), 3.94−3.97 (m, 1H), 3.94−4.08
(m, 2H), 4.43−4.73 (m, 8H), 4.73−4.78 (m, 1H), 5.63 (dd, J = 6.3,
15.3 Hz, 1H), 5.73 (dt, J = 6.6, 15.3 Hz, 1H), 7.23−7.35 (m, 20H);
13C NMR (100 MHz, CDCl3) δ 14.1, 18.8, 22.6, 28.6, 28.9, 29.1, 29.3,
29.5, 29.60, 29.62, 31.9, 63.2, 72.4, 73.0, 73.2, 74.2, 76.3, 79.4, 86.7,
127.46, 127.53, 127.57, 127.73, 127.81, 127.86, 127.91, 128.25, 128.32,
129.4, 132.2, 138.2, 138.3, 138.5; ESI-HRMS [M + Na]+ calcd for m/z
+
C52H66NaO6 809.4752, found 809.4762.
(2′R,3′R,4′S)-1-(2′,3′-Oxiran-4′-hydroxyoctadec-5′-ynyl)-
(2,3,4,6-tetra-O-benzyl)-α-C-D-galactopyranoside (4) and (R,E)-
1-(4′-Hydroxyoctadec-2′-en-5′-ynyl)-(2,3,4,6-tetra-O-benzyl)-
α-C-D-galactopyranoside (35b, Recovered). A mixture of acti-
vated 4 Å molecular sieves (2.0 g), D-(−)-DIPT (480 mg, 2.05 mmol),
and CH2Cl2 (50 mL) was stirred at rt for 30 min. The mixture was
cooled to −40 °C, and Ti(O-iPr)4 (486 mg, 1.71 mmol, 512 μL) was
added; see Scheme S1. After the resultant mixture was allowed to stir
at −40 °C for 1 h, a solution of 35a and 35b (ratio of 3.5:1, 1.35 g,
1.71 mmol) in CH2Cl2 (30 mL) was added over a 15 min period. The
reaction mixture was allowed to stir at −40 °C for another 30 min, and
cumene hydroperoxide (316 μL, 1.71 mmol, 80% technical grade) was
added via syringe. The reaction mixture was stored at −20 °C without
stirring for 3 days, and 10% aqueous D-tartaric acid solution (5 mL)
was added. The reaction mixture was stirred vigorously at rt for 30 min
and filtered through a plug of Celite. The filtrate was separated, and
the aqueous layer was further extracted with CH2Cl2 (3 × 30 mL).
The combined organic phases were concentrated under reduced
pressure. The residue was dissolved in Et2O (50 mL), and a 5%
aqueous NaOH solution (50 mL) was added. The biphasic mixture
was vigorously stirred at 0 °C for 1 h. The organic phase was
separated, dried (MgSO4), and concentrated. Purification of the
residue by flash chromatography on silica gel (hexane/EtOAc 3.5:1)
afforded a mixture of epoxides 4 and 4′ in a ratio of 3.2:1 (1.21 g, 88%
combined yield) as a colorless oil. The ratio of 4 and 4′ and the
absolute configuration of the OH-bearing carbon (C-4 position) in 4
and 4′ were determined by analysis of the corresponding (S)- and (R)-
MTPA esters.19 The 1H and 13C NMR spectra of 4 matched the
1
(hexane/EtOAc 7:1) afforded 36 (55 mg, 35% yield): H NMR (400
MHz, CDCl3) δ 0.88 (t, J = 7.1 Hz, 3H), 1.17−1.36 (m, 16H), 1.43−
1.54 (m, 2H), 2.33 (dt, J = 2.1, 7.2 Hz, 2H), 2.76−2.96 (m, 2H), 3.46
(dd, J = 5.5, 8.9 Hz, 1H), 3.58 (dd, J = 7.8, 9.0 Hz, 1H), 3.77 (dd, J =
2.7, 9.5 Hz, 1H), 4.02−4.05 (m, 1H), 4.08−4.19 (m, 2H), 4.39 (d, J =
11.8 Hz, 1H), 4.48 (d, J = 11.7 Hz, 1H), 4.47−4.53 (m, 1H), 4.57 (d, J
= 11.5 Hz, 1H), 4.64−4.81 (m, 4H), 4.88 (d, J = 11.6 Hz, 1H), 6.42 (t,
J = 2.0 Hz, 1H), 7.20−7.41 (m, 20H), 9.40 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 14.1, 20.1, 22.7, 28.4, 29.0, 29.1, 29.3, 29.5, 29.6, 31.9,
68.2, 70.8, 72.7, 72.8, 73.3, 74.4, 74.7, 76.5, 77.1, 78.5, 110.0, 127.35,
127.38, 127.47, 127.49, 127.62, 127.66, 128.0, 128.1, 128.3, 131.5,
138.3, 138.5, 138.8, 148.4, 193.95; ESI-HRMS [M + H]+ calcd for m/z
+
C52H65O6 785.4776, found 785.4784.
