Total synthesis of the cytotoxic anhydrophytosphingosine pachastrissamine (Jaspine B)

Article abstract of DOI:10.1021/jo4013223

A short, 8-step synthesis of the marine natural product pachastrissamine has been developed that relies on a diastereoselective aldol reaction between a suitably protected hydantoin and an optically enriched α-chloroaldehyde. This synthetic route provides new opportunities for exploring structure activity relationships within this family of natural products.

Full text of DOI:10.1021/jo4013223

Note
pubs.acs.org/joc
Total Synthesis of the Cytotoxic Anhydrophytosphingosine
Pachastrissamine (Jaspine B)
Vijay Dhand, Stanley Chang, and Robert Britton*
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6
S
* Supporting Information
ABSTRACT: A short, 8-step synthesis of the marine natural
product pachastrissamine has been developed that relies on a
diastereoselective aldol reaction between a suitably protected
hydantoin and an optically enriched α-chloroaldehyde. This
synthetic route provides new opportunities for exploring structure
activity relationships within this family of natural products.
achastrissamine (1), also known as jaspine B, is a naturally
from the reaction of lithium enolates derived from methyl
ketones with α-chloroaldehydes.10 In a single example, it was
also shown that microwave-assisted heating the β-amidochlor-
ohydrin 4 in a mixture of CH3OH−H2O afforded the β-
hydroxy-γ-lactone 5 in excellent yield (Scheme 1).11 While our
P
occurring anhydrophytosphingosine that possesses a
tetrahydrofuran core1 and was first isolated from the Okinawan
marine sponge Pachastrissa sp. in 2002 by Higa.2 More recently,
Debitus and co-workers reported the isolation of 1 along with a
related anhydrophytosphingosine from the Vanuatuan marine
sponge Jaspis sp. and assigned these compounds the common
names jaspine A (2) and jaspine B (1) (Figure 1).3 The all-cis
Scheme 1. Synthesis of γ-Lactone 5 and a Synthetic Strategy
for Pachastrissamine (1) and Analogues
Figure 1. Anhydrophytosphingosines 1 and 2 and furanodictine A (3).
trisubsituted tetrahydrofuran ring and absolute configuration
(2S,3S,4S) of 1 were assigned by a combination of detailed
NMR spectroscopic studies, mass spectral analysis, and
chemical derivatization (e.g., formation of MTPA mono-
amides).2 Importantly, pachastrissamine exhibited submicro-
molar cytotoxicity against P388, A549, HT29, MEL28, and
HeLa cell lines and represents a potential lead for cancer
therapy.2−4 More recent studies demonstrated that pachastriss-
amine inhibits the activity of sphingomyelin synthase and
consequently increases intracellular ceramide levels, resulting in
apoptosis in tumor cells by a caspase-dependent pathway.5
Owing to its potential importance as a lead for cancer therapy,
considerable effort has been devoted to the synthesis of
pachastrissamine.6−8 Presently, more than 25 syntheses of 1
have been reported; however, many of the synthetic strategies
are lengthy (ranging from 9 to 19 steps) and have limited
ability to access analogues or related natural products (e.g.,
furanodictine A (3))9 due to their reliance on carbohydrates or
amino acids as chiral pool starting materials.
efforts to date have focused almost exclusively on the reaction
of enolates derived from methyl ketones with α-chloroalde-
hydes,12 we endeavored to extend this methodology to the
preparation of aminotetrahydrofuranols, including pachastriss-
amine (1). As outlined in Scheme 1, it was envisaged that the
reaction of a conformationally constrained α-aminoenolate
(e.g., 6) with an α-chloroaldehyde (e.g., 7) would give rise to an
anti-anti-aminochlorohydrin (e.g., 8) based on Evans-Cornforth
type stereodirecting effect of the chlorine atom13 and the
progression of the reaction through a chairlike 6-membered
ring transition structure.14 A subsequent thermal cyclization
would then provide direct access to α-amino-β-hydroxy-γ-
lactones (e.g., 9) and serve as a launching point for the
preparation of pachastrissamine and analogues of this
potentially important natural product. Notably, and in contrast
to chiral pool syntheses of pachastrissamine, this approach
Previously, we have demonstrated that 1,2-anti-configured β-
ketochlorohydrins can be accessed in a straightforward manner
Received: June 20, 2013
© XXXX American Chemical Society
A
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would rely on a single chlorine atom introduced via
organocatalytic asymmetric α-chlorination12 to control the
relative stereochemistry of the amino alcohol function in 1.15
As summarized in Table 1, these studies initiated with an
investigation of the lithium aldol reaction between a small
corresponding chlorohydrin (entries 2 and 3). Similarly,
reaction of the protected diketopiperazines 13 and 14 with
19 provided only small amounts (<10%) of the corresponding
aldol adducts (entries 4 and 5). Based on the modest success
obtained with the TBS protected hydantoin 10, we next
evaluated the benzyl- and Boc-protected analogues 15 and 16,
respectively. As indicated in entries 6 and 7, these hydantoin
derivatives reacted with α-chloropentanal to provide the desired
β-amidochlorohydrins 22 and 23 in good yield and
diastereoselectivity. In the latter example, formation of 23
also involves a 1,3-migration of a Boc protecting group17 and
the β-amidochlorohydrin 23 could be isolated in good yield. It
is noteworthy that this straightforward strategy for the synthesis
of 23 could also be exploited for the preparation of various β-
hydroxy-α-amino acids by radical reduction of the chlorome-
thine function,18 or more elaborate amino acid derivatives
through displacement of the chloride with nitrogen or oxygen
nucleophiles.