(2′S,3′S,4′R)-1-(2′-Azido-3′,4′-diacetoxyoctadec-5′-ynyl)-
(2,3,4,6-tetra-O-benzyl)-α-C-D-galactopyranoside (37). To a
solution of 5 (29 mg, 0.034 mmol) in anhydrous pyridine (2 mL)
was added Ac2O (0.5 mL, 5.30 mmol) at 0 °C; see Scheme S4. The
reaction mixture was stirred at rt overnight. After the solvent was
removed under reduced pressure, the residue was further dried under
high vacuum (0.7 Torr) for 1 h, dissolved in a minimal volume of
CH2Cl2, and filtered through a pad of silica gel in a Pasteur pipet. The
pad was rinsed with 10 mL of hexane/EtOAc 3:1. Concentration of
1
reported data: ESI-HRMS [M + Na]+ calcd for m/z C52H66NaO7
+
825.4701, found 825.4712. Data for 35b: 1H NMR (500 MHz,
CDCl3) δ 0.88 (t, J = 7.0 Hz, 3H), 1.18−1.39 (m, 18H), 1.45−1.53
(m, 2H), 1.91 (d, J = 6.2 Hz, 1H), 2.18 (dt, J = 1.9, 7.2 Hz, 2H), 2.30−
2.37 (m, 1H), 2.38−2.46 (m, 1H), 3.61 (dd, J = 4.2, 10.7 Hz, 1H),
3.69−3.77 (m, 2H), 3.80−3.88 (m, 1H), 3.95−3.99 (m, 1H), 3.99−
4.07 (m, 2H), 4.45−4.72 (m, 8H), 4.75 (t, J = 5.0 Hz, 1H), 5.64 (dd, J
= 6.0, 15.4 Hz, 1H), 5.78 (dt, J = 6.7, 15.4 Hz, 1H), 7.23−7.35 (m,
20H); 13C NMR (100 MHz, CDCl3) δ 14.1, 18.7, 22.7, 28.6, 28.9,
29.1, 29.3, 29.5, 29.6, 30.4, 31.9, 60.4, 62.9, 67.4, 70.5, 72.0, 72.5, 73.0,
73.1, 73.2, 74.2, 76.3, 79.4, 86.8, 127.48, 127.55, 127.58, 127.60,
127.78, 127.86, 127.95, 128.04, 128.27, 128.34, 129.1, 131.9, 138.2,
138.3, 138.4, 138.5.
1
the filtrate gave diacetate 37 (21 mg, 67%) as a colorless syrup: H
NMR (400 MHz, CDCl3) δ 0.88 (t, J = 7.1 Hz, 3H), 1.20−1.37 (m,
18H), 1.44−1.52 (m, 2H), 1.79−1.88 (m, 1H), 1.97 (s, 3H), 2.01 (s,
3H), 1.95−2.06 (m, 1H), 2.17 (dt, J = 2.0, 7.2 Hz, 2H), 3.64−3.72 (m,
3H), 3.73−3.80 (m, 1H), 3.85−3.91 (m, 1H), 3.99−4.05 (m, 2H),
4.15−4.22 (m, 1H), 4.43−4.78 (m, 8H), 5.09 (dd, J = 3.9, 7.1 Hz,
1H), 5.77 (dt, J = 2.0, 3.9 Hz, 1H), 7.23−7.36 (m, 20H); 13C NMR
(100 MHz, CDCl3) δ 14.1, 18.7, 20.71, 20.74, 22.7, 28.4, 28.9, 29.1,
29.4, 29.5, 29.63, 29.64, 31.9, 63.7, 72.8, 73.0, 73.3, 73.6, 74.1, 76.3,
89.1, 127.5, 127.6, 127.75, 127.76, 127.9, 128.3, 128.4, 138.1, 138.2,
138.4, 138.5, 169.4, 169.7; ESI-HRMS [M + Na]+ calcd for m/z
(2′S,3′S,4′R)-1-(2′-Azido-3′,4′-dihydroxyoctadec-5′-ynyl)-
(2,3,4,6-tetra-O-benzyl)-α-C-D-galactopyranoside (5) and
(4R,5S,6S)-6-[(2′,3′,4′,6′-Tetra-O-benzyl)-α-C-D-galactopyrano-
side]-3-dodecyl-5,6-dihydro-4H-pyrrolo[1,2-e][1,2,3]triazole-
4,5-diol (6). NH4Cl (203 mg, 3.8 mmol) and NaN3 (494 mg, 7.6
mmol) were added to a mixture of epoxy alcohols 4 and 4′ (3.2:1, 320
mg, 0.38 mmol) in 9 mL of MeOH/H2O (8/1); see Scheme S2. The
+
C56H71N3NaO9 952.5083, found 952.5078.