Table 1. Lithium Aldol Reactions between α-Chloroaldehyde
( )-19 and Different α-Amino Amides
Following the successful preparation of the β-amidochlor-
ohydrins 20, 22, and 23, we next investigated the thermal
cyclization of these compounds.11 Fortunately, while attempts
to effect cyclization of the β-amidochlorohydrins 20 or 22 at
temperatures ranging from 50 °C to reflux in a variety of
solvents (e.g., H2O, CH3OH, DMSO, MeCN, pH 7 buffered
H2O) led largely to their decomposition,11 heating of the β-
amidochlorohydrin 23 in a mixture of CH3OH−H2O afforded
the γ-lactone 27, which could be isolated in 15% yield along
with the fully deprotected β-amidochlorohydrin 28 (Table 2,
Table 2. Reaction Conditions for Formation of the γ-
Lactone 27 from 23
a
b
c
entry
solvent(s)
temp (°C)
27:28 (% yield)
1
2
3
4
5
6
H2O−CH3OH (1:1)
dimethyl carbonate
DMSO
60
60
1:3 (62)
d
nd
d
60
nd
H2O−CH3OH (1:1)
H2O-tBuOH (1:1)
H2O−CF3CH2OH (1:1)
H2O−CH3OH (1:1.2)
100
100
100
100
1.7:1
1.1:1
1.2:1
e
7
2.7:1 (58)
a
b
Reaction carried out in a sealed tube in an oil bath. Determined by
analysis of 1H NMR spectra recorded on crude reaction mixture.
c
d
e
Combined isolated yield. No product detected. Reaction carried out
in a microwave reactor.
entry 1). Surprisingly, we were unable to convert the
chloroamide 28 into the corresponding lactone even after
heating at reflux for more than 24 h in H2O, which resulted in
complete recovery of the starting material. Together, these
results suggest that formation of the desired γ-lactone 27 most
likely proceeds via initial deprotection of the Boc-protected
alcohol in 23 to provide the chlorohydrin 24 (Scheme 2). A
second deprotection would then afford the chloroamide 28,
while a structural rearrangement from the hydantoin 24 to
carbamate 25 is a necessary step preceding the formation of γ-
lactone 27. In an effort to optimize the fortuitous rearrange-
ment of hydantoin 24 to carbamate 25 necessary for the
formation of lactone 27, we screened a variety of solvents and
temperatures for this reaction (Table 2). As indicated in entries
2 and 3, heating of chlorohydrin 23 in dimethyl carbonate or
DMSO at 60 °C afforded none of the desired γ-lactone 27.
Interestingly, formation of the γ-lactone 27 was significantly
enhanced when the reaction was heated in a mixture of
a
Conditions: (A) LDA, THF, −78 °C, 30 min, then 19; (B) LiHMDS,
b
THF, −78 °C, 30 min, then 19. Yield and diastereomeric ratio
determined by analysis of 1H NMR spectra recorded on crude reaction
c
products with internal standard. The relative stereochemistry was not
determined. No product detected. Products partially decompose
during purification by flash column chromatography. Major
diastereomer is 23 (isolated in 45% yield).
d
e
f
collection of α-amino lactams/lactones 10-1616 and α-
chloropentanal (19).12a As indicated in entry 1, treatment of
the TBS-protected hydantoin 10 with freshly prepared lithium
diisopropylamide, followed by slow addition of the α-
chloroaldehyde 19 afforded the desired aldol adduct in 50%
yield albeit with low diastereoselectivity (dr = 1:1).