8594
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Featured Article
(4R,5S,6S)-6-[(2′,3′,4′,6′-Tetra-O-benzyl)-α-C-D-galactopyra-
noside]-3-dodecyl-4,5-diacetoxy-5,6-dihydro-4H-pyrrolo[1,2-
e][1,2,3]triazole (21). For the preparation of this compound from 6
(Scheme S4): To a solution of 6 (17 mg, 0.020 mmol) in anhydrous
pyridine (2 mL) was added 0.5 mL (5.3 mmol) of Ac2O at 0 °C. The
solution was stirred at rt overnight. After the solvent was removed
under reduced pressure, the residue was further dried under high
vacuum (0.7 Torr) for 1 h, dissolved in a minimal volume of CH2Cl2,
and filtered through a pad of silica gel in a Pasteur pipet. The pad was
rinsed with 10 mL of hexane/EtOAc 3:1. Concentration of the filtrate
gave diacetate 21 (18 mg, 97%) as a colorless syrup. For the
preparation of compound 21 from 37: A solution of 37 (10 mg, 0.011
mmol) in 2 mL of toluene was heated at reflux overnight. After the
reaction was cooled to rt, removal of the solvent under reduced
pressure provided 21 (10 mg, 100%) as a colorless syrup: [α]D28 −3.0
(c 1.0, THF); 1H NMR (400 MHz, CDCl3) δ 0.88 (t, J = 7.1 Hz, 3H),
1.20−1.36 (m, 18H), 1.54−1.69 (m, 2H), 2.01 (s, 3H), 2.03 (s, 3H),
2.24 (ddd, J = 2.0, 7.8, 15.1 Hz, 1H), 2.57−2.74 (m, 3H), 3.53 (dd, J =
4.9, 10.5 Hz, 1H), 3.64−3.67 (m, 1H), 3.70 (dd, J = 2.7, 7.5 Hz, 1H),
3.77−3.84 (m, 1H), 3.88−3.94 (m, 1H), 3.97 (t, J = 3.0 Hz, 1H),
4.04−4.10 (m, 1H), 4.36−4.75 (m, 9H), 5.81 (t, J = 5.6 Hz, 1H), 6.23
(d, J = 5.8 Hz, 1H), 7.22−7.36 (m, 20H); 13C NMR (100 MHz,
CDCl3) δ 14.1, 20.38, 20.44, 22.7, 25.4, 29.3, 29.4, 29.56, 29.63, 29.7,
31.9, 59.9, 64.0, 67.6, 72.1, 72.9, 73.0, 73.1, 73.9, 76.1, 78.9, 127.47,
127.53, 127.55, 127.62, 127.7, 127.8, 128.0, 128.1, 128.3, 128.39,
128.42, 133.9, 137.9, 138.2, 138.3, 144.0, 169.3, 169.4; ESI-HRMS [M
17H), 1.43−1.59 (m, 3H), 1.72 (s, 1H), 1.98−2.11 (m, 2H), 2.13−
2.24 (m, 3H), 2.30−2.41 (m, 1H), 3.61−3.70 (m, 1H), 3.72−3.76 (m,
1H), 3.77−3.83 (m, 1H), 3.84−3.94 (m, 1H), 3.96−4.07 (m, 2H),
4.46−4.75 (m, 6H), 4.76−4.82 (m, 1H), 5.62 (dd, J = 6.3, 15.3 Hz,
1H), 5.73−5.86 (m, 1H), 7.21−7.38 (m, 15H); 13C NMR (100 MHz,
CDCl3) δ 14.1, 18.8, 22.7, 28.6, 28.9, 29.1, 29.3, 29.5, 29.61, 29.63,
31.9, 35.8, 63.1, 68.0, 71.2, 72.5, 73.2, 73.5, 74.8, 79.4, 86.8, 127.30,
127.47, 127.55, 127.79, 127.84, 128.26, 128.32, 128.34, 129.0, 132.3,
138.3, 138.4, 138.6; ESI-HRMS [M + Na]+ calcd for m/z
+
C45H60NaO5 703.4333, found 703.4338.
(2′R,3′R,4′S)-1-(2′,3′-Oxiran-4′-hydroxyoctadec-5′-ynyl)-
(3,4,6-tri-O-benzyl)-2-deoxy-α-C-D-galactopyranoside (26). A
mixture of activated 4 Å molecular sieves (0.15 g), D-(−)-DIPT
(28.5 mg, 0.122 mmol), and CH2Cl2 (10 mL) was stirred at rt for 30
min; see Scheme S5. After the mixture was cooled to −40 °C, Ti(O-
iPr)4 (29 mg, 0.101 mmol, 30 μL) was added. The resultant mixture
was allowed to stir at −40 °C for 1 h, and a solution of 40a and 40b
(3:2, 115 mg, 0.169 mmol) in CH2Cl2 (3 mL) was added dropwise.
The reaction mixture was allowed to stir at −40 °C for another 30
min, and cumene hydroperoxide (19 μL, 0.10 mmol, 80% technical
grade) was added via syringe. The reaction mixture was stored at −20
°C without stirring for 3 days, and 10% aqueous D-tartaric acid
solution (1 mL) was added. The reaction mixture was stirred
vigorously at rt for 30 min and filtered through a plug of Celite. The
aqueous layer of the filtrate was further extracted with CH2Cl2 (3 × 10
mL). The combined organic phases were concentrated under reduced
pressure. The residue was dissolved in Et2O (20 mL), and 5% aqueous
NaOH solution (20 mL) was added. The biphasic mixture was stirred
vigorously at 0 °C for 1 h. The organic phase was separated, dried
(MgSO4), and concentrated. Purification of the residue by flash
chromatography on silica gel (hexane/EtOAc 4:1 to 3:1) afforded a
mixture of epoxides 26 and 26′ in a ratio of 3.4:1 (38 mg, 32%
combined yield) as a colorless oil. The ratio of 26 and 26′ and the
absolute configurations of the OH-bearing carbons (C-4 position) in
26 and 26′ were determined by analysis of the corresponding (S)- and
(R)-MTPA esters.19 Data for the major diastereoisomer 26: 1H NMR
(500 MHz, CDCl3) δ 0.88 (t, J = 7.0 Hz, 3H), 1.20−1.39 (m, 17H),
1.45−1.52 (m, 2H), 1.52−1.58 (m, 1H), 1.64 (s, 1H), 1.66−1.72 (m,
2H), 2.03−2.10 (m, 1H), 2.19 (dt, J = 1.9, 7.2 Hz, 2H), 2.84−2.87 (m,
1H), 2.92−2.95 (m, 1H), 2.99 (dt, J = 2.0, 5.9 Hz, 1H), 3.56−3.62 (m,
1H), 3.68−3.71 (m, 1H), 3.78−3.83 (m, 1H), 3.99−4.08 (m, 2H),
4.08−4.14 (m, 1H), 4.18−4.22 (m, 1H), 4.51−4.69 (m, 6H), 7.24−
7.36 (m, 15H); 13C NMR (100 MHz, CDCl3) δ 14.1, 18.7, 22.7, 28.5,
28.9, 29.1, 29.3, 29.5, 29.61, 29.64, 31.9, 55.2, 60.4, 62.6, 67.3, 71.5,
72.1, 73.21, 73.28, 73.30, 75.0, 87.2, 127.3, 127.5, 127.63, 127.70,
127.75, 128.1, 128.31, 128.33, 128.38, 137.9, 138.2, 138.5; ESI-HRMS
+ H]+ calcd for m/z C56H72N3O9 930.5263, found 930.5273.