Unfortunately, coupling of the lithium enolates derived from
compounds 11 or 12 with α-chloroaldehyde 19 under the same
conditions failed to provide detectable amounts of the
B
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Scheme 2. Potential Mechanism for the Formation of γ-
Lactone 27
Scheme 3. Total Synthesis of (+)-Pachastrissamine (1) and
the Dodecyl Analogue 39
CH3OH−H2O at 100 °C (entry 4). Further increases to the
reaction temperature (eg., 120 °C in a microwave reactor) in
CH3OH−H2O (1:1) did not alter the ratio of γ-lactone 27 to β-
amidochlorohydrin 28. To further examine this process, a series
of solvent mixtures were examined. As indicated in entries 5
and 6, heating the β-amidochlorohydrins 23 in H2O−tBuOH or
H2O−CF3CH2OH under the same reaction conditions failed to
improve on the results obtained in CH3OH−H2O (1:1). After
screening the reaction in several different mixtures of CH3OH−
H2O, we eventually found that the ratio of γ-lactone 27 to β-
amidochlorohydrin 28 could be optimized to 2.7:1 in a H2O−
CH3OH mixture of 1:1.2 (entry 7). This latter reaction could
be carried out in a microwave reactor and was complete in 20
min, affording the desired γ-lactone 27 in 40% yield
accompanied with a 18% yield of the deprotected β-
amidochlorohydrin 28 (entry 7).
Having developed a short synthetic route to the γ-lactone 27,
we focused our efforts on applying this strategy to the total
synthesis of (+)-pachastrissamine (1). As depicted in Scheme 3,
the synthesis of 1 commenced with the asymmetric α-
chlorination of 6-heptenal (29) following the procedure
reported by MacMillan.12c While the chlorination of
hexadecanal would eliminate two steps from the total synthesis
(see below), the choice of 6-heptenal provides opportunities for
the late stage production of pachastrissamine analogues through
cross metathesis.19 A subsequent aldol reaction between the
Boc-protected hydantoin 16 and the optically enriched α-
chloroaldehyde 30 afforded a mixture of chlorohydrins in good
yield (68%) and diastereoselectivity (dr = 10:1:1:1), from
which the desired aldol adduct could be isolated in 52% yield.
Cyclization of the chlorohydrin 32 using the optimized reaction
conditions (Table 2, entry 7) produce a 2.7:1 mixture of the
desired the γ-lactone 33 and the chlorohydrin 34, in 60% yield.
Cross-metathesis of the purified the γ-lactone 33 with 1-
undecene catalyzed by the second-generation Grubbs−
Hoveyda catalyst20 afforded the corresponding tetradecene,
which was directly hydrogenated to give the lactone 35 in 43%
yield over the two steps. Reduction of the lactone function
involved treatment of compound 35 with DIBAL-H followed
by reaction of the resulting mixture of lactols with Et3SiH and
providing access to structural analogues of pachastrissamine,
the γ-lactone 33 was also converted into the truncated
derivative 39 (i.e., dodecyl analogue) following an identical
sequence of reactions that initiated with cross metathesis of 33
with 1-nonene (see inset, Scheme 3).
In conclusion, we have developed a short (eight step, 5%
overall yield) asymmetric synthesis of pachastrissamine (1) that
relies on the diastereoselective aldol reaction between a Boc-
protected hydantoin and an optically enriched α-chloroalde-
hyde to secure the correctly configured core of 1. A fortuitous
Boc protecting group migration proved key in the thermal
cyclization of this material, which proved to be extremely
sensitive to both temperature and solvent. Notably, the present
synthesis compares well with those reported and, as
demonstrated through the production of the dodecyl analogue
39, should be readily adapted to the production of analogues of
pachastrissamine through cross-metathesis or initiation of the
process with other readily available α-chloroaldehydes (e.g., 27,
Scheme 2). Furthermore, the ready access to optically enriched
β-amidochlorohydrins afforded by this process may also prove
useful for the production of β-hydroxyamino acids and other
more elaborate amino acid derivatives.
21
BF3·OEt2 to afford the cyclic carbamate 37.6b Finally, the
carbamate was removed under basic conditions to afford
(+)-pachastrissamine (1) in 91% yield. The spectroscopic data
(1H NMR, 13C NMR, HRMS, and IR) of our synthetic
pachastrissamine (1) were in complete agreement with those
reported in the literature,6c and the specific rotation was
consistent with that reported ([α]D = +10 (c = 0.48 CHCl3)).6c
To further demonstrate the potential of this synthetic route for
EXPERIMENTAL SECTION
Preparation of ( )-Hydantoin 23. To a cold (−78 °C), stirred
solution of hexamethyldisilazane (1.2 mL, 5.5 mmol) in THF (4.0
■
C
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mL) was added n-butyllithium (2.59 M solution in hexanes, 2.0 mL,
5.1 mmol) dropwise. The resulting mixture was allowed to warm to rt
slowly over 15 min and then added dropwise via cannula to a cold
(−78 °C), stirred solution of Boc-protected hydantoin 16 (1.4 g, 4.6
mmol) in THF (34 mL). After the mixture was stirred for 45 min,
( )-2-chloropentanal (19) (674 mg, 5.5 mmol) in THF (4.0 mL) was
added dropwise, and the resulting mixture was stirred for an additional
1.2 h. After this time, the reaction was treated with saturated aqueous
solution of sodium dihydrogen phosphate (10 mL) and diluted with
EtOAc (60 mL) and H2O (60 mL). The phases were separated, and
the aqueous phase was extracted with EtOAc (3 × 50 mL). The
combined organic phases were washed with brine (50 mL), dried
(MgSO4), filtered, and concentrated. Purification of the crude product
by flash chromatography (silica gel, hexanes−EtOAc 3:1) afforded
hydantoin 23 (876 mg, 45%) as a colorless oil. The stereochemical
assignment for compound 23 was based on analysis of 1D NOESY
spectra and comparison of its spectral data with that recorded on the
744 cm−1. HRMS: [M + H]+ calcd for C7H12ClO 147.0566, found
147.0571.
Preparation of Hydantoin 32. To a cold (−78 °C), stirred
solution of hexamethyldisilazane (1.4 mL, 6.6 mmol) in THF (6.0
mL) was added n-butyllithium (2.66 M solution in hexanes, 2.3 mL,
6.0 mmol) dropwise. The resulting mixture was allowed to warm to rt
slowly over 15 min and then added dropwise via cannula to a cold
(−78 °C), stirred solution of Boc-protected hydantoin 16 (1.65 g, 5.5
mmol) in THF (36 mL). After the mixture was stirred for 45 min,
(+)-(R)-2-chlorohept-6-enal (30) (886 mg, 6.0 mmol) in THF (4.0
mL) was added dropwise, and the resultant mixture was stirred for an
additional 1.2 h. After this time, the reaction mixture was treated with
saturated aqueous sodium dihydrogen phosphate (10 mL) and diluted
with EtOAc (60 mL) and H2O (60 mL). The phases were separated,
and the aqueous phase was extracted with EtOAc (3 × 50 mL). The
combined organic phases were washed with brine (50 mL), dried
(MgSO4), filtered, and concentrated. Purification of the crude product
by flash chromatography (silica gel, hexanes−EtOAc 3:1) afforded the
hydantoin (32) as a white solid (1.28 g, 52%). [α]25D: −12 (c 0.65,
1
structurally related hydantoin 35 (see below). H NMR (400 MHz,
CDCl3) δ: 5.68 (br s, 1H), 5.11 (dd, 1H, J = 5.2, 2.1 Hz), 4.39 (dd,
1H, J = 2.1, 1.5 Hz), 4.14 (m, 1H), 1.81−1.64 (m, 2H), 1.57 (s, 9H),
1.53−1.41 (m, 2H), 0.94 (t, 3H, J = 7.8 Hz). 13C NMR (150 MHz,
CDCl3) δ: 167.8, 152.2, 152.1, 145.6, 85.7, 84.1, 75.3, 61.2, 56.5, 36.0,
27.7, 27.5, 19.3, 13.3. IR (neat): 3312, 2980, 2936, 2876, 1813, 1774,
1
CHCl3). H NMR (600 MHz, CDCl3) δ: 5.76 (m, 1H), 5.62 (br s,
1H), 5.12 (dd, 1H, J = 2.1, 5.2 Hz), 5.01 (m, 2H), 4.39 (br s, 1H), 4.12
(m, 1H), 2.10 (m, 2H), 1.84 (m, 1H), 1.74 (m, 1H), 1.57 (s, 9H),
1.51−1.54 (m, 2H), 1.46 (s, 9H). 13C NMR (150 MHz, CDCl3) δ
167.7, 152.2, 152.1, 145.6, 137.5, 115.6, 85.8, 84.1, 75.2, 61.3, 56.5,
33.4, 32.8, 27.8, 27.5, 25.1. IR (neat): 3307, 2981, 2936, 1813, 1774,
1725, 1370, 1274, 1153 cm−1. HRMS: [M + Na]+ calcd for
C20H31ClN2NaO7 469.1712, found 469.1707.