+
(E)-4-[(3′,4′,6′-Tri-O-benzyl)-2′-deoxy-α-C-D-galactopyrano-
side)]-2-butenal (39). A solution of alcohol 3832 (1.10 g, 2.25
mmol) in anhydrous CH2Cl2 (25 mL) at rt was treated with Dess−
Martin periodinane (1.91 g, 4.50 mmol); see Scheme S5. After 1 h,
TLC analysis indicated the complete consumption of the starting
material. An aqueous solution of Na2S2O3 (10%, 5 mL) was added,
and the mixture was stirred until both layers became clear. The organic
layer was separated and washed with saturated aqueous NaHCO3
solution and water and dried (Na2SO4). The solvent was evaporated
under reduced pressure, and the residue was purified by flash
chromatography on silica gel (hexane/EtOAc 3:1) to afford aldehyde
1
39 (1.00 g, 91%) as a colorless oil: H NMR (400 MHz, CDCl3) δ
1.46−4.56 (m, 1H), 1.98−2.08 (m, 1H), 2.36−2.46 (m, 1H), 2.52−
2.62 (m, 1H), 3.70 (dd, J = 3.7, 10.7 Hz, 1H), 3.73−3.78 (m, 1H),
3.81−3.87 (m, 1H), 3.94−4.03 (m, 1H), 4.04−4.15 (m, 2H), 4.50−
4.73 (m, 6H), 6.13 (dd, J = 7.9, 15.7 Hz, 1H), 6.80 (dt, J = 7.0, 15.7
Hz, 1H), 7.24−7.37 (m, 15H), 9.46 (d, J = 7.9 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 33.2, 36.9, 66.3, 67.2, 71.6, 72.2, 73.2, 73.7, 75.0,
127.3, 127.5, 127.60, 127.65, 127.68, 127.8, 128.32, 128.35, 134.5,
138.2, 138.3, 138.5, 154.3, 193.8; ESI-HRMS [M + NH4]+ calcd for
[M + NH4]+ calcd for m/z C45H64NO6 714.4728, found 714.4729.
+
+
m/z C31H38NO5 504.2745, found 504.2746.
(4R,5S,6S)-6-[(3′,4′,6′-Tri-O-benzyl)-2′-deoxy-α-C-D-galacto-
pyranoside]-3-dodecyl-5,6-dihydro-4H-pyrrolo[1,2-e][1,2,3]-
triazole-4,5-diol (41). NH4Cl (12 mg, 0.22 mmol) and NaN3 (28
mg, 0.43 mmol) were added to epoxy alcohols 26 and 26′ (3.4:1, 15
mg, 0.022 mmol) in 2.25 mL of MeOH/H2O (2/0.25); see Scheme
S5. The reaction mixture was heated at reflux for 2 days. The reaction
mixture was allowed to cool to rt, and the solvents were removed
under reduced pressure. The residue was extracted with EtOAc (3 × 5
mL). The combined organic phases were dried (Na2SO4), filtered, and
concentrated under reduced pressure to provide a residue that was
dissolved in 5 mL of toluene. The solution was heated at reflux
overnight, and the solvent was removed under reduced pressure.
Purification of the residue by flash chromatography on silica gel
(hexane/EtOAc 1:1) provided bicyclic triazole 41 along with an
inseparable byproduct (13 mg, 82%, two steps). Data for 41: 1H NMR
(500 MHz, CDCl3) δ 0.88 (t, J = 7.0 Hz, 3H), 1.19−1.39 (m, 20H),
1.57−1.74 (m, 4H), 1.79−1.86 (m, 1H), 2.07−2.14 (m, 1H), 2.70−
2.76 (m, 2H), 2.92 (s, 1H), 3.56 (dd, J = 2.4, 10.9 Hz, 1H), 3.73 (dd, J
= 2.9, 4.4 Hz, 1H), 3.90−3.95 (m, 1H), 4.14−4.19 (m, 1H), 4.21−4.28
(m, 1H), 4.45−4.72 (m, 8H), 4.83−4.88 (m, 1H), 7.24−7.39 (m,
15H); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.7, 25.6, 29.1, 29.36,
29.38, 29.42, 29.59, 29.64, 29.66, 31.9, 71.9, 72.2, 72.89, 72.94, 73.3,
75.0, 78.2, 127.5, 127.7, 127.8, 127.9, 128.1, 128.3, 128.46, 128.51,
(S,E)-1-(4-Hydroxyoctadec-2-en-5-ynyl)-(3,4,6-tri-O-benzyl)-
2-deoxy-α-C-D-galactopyranoside (40a). A flame-dried 100 mL
round-bottom flask was charged with commercially available
ProPhenol ligand (R,R)-347 (76 mg, 0.12 mmol), 1-tetradecyne
(682 mg, 3.51 mmol), and toluene (15 mL); see Scheme S5. A
solution of Me2Zn in toluene (2.9 mL, 1.2 M, 3.51 mmol) was added
rapidly via syringe. The reaction mixture was stirred for 90 min at rt,
and gas slowly evolved. A solution of α,β-unsaturated aldehyde 39
(0.57 g, 1.17 mmol) in 5 mL of toluene was added via syringe over 10
s. The reaction mixture was sealed and cooled to 4 °C for 13 days
without stirring. Then the reaction was slowly quenched with aqueous
saturated NH4Cl solution, with vigorous stirring for 15 min. The
organic layer was separated, and the aqueous layer was extracted with
EtOAc (3 × 30 mL). The combined organic phases were dried
(Na2SO4), filtered, and concentrated under reduced pressure.
Purification of the residue by flash chromatography on silica gel
(hexane/EtOAc 3:1) provided a mixture of 40a and 40b in a ratio of
3:2 (327 mg, 41% combined yield). The ratio of 40a and 40b and the
absolute configuration of the OH-bearing carbon (C-4 position) in
40a and 40b were determined by analysis of the corresponding (S)-
and (R)-MTPA esters.19 Data for the major diastereoisomer 40a: H
1
NMR (400 MHz, CDCl3) δ 0.88 (t, J = 7.0 Hz, 3H), 1.16−1.39 (m,
8595
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Featured Article
136.3, 137.2, 138.0, 138.3, 143.8; ESI-HRMS [M + Na]+ calcd for m/z
C45H61N3NaO6 762.4453, found 762.4463.
with Et2O, and the combined organic layers were dried over MgSO4.
The solvent was evaporated under reduced pressure, and the residue
was purified by flash chromatography on silica gel (hexane/EtOAc
3:1) to afford 22 (1.05 g, 56%, maximum yield 77%, dr >20:1). The dr
value and the absolute configurations of OH-bearing carbons (C-4
position) in 22 were determined by analysis of its corresponding (S)-
and (R)-MTPA esters.19 Data for 22: 1H NMR (500 MHz, CDCl3) δ
0.88 (t, J = 6.9 Hz, 3H), 1.20−1.51 (m, 26H), 1.56−1.62 (m, 2H),
2.13−2.19 (m, 1H), 3.02 (dd, J = 2.5, 3.1 Hz, 1H), 3.11 (dt, J = 2.2,
5.7 Hz, 1H), 3.81 (s, 3H), 4.19 (d, J = 1.6 Hz, 2H), 4.52 (s, 2H),
4.62−4.66 (m, 1H), 6.86−6.90 (m, 2H), 7.26−7.29 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 14.1, 22.7, 25.9, 29.33, 29.35, 29.52, 29.55,
29.64, 29.68, 31.2, 31.9, 55.3, 56.1, 56.9, 59.5, 61.0, 71.3, 82.7, 82.9,
113.8, 129.2, 129.8, 159.4; ESI-HRMS [M + Na]+ calcd for m/z
+
(4R,5S,6S)-6-[(3′,4′,6′-Tri-O-benzyl)-2′-deoxy-α-C-D-galacto-
pyranoside]-3-dodecyl-4,5-diacetoxy-5,6-dihydro-4H-pyrrolo-
[1,2-e][1,2,3]triazole (27). To a solution of 41 (5 mg, 6.7 μmol) in
anhydrous pyridine (1 mL) was added 0.25 mL (2.7 mmol) of Ac2O at
0 °C; see Scheme S5. The solution was stirred at rt overnight. After
the solvent was removed under reduced pressure, the residue was
further dried under high vacuum (0.7 Torr) for 1 h, dissolved in a
minimal volume of CH2Cl2, and filtered through a pad of silica gel in a
Pasteur pipet. The pad was rinsed with 10 mL of hexane/EtOAc 3:1.
Concentration of the filtrate gave diacetate 27 (5 mg, 91%) as a
1
colorless syrup: H NMR (500 MHz, CDCl3) δ 0.88 (t, J = 7.0 Hz,
3H), 1.19−1.35 (m, 18H), 1.50−1.66 (m, 2H), 1.96−2.15 (m, 8H),
2.56−2.72 (m, 4H), 3.59−3.65 (m, 1H), 3.74−3.84 (m, 3H), 3.86−
3.93 (m, 1H), 4.08−4.14 (m, 1H), 4.39−4.74 (m, 7H), 5.83 (t, J = 5.5
Hz, 1H), 6.27 (d, J = 5.8 Hz, 1H), 7.24−7.35 (m, 15H); 13C NMR
(125 MHz, CDCl3) δ 14.1, 20.4, 20.5, 22.7, 25.4, 29.34, 29.35, 29.39,
29.57, 29.64, 29.65, 29.67, 31.9, 60.1, 64.2, 68.0, 71.2, 72.96, 73.00,
79.0, 127.39, 127.43, 127.5, 127.6, 127.7, 127.9, 128.29, 128.32, 128.4,
134.0, 138.26, 138.33, 138.37, 169.49, 169.53; ESI-HRMS [M + H]+
+
C29H46NaO4 481.3288, found 481.3287.
(4R,5S,6S)-3-((4′-Methoxybenzyloxy)methyl)-5,6-dihydro-6-
pentadecyl-4H-pyrrolo[1,2-e][1,2,3]-triazole-4,5-diol (46). To
epoxy alcohol 22 (1.0 g, 2.18 mmol) in 27 mL of
MeOCH2CH2OH/H2O (8:1) were added NH4Cl (1.17 g, 21.8
mmol) and NaN3 (2.83 g, 43.6 mmol); see Scheme S6. The reaction
mixture was heated at reflux for 48 h. The reaction mixture was
allowed to cool to rt, and the solvents were evaporated. The residue
was extracted with CH2Cl2 (3 × 50 mL). The combined extracts were
dried (Na2SO4) and concentrated under reduced pressure. Purification
of the residue by flash chromatography on silica gel (EtOAc/hexane
1:1) afforded 46 (951 mg, 87%, two steps): [α]D26 +3.7 (c 1.7, THF);
1H NMR (500 MHz, CDCl3) δ 0.88 (t, J = 6.9 Hz, 3H), 1.20−1.40
+
calcd for m/z C49H66N3O8 824.4844, found 824.4840.