1725, 1274, 1153 cm−1
. HRMS: [M +
Na]+ calcd for
C18H29ClN2NaO7 443.1556, found 443.1584.
Preparation of ( )-γ-Lactone 27. To an 80 mL vial containing
hydantoin 23 (876 mg, 2.1 mmol) was added 1:1.2 mixture of
deionized H2O−CH3OH (1:1.2, 25.6 mL), and the vial was sealed in a
CEM Discover LabMate microwave reactor. The reaction mixture was
then heated for 20 min at 100 °C (as monitored by a vertically focused
IR temperature sensor). After this time, the mixture was diluted with
EtOAc (30 mL) and H2O (30 mL), and the phases were separated.
The aqueous phase was extracted with EtOAc (3 × 30 mL), and the
combined organic phases were washed with brine (30 mL), dried
(MgSO4), filtered, and concentrated. Purification of the crude product
by flash chromatography (silica gel, CH2Cl2−CH3OH 20:1) afforded
γ-lactone 27 as a white solid (157 mg, 40%, mp = 136−138 °C) and
Preparation of γ-Lactone 33. To the 80 mL vial containing
hydantoin 32 (1.25 g, 2.7 mmol) was added a mixture of deionized
H2O−CH3OH (1:1.2, 36 mL), and the vial was sealed in a CEM
Discover LabMate microwave reactor. The reaction mixture was then
heated for 20 min at 100 °C (as monitored by a vertically focused IR
temperature sensor). After this time, the mixture was diluted with
EtOAc (60 mL) and H2O (60 mL), and the phases were separated.
The aqueous phase was extracted with EtOAc (3 × 50 mL), and the
combined organic phases were washed with brine (50 mL), dried
(MgSO4), filtered, and concentrated. Purification of the crude product
by flash chromatography (silica gel, CH2Cl2−CH3OH 20:1) afforded
the γ-lactone 33 as an off-white solid (250 mg, 44%; mp = 108−111
°C). [α]20D: −13 (c 1.0, CHCl3). 1H NMR (600 MHz, CDCl3) δ: 5.79
(m, 1H), 5.63 (s, 1H), 5.21 (dd, 1H, J = 4.5, 7.4 Hz), 5.02 (m, 2H),
4.65 (m, 1H), 4.44 (dd, 1H, J = 0.71, 7.4 Hz), 2.15 (m, 2H), 1.95 (m,
1
hydantoin 28 (82 mg, 18%). Data for γ-lactone 27. H NMR (500
MHz, CDCl3) δ: 5.68 (br s, 1H), 5.21 (dd, 1H, J = 4.5, 7.6 Hz), 4.66
(m, 1H), 4.44 (d, 1H, J = 7.5 Hz), 1.96−1.81 (m, 2H), 1.57−1.49 (m,
2H), 1.01 (t, 3H, J = 7.4 Hz). 13 C NMR (150 MHz, CDCl3) δ: 172.5,
156.7, 82.2, 77.0, 54.9, 30.9, 18.5, 13.7. IR (neat): 3268, 2962, 2877,
1753, 1710, 1222, 968 cm−1. HRMS: [M + H]+ calcd for C8H12NO4
13
1H), 1.88 (m, 1H), 1.60 (m, 2H). C NMR (150 MHz, CDCl3) δ:
172.2, 156.3, 137.5, 115.6, 82.3, 76.9, 54.7, 33.2, 28.4, 24.4. IR (neat):
3251, 2925, 1774, 1726, 1365, 1218, 1110, 964, 655 cm−1. HRMS: [M
+ Na]+ calcd for C10H13NNaO4 234.0737, found 234.0763.
1
186.0761, found 186.0741. Data for hydantoin 28. H NMR (600
MHz, DMSO) δ: 5.87 (d, 1H, J = 7.5 Hz), 4.35 (t, 1H, J = 1.4 Hz),
4.00 (dt, 1H, J = 2.7, 9.8 Hz), 3.69 (ddd, 1H, J = 1.4, 7.5, 9.4 Hz), 1.54
Preparation of γ-Lactone 35. To a stirred solution of 1-undecene
(0.24 mL, 1.2 mmol) in CH2Cl2 (7.5 mL) was added γ-lactone 33 (31
mg, 0.15 mmol) in CH2Cl2 (1.0 mL) followed by the second-
generation Grubbs−Hoveyda catalyst (17 mg, 0.027 mmol). Nitrogen
was bubbled through the mixture for 5 min, after which time the
mixture was heated to reflux and maintained at this temperature for 3
h. The reaction mixture was then cooled to rt, filtered through a pad of
Celite, and concentrated under reduced pressure. The residue was
purified by flash chromatography (silica gel, 1:1 hexanes−EtOAc) to
13
(m, 2H), 1.36 (m, 2H), 0.90 (t, 3H, J = 7.2 Hz). C NMR (150
MHz, DMSO) δ: 174.8, 158.1, 72.3, 62.2, 60.3, 35.3, 18.5, 13.3. IR
(neat): 3263, 2920, 1768, 1716, 1261, 1147 cm−1. HRMS: [M + H]+
Calcd for C8H14ClN2O3 221.0725; Found 221.0719.
Preparation of (+)-(R)-2-Chlorohept-6-enal (30). To a cold
(−10 °C), stirred solution of LiCl (1.91 g, 0.045 mol), copper(II)
trifluoroacetate hydrate (4.36 g, 0.015 mol), sodium persulfate (7.18 g,
0.030 mol), and H2O (1.2 mL, 0.066 mol) in acetonitrile (130 mL)
was added imidazolidinone catalyst 31 (1.72 g, 6.0 mmol). After the
mixture was stirred for 5 min, 6-heptenal (29) (3.38 g, 0.030 mol) in
acetonitrile (20 mL) was added dropwise. The resulting mixture was
stirred at −10 °C for 2 days, after which EtOAc (70 mL) and H2O (70
mL) were added. The phases were separated, and the aqueous phase
was washed with EtOAc (3 × 70 mL). The combined organic phases
were washed with brine (70 mL), dried (MgSO4), filtered, and
concentrated. Purification of the crude product by flash chromatog-
raphy (silica gel, 1:1 CH2Cl2−pentane) afforded (+)-(R)-2-chlor-
1
give the cross-metathesis product as an off-white solid (25 mg). H
NMR (400 MHz, CDCl3) δ: 6.28 (br s, 1H), 5.55−5.29 (m, 2H), 5.20
(dd, 1H, J = 4.2, 7.0 Hz), 4.65 (m, 1H), 4.47 (d, 1H, J = 7.3 Hz),
2.28−1.79 (m, 6H), 1.66−1.46 (m, 2H), 1.46−1.23 (m, 16H), 0.88 (t,
3H, J = 6.7 Hz).
To a stirred solution of the cross-metathesis product (25 mg, 0.073
mmol) in EtOAc−CH3OH (1:1, 3.6 mL) was added Pd(OH)2 (5.4
mg). Hydrogen was bubbled through the mixture for 30 min, and then
the reaction was kept under hydrogen atmosphere for 1.5 h. After this
time, the mixture was filtered through a pad of Celite and concentrated
to afford γ-lactone 35 as an off-white solid (22 mg, 43% over two
steps; mp = 146−148 °C). 1H NMR (400 MHz, CDCl3) δ: 5.97 (br s,
1H), 5.21 (dd, 1H, J = 4.4, 7.4 Hz), 4.65 (m, 1H), 4.45 (d, 1H, J = 7.4
Hz), 1.99−1.80 (m, 2H), 1.48 (m, 1H), 1.41−1.20 (m, 23H), 0.88 (t,
3H, J = 6.5 Hz). 13C NMR (100 MHz, CDCl3) δ: 172.4, 156.6, 82.6,
ohept-6-enal (30) as a colorless oil (2.60 g, 60%, ee >99.0%). [α]25
:
D
+37 (c 1.0, CHCl3). 1H NMR (600 MHz, CDCl3) δ: 9.49 (d, 1H, J =
2.4 Hz), 5.77 (m, 1H), 5.03 (m, 1H), 5.00 (m, 1H), 4.16 (ddd, 1H, J =
8.1, 5.4, 2.4 Hz), 2.10 (m, 2H), 2.00 (m, 1H), 1.84 (m,1H), 1.64 (m,
1H), 1.55 (m, 1H). 13C NMR (150 MHz, CDCl3) δ: 195.6, 137.9,
115.9, 64.2, 33.2, 31.7, 25.1. IR (neat): 2923, 2855, 1736, 1460, 913,
D
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77.0, 54.9, 31.9, 29.7, 29.7, 29.6, 29.6, 29.6, 29.6, 29.5, 29.3, 29.2, 29.0,
25.2, 22.7, 14.1. IR (neat): 3260, 2957, 2918, 2850, 1778, 1724, 1217
cm−1. HRMS: [M + H]+ calcd for C19H34NO4 340.2482, found
340.2462.