(S,E)-1-(4′-Methoxybenzyloxy)henicos-5-en-2-yn-4-ol
(44a). A flame-dried round-bottom flask was charged with
commercially available ProPhenol ligand (R,R)-347 (360 mg, 0.563
mmol), alkyne 43 (2.98 g, 16.9 mmol), and 150 mL of toluene; see
Scheme S6. A solution of Me2Zn in toluene (14.1 mL, 1.2 M, 16.9
mmol) was added rapidly via syringe. The reaction mixture was stirred
for 90 min at rt, and gas slowly evolved. A solution of α,β-unsaturated
aldehyde 42 (1.50 g, 5.63 mmol) in a minimal volume of toluene was
added via syringe over 10 s. The reaction mixture was sealed and
cooled to 4 °C for 4 days without stirring. Then the reaction was
slowly quenched with aqueous saturated NH4Cl solution, and the
layers were separated. The aqueous layer was extracted with EtOAc (3
× 200 mL), and the combined organic layers were dried (Na2SO4),
filtered, and concentrated under reduced pressure. Purification of the
residue by flash chromatography on silica gel (hexane/EtOAc 7:2)
provided a mixture of 44a and 44b in a ratio of 3.2:1 (2.15 g, 86%
combined yield). The ratio of 44a and 44b and the absolute
configurations of OH-bearing carbons (C-4 position) in 44a and 44b
were determined by analysis of its corresponding (S)- and (R)-MTPA
esters.19 Data for 44a/44b (ratio = 3.2:1): 1H NMR (400 MHz,
CDCl3) δ 0.88 (t, J = 6.9 Hz, 3H), 1.19−1.43 (m, 26H), 2.01−2.09
(m, 2H), 2.54 (s, 1H), 3.78 (s, 3H), 4.18 (d, J = 1.6 Hz, 2H), 4.52 (s,
2H), 4.84−4.90 (m, 1H), 5.59 (dd, J = 6.1, 15.3 Hz, 1H), 5.87 (dt, J =
6.7, 15.3 Hz, 1H), 6.84−6.89 (m, 2H), 7.24−7.29 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 14.1, 22.6, 28.8, 29.1, 29.3, 29.4, 29.51, 29.55,
29.59, 31.82, 31.86, 55.1, 56.9, 62.8, 71.1, 81.6, 86.1, 113.7, 128.7,
129.3, 129.7, 133.9, 159.3; ESI-HRMS [M + NH4]+ calcd for m/z
(m, 24H), 1.43−1.53 (m, 1H), 1.55−1.66 (m, 1H), 1.78−1.87 (m,
1H), 1.90−1.99 (m, 1H), 3.42−3.47 (m, 1H), 3.81 (s, 3H), 3.81 (m,
1H), 4.42 (dt, J = 3.2, 6.8 Hz, 1H), 4.53 (dd, J = 5.0, 8.3 Hz, 1H), 4.59
(s, 2H), 4.76 (s, 2H), 5.08−5.11 (m, 1H), 6.88−6.92 (m, 2H), 7.27−
7.31 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.7, 25.5, 29.36,
29.38, 29.56, 29.63, 29.68, 29.71, 31.9, 32.2, 55.3, 63.9, 64.8, 66.6, 73.2,
80.7, 114.1, 129.0, 129.8, 138.3, 140.3, 159.7; ESI-HRMS [M + H]+
+
calcd for m/z C29H48N3O4 502.3639, found 502.3651.
(4R,5S,6S)-3-((4′-Methoxybenzyloxy)methyl)-4,5-diacetoxy-
5,6-dihydro-6-pentadecyl-4H-pyrrolo-[1,2-e][1,2,3]triazole
(23). To a solution of 20 mg (40 μmol) of 46 in 1 mL of CH2Cl2
were added Et3N (100 μL, 717 μmol) and Ac2O (50 μL, 530 μmol);
see Scheme S6. The solution was stirred overnight at rt. After the
solvent was removed, the residue was further dried under high vacuum
(0.7 Torr) for 1 h, dissolved in a minimal volume of CH2Cl2, and
filtered through a pad of silica gel in a Pasteur pipet. The pad was
rinsed with 10 mL of hexane/EtOAc 4:1. Concentration gave diacetate
23 (24 mg, 99%) as a colorless syrup: 1H NMR (500 MHz, CDCl3) δ
0.88 (t, J = 6.9 Hz, 3H), 1.20−1.48 (m, 25H), 1.60−1.70 (m, 1H),
1.86−1.96 (m, 1H), 1.99 (s, 3H), 2.06−2.16 (m, 1H), 2.12 (s, 3H),
3.80 (s, 3H), 4.52 (s, 2H), 4.57 (q, J = 6.2 Hz, 1H), 4.65 (s, 2H), 5.54
(t, J = 5.8 Hz, 1H), 6.20 (d, J = 5.6 Hz, 1H), 6.84−6.88 (m, 2H),
7.24−7.28 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 14.1, 20.3, 20.4,
22.6, 25.0, 29.21, 29.24, 29.29, 29.4, 29.52, 29.56, 29.58, 29.62, 31.6,
31.8, 55.2, 62.0, 63.0, 63.7, 72.3, 78.3, 113.7, 129.5, 129.9, 134.9, 140.6,
+
C29H50NO3 460.3785, found 460.3785.
(R)-4-(4″-Methoxybenzyloxy)-1-((2′R,3′R)-3′-pentadecyloxir-
an-2′-yl)but-2-yn-1-ol (22). Four Å molecular sieves (the amount is
not critical if the allyl propargyl alcohol, CH2Cl2, and cumene
hydroperoxide are predried) were added to a solution of D-(−)-DIPT
(881 mg, 3.76 mmol) in 30 mL of dry CH2Cl2; see Scheme S6. The
mixture was stirred at rt for 30 min before it was cooled to −40 °C.