1H, J = 7.7, 7.7 Hz), 3.87 (m, 1H), 3.73 (m, 1H), 3.65 (m, 1H), 3.52
(dd, 1H, J = 7.7, 7.7 Hz), 2.25 (br s, 2H), 1.72−1.59 (m, 2H), 1.47−
1.19 (m, 24H), 0.88 (t, 3H, J = 6.8 Hz). 13C NMR (150 MHz, CDCl3)
δ: 83.2, 72.3, 71.7, 54.3, 31.9, 29.8, 29.7, 29.7, 29.6, 29.6, 29.6, 29.4,
29.4, 29.3, 26.3, 22.7, 14.1 cm−1. IR (neat): 3341, 2917, 2849, 1583,
1470, 1034 cm−1. HRMS: [M + H]+ calcd for C18H38NO2 300.2897,
found 300.2900.
Preparation of Lactol 36. To a stirred solution of γ-lactone 35
(31 mg, 0.090 mmol) in CH2Cl2 (4.4 mL) at −55 °C was slowly
added a solution of diisobutylaluminum hydride (1.0 M in THF, 0.32
mL, 0.32 mmol), and the resulting mixture was stirred for 12 h. An
additional amount of diisobutylaluminum hydride (1.0 M in THF,
0.32 mL, 0.32 mmol) was then added, and the resulting mixture was
stirred for 9 h at −55 °C. The excess reagent was then quenched by
addition of 1 M HCl (1.5 mL), and the resulting mixture was diluted
with EtOAc (10 mL), H2O (5 mL), and brine (5 mL). The phases
were separated, and the aqueous phase was extracted with EtOAc (3 ×
10 mL). The combined organic phases were washed with brine (10
mL), dried (MgSO4), filtered, and concentrated. Purification of the
crude material by flash chromatography (silica gel, EtOAc-hexanes
7:3) afforded lactol 36 as a white solid (26 mg, 85%, mp = 94−96 °C).
1H NMR (400 MHz, CDCl3) δ: 6.54 (br s, 1H), 5.30 (br s, 1H), 5.03
(dd, 1H, J = 3.6, 7.2 Hz), 4.27−4.20 (m, 2H), 3.46 (br s, 1H), 1.74 (m,
2H), 1.48−1.41 (m, 24H), 0.88 (t, 3H, J = 6.7 Hz). 13C NMR (100
MHz, CDCl3) δ: 159.4, 100.9, 80.5, 80.1, 62.8, 31.9, 29.7, 29.6, 29.6,
29.6, 29.5, 29.3, 28.0, 26.0, 22.7, 14.1. IR (neat): 3428, 3304, 2918,
2850, 1762, 1733, 1071, 1014 cm−1. HRMS: [M + H]+ calcd for
C19H36NO4 342.2639, found 342.2650.
Preparation of Carbamate 37. To a cold (−78 °C), stirred
solution of lactol 36 (26 mg, 0.076 mmol) and triethylsilane (0.12 mL,
0.76 mmol) in CH2Cl2 (3.6 mL) was added BF3·OEt2 (0.050 mL, 0.38
mmol), and the reaction mixture was allowed to warm to rt and stir for
an additional 19.5 h. After this time, the reaction was treated with
saturated aqueous solution of NaHCO3 (5 mL) and diluted with
EtOAc (10 mL). The phases were separated, and the aqueous phase
was washed with EtOAc (3 × 10 mL). The combined organic phases
were washed with brine (10 mL), dried (MgSO4), filtered, and
concentrated. Purification of the crude material by flash chromatog-
raphy (7:3 EtOAc−hexanes) provided the carbamate 37 as a white
solid (8.0 mg, 32%; mp = 112−115 °C). Additional amounts of the
starting lactol 36 (11 mg) were also isolated and redissolved in
CH2Cl2 (5.0 mL). The resulting solution was cooled to 0 °C, and both
Et3SiH (0.10 mL, 0.63 mmol) and BF3·OEt2 (0.040 mL, 0.30 mmol)
were added. The mixture was warmed to rt and allowed to stir for 48
h, after which time additional Et3SiH (0.10 mL, 0.63 mmol) and BF3·
OEt2 (0.040 mL, 0.30 mmol) were added. After a further 48 h, the
reaction mixture was treated with saturated aqueous NaHCO3 (5 mL)
and diluted with EtOAc (10 mL). The phases were separated, and the
aqueous phase was washed with EtOAc (3 × 10 mL). The combined
organic phases were washed with brine (10 mL), dried (MgSO4),
filtered, and concentrated to give tetrahydrofuran carbamate 37 as a
white solid (9.5 mg, 38%). Total isolated yield of carbamate 37 = 70%.