Ti(O-iPr)4 (890 mg, 3.13 mmol) was added to the reaction mixture,
which was stirred for 30 min. After cumene hydroperoxide (578 μL,
3.13 mmol, 80% technical grade) was added, the reaction mixture was
stirred for 30 min. A solution of 44a/44b (ratio of 3.2:1, 1.80 g, 4.07
mmol) in a minimal volume of dry CH2Cl2 was added dropwise, and
the reaction mixture was sealed and stored at −20 °C without stirring
for 3 days. An aqueous precooled (0 °C) solution of tartaric acid (2
mL, 10% w/v) was added dropwise, and the reaction mixture was
stirred vigorously at rt for 30 min and filtered through a pressed pad of
Celite. The organic layer was separated, washed with brine, and
concentrated. The residue was dissolved in Et2O (10 mL) at 0 °C, and
the solution was treated with a solution (1 mL) of 30% w/v NaOH in
saturated brine. The two-phase mixture was stirred vigorously for 1 h
at 0 °C. The phases were separated, the aqueous layer was extracted
159.2, 169.2, 169.4; ESI-HRMS [M + H]+ calcd for m/z C33H52N3O6
+
586.3851, found 586.3848.
(4R,5S,6S)-5,6-Dihydro-3-(hydroxymethyl)-6-pentadecyl-4H-
pyrrolo[1,2-e][1,2,3]triazole-4,5-diol (47). To a solution of 46
(770 mg, 1.53 mmol) in CH2Cl2/H2O (10 mL, 20:1) was added DDQ
(3.48 mg, 15.3 mmol) at rt under N2; see Scheme S6. The reaction
was stirred at rt for 3 h and diluted with CH2Cl2. The solution was
extracted with saturated aqueous NaHCO3 solution, dried (Na2SO4),
and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (CHCl3/MeOH 20:1) to provide triol
25
1
47 (584 mg, 91%) as a white solid: [α]D −4.2 (c 0.52, THF); H
NMR (500 MHz, CD3OD/CDCl3 1:1) δ 0.88 (t, J = 6.9 Hz, 3H),
1.20−1.46 (m, 24H), 1.51−1.61 (m, 1H), 1.67−1.76 (m, 1H), 1.89−
1.98 (m, 1H), 2.02−2.11 (m, 1H), 4.36 (q, J = 6.0 Hz, 1H), 4.42 (t, J =
5.5 Hz, 1H), 4.75 (d, J = 4.8 Hz, 2H), 5.07 (d, J = 5.3 Hz, 1H); 13C
NMR (125 MHz, CD3OD/CDCl3 1:1) δ 13.1, 22.0, 24.7, 28.7, 28.8,
28.9, 29.0, 31.0, 31.3, 54.6, 63.3, 64.0, 79.8, 138.1, 141.4; ESI-HRMS
[M + H]+ calcd for m/z C21H40N3O3 382.30697, found 382.30675.
+
8596
dx.doi.org/10.1021/jo201450s|J. Org. Chem. 2011, 76, 8588−8598

The Journal of Organic Chemistry
Featured Article
(4R,5S,6S)-4,5-Dibenzoyloxy-5,6-dihydro-3-(benzoyloxy)-
methyl)-6-pentadecyl-4H-pyrrolo[1,2-e][1,2,3]triazole (32). To
a solution of 47 (10 mg, 0.026 mmol) in 2 mL of THF were added
iPr2NEt (68 μL, 0.393 mmol), benzoyl chloride (27.4 μL, 0.236
mmol), and DMAP (1 mg, 8.2 μmol) at rt; see Scheme S6. The
solution was stirred overnight at rt. After the solvent was removed, the
residue was further dried under high vacuum (0.7 Torr) for 1 h,
dissolved in a minimal volume of CH2Cl2, and filtered through a pad
of silica gel in a Pasteur pipet. The pad was rinsed with 5 mL of
hexane/EtOAc 3:1. The filtrate was concentrated under reduced
pressure. Purification of the residue by flash chromatography on silica
gel (hexane/EtOAc 15:1) gave 32 (18 mg, 99%) as a slightly yellow
solid: [α]D27 −16.0 (c 0.3, THF); 1H NMR (500 MHz, CDCl3) δ 0.88
(t, J = 7.0 Hz, 3H), 1.17−1.34 (m, 22H), 1.35−1.45 (m, 2H), 1.46−
1.56 (m, 1H), 1.68−1.79 (m, 1H), 2.03−2.13 (m, 1H), 2.23−2.33 (m,
1H), 4.85 (q, J = 6.1 Hz, 1H), 5.54 (d, J = 12.8 Hz, 1H), 5.61 (d, J =
12.8 Hz, 1H), 6.00 (t, J = 5.8 Hz, 1H), 6.61 (d, J = 5.7 Hz, 1H), 7.21−
7.27 (m, 4H), 7.31−7.35 (m, 1H), 7.43 (tt, J = 7.5, 1.2 Hz, 1H), 7.47
(tt, J = 7.5, 1.2 Hz, 1H), 7.54 (tt, J = 7.5, 1.2 Hz, 1H), 7.73−7.77 (m,
2H), 7.87−7.94 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.7,
25.0, 29.3, 29.5, 29.6, 29.7, 31.8, 31.9, 57.7, 62.9, 64.7, 78.8, 128.2,
128.3, 128.4, 128.5, 129.5, 129.7, 129.8, 132.9, 133.4, 133.8, 135.9,
138.7, 164.9, 165.1, 166.1; ESI-HRMS [M + H]+ calcd for m/z
residue was further dried under high vacuum (0.7 Torr) for 1 h,
dissolved in a minimal volume of CH2Cl2, and filtered through a pad
of silica gel in a buret. The pad was rinsed with 5 mL of hexane/EtOAc
4:1. The filtrate was concentrated under reduced pressure. Purification
of the residue by flash chromatography on silica gel (hexane/EtOAc
3:1) gave a mixture of 29 and 23 in a ratio of 2.7:1 (41 mg, 76%
combined yield) as a colorless syrup. Data for the major
1
diastereoisomer 29: H NMR (500 MHz, CDCl3) δ 0.88 (t, J = 6.9
Hz, 3H), 1.20−1.48 (m, 26H), 1.60−1.70 (m, 1H), 1.97−2.06 (m,
1H), 2.01 (s, 3H), 2.11 (s, 3H), 3.80 (s, 3H), 4.43 (dt, J = 1.9, 6.9 Hz,
1H), 4.51 (s, 2H), 4.63 (s, 2H), 5.51 (t, J = 1.7 Hz, 1H), 5.98 (d, J =
1.4 Hz, 1H), 6.84−6.88 (m, 2H), 7.24−7.28 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 14.1, 20.5, 20.7, 22.7, 25.4, 29.1, 29.29, 29.32, 29.5,
29.56, 29.61, 29.65, 31.9, 33.2, 55.2, 62.9, 65.4, 69.1, 72.3, 85.6, 113.7,
127.5, 127.8, 128.0, 129.6, 135.9, 169.4, 169.6.
ASSOCIATED CONTENT
■
S
* Supporting Information
Schemes S1−S7, copies of 2D NOESY spectra of 25 and 32
using different mixing times, and copies of H NMR and 13C
1
NMR spectra of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
+
C42H52N3O6 694.3851, found 694.3850.
(R)-4-(4″-Methoxybenzyloxy)-1-((2′S,3′S)-3′-pentadecyloxir-
an-2′-yl)but-2-yn-1-ol (28). Four Å molecular sieves (the amount is
not critical if the allyl propargyl alcohol, CH2Cl2, and cumene
hydroperoxide are predried) were added to a solution of L-(+)-DIPT
(81 mg, 0.35 mmol) in 5 mL of dry CH2Cl2; see Scheme S7. The
mixture was stirred at rt for 30 min before it was cooled to −40 °C.
Ti(O-iPr)4 (86 μL, 0.29 mmol) was added to the reaction mixture,
which was stirred for 30 min. After cumene hydroperoxide (54 μL,
0.29 mmol, 80% technical grade) was added, the reaction mixture was
stirred for 30 min. A solution of 44a/44b (ratio of 7:1, 128 mg, 0.29
mmol) in a minimal volume of dry CH2Cl2 was added dropwise, and
the reaction mixture was sealed and stored at −20 °C without stirring
for 3 days. After an aqueous precooled (0 °C) solution of tartaric acid
(1 mL, 10% w/v) was added dropwise, the reaction mixture was stirred
vigorously at rt for 30 min and filtered through a pressed pad of Celite.
The organic layer was separated, washed with brine, and concentrated.
The residue was dissolved in Et2O (5 mL) at 0 °C, and the solution
was treated with a solution (1 mL) of 30% w/v NaOH in saturated
brine. The two-phase mixture was stirred vigorously for 1 h at 0 °C.
The phases were separated, the aqueous layer was extracted with Et2O,
and the combined organic layers were dried over MgSO4. The solvent
was evaporated under reduced pressure, and the residue was purified
by flash chromatography on silica gel (hexane/EtOAc 5:1) to afford a
mixture of 28 and 22 in a ratio of 3.7:1 (55 mg, 61% combined yield).
The ratio of 28 and 22 and the absolute configurations of the OH-
bearing carbons (C-4 position) in 28 and 22 were determined by
analysis of its corresponding (S)- and (R)-MTPA esters.19 Data for the
major diastereoisomer 28: 1H NMR (500 MHz, CDCl3) δ 0.88 (t, J =
6.9 Hz, 3H), 1.15−1.49 (m, 26H), 1.51−1.61 (m, 2H), 2.53−2.70 (m,
1H), 2.97−3.02 (m, 2H), 3.79 (s, 3H), 4.17 (d, J = 1.4 Hz, 2H), 4.32−
4.37 (m, 1H), 4.51 (s, 2H), 6.84−6.89 (m, 2H), 7.24−7.29 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 14.1, 22.6, 25.8, 29.29, 29.31, 29.47,
AUTHOR INFORMATION
Corresponding Author
*E-mail: robert.bittman@qc.cuny.edu. Phone: (718) 997-3279.
■
ACKNOWLEDGMENTS
This work was supported by National Institutes of Health
Grant HL-083187.
■
REFERENCES
■
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(29). To epoxy alcohol 28/22 (3.7:1, 42 mg, 0.092 mmol) in 4.5 mL
of MeOCH2CH2OH/H2O (8:1) were added NH4Cl (49 g, 0.92
mmol) and NaN3 (119 g, 1.83 mmol); see Scheme S7. The reaction
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possible involvement of a Payne rearrangement during epoxide
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Although the regioselectivity of epoxide opening of 4 was verified by
converting diol 5 to the corresponding isopropylidene acetal and
analysis of the 13C NMR chemical shift of the acetal carbon,1 this
evidence only supports the generation of a vicinal diol instead of a 2,4-
diol. However, it cannot indicate if a Payne rearrangement is involved
in the opening process. The fact that 5 underwent an intramolecular
click reaction to form 6 on extended reaction times confirms that 5 is a
3,4-diol and not a 2,3-diol and thus excludes the occurrence of a Payne
8597
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The Journal of Organic Chemistry
Featured Article
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1
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