[α]20D: +54 (c 0.72, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 6.06 (br
s, 1H), 4.95 (dd, 1H, J = 3.6, 7.4 Hz), 4.37 (dd, 1H, J = 3.6, 7.4 Hz),
3.94 (d, 1H, J = 10.4 Hz), 3.54−3.48 (m, 2H), 1.83−1.71 (m, 2H),
1.51−1.20 (m, 24H), 0.88 (t, 3H, J = 6.6 Hz). 13C NMR (150 MHz,
CDCl3) δ: 159.2, 83.2, 80.9, 73.3, 57.1, 31.9, 29.7, 29.7, 29.7, 29.6,
29.6, 29.6, 29.6, 29.5, 29.3, 28.1, 26.0, 22.7, 14.1. IR (neat): 3330,
3242, 2921, 2848, 1756, 1720, 1070 cm−1. HRMS: [M + H]+ calcd for
C19H36NO3 326.2690, found 326.2686.
Preparation of ( )-γ-Lactone 38. To a stirred solution of γ-
lactone 33 (20 mg, 0.094 mmol) in CH2Cl2 (5.0 mL) was added 1-
nonene (0.13 mL, 0.76 mmol) followed by the second-generation
Grubbs−Hoveyda catalyst (12 mg, 0.019 mmol). The reaction mixture
was heated to reflux and maintained at this temperature for 3 h, after
which time the mixture was filtered through a pad of Celite and the
filtrate was concentrated under reduced pressure. The residue was
purified by flash chromatography (silica gel, 1:1 hexanes−EtOAc) to
give the γ-lactone 38 as a white solid (17 mg, 54%, mp = 158−161
1
°C). H NMR (600 MHz, CDCl3) δ: 5.59 (s, 1H), 5.46−5.34 (m,
2H), 5.20 (dd, 1H, J = 4.4, 7.3 Hz), 4.65 (m, 1H), 4.44 (d, 1H, J = 7.3
Hz), 2.10−1.84 (m, 7H), 1.61−1.51 (m, 3H), 1.35−1.23 (m, 14H),
0.87 (t, 3H, J = 6.8 Hz). 13C NMR (150 MHz, CDCl3) δ: 172.2, 156.3,
131.9, 128.6, 82.4, 77.0, 54.9, 32.5, 32.0, 31.8, 29.5, 29.1, 29.1, 28.4,
25.1, 22.6, 14.1. IR (neat): 3344, 2959, 2923, 2854, 1784, 1751, 1242,
1103, 965 cm−1.
To a stirred solution of cross-metathesis product (17 mg, 0.050
mmol) in EtOAc−CH3OH 1:1 (3.0 mL), was added Pd(OH)2 (3.4
mg), and the resulting mixture was stirred under a hydrogen
atmosphere (balloon) for 1.5 h. After this time, the mixture was
filtered through a pad of Celite and concentrated. Purification of crude
product by flash chromatography (silica gel, 1:1 hexanes−EtOAc)
afforded the γ-lactone 38 (14 mg, 82%). 1H NMR (600 MHz, CDCl3)
δ: 5.55 (b, 1H), 5.21 (dd, 1H, J = 4.5, 7.5 Hz), 4.64 (m, 1H), 4.44 (dd,
1H, J = 0.66, 7.5 Hz), 1.93 (m, 1H), 1.86 (m, 1H), 1.51−1.42 (m,
5H), 1.40−1.34 (m, 3H), 1.32−1.23 (m, 16H), 0.88 (t, 3H, J = 6.8
Hz). 13C NMR (150 MHz, CDCl3) δ: 172.2, 156.3, 82.5, 76.9, 54.8,
31.9, 29.6, 29.6, 29.5, 29.4, 29.3, 29.2, 28.9, 25.1, 22.7, 14.1. IR (neat):
3673, 3250, 2981, 2917, 2854, 1777, 1726, 1393, 1219, 1066 cm−1.
HRMS: [M + H]+ calcd for C17H30NO4 312.2200, found 312.2169.
Preparation of the ( )-Dodecyl Analogue of Pachastriss-
amine (39). To a cold (−78 °C), stirred solution of γ-lactone 38 (28
mg, 0.082 mmol) in CH2Cl2 (4.0 mL) was slowly added a solution of
diisobutylaluminum hydride (1.0 M in THF, 0.29 mL, 0.29 mmol),
and the resulting mixture was stirred for 7 h. The excess reagent was
then quenched by addition of 1 M HCl (1.0 mL), and the resulting
mixture was diluted with EtOAc (10 mL) and H2O (10 mL). The
phases were separated, and the aqueous phase was extracted with
EtOAc (3 × 10 mL). The combined organic phases were washed with
brine (10 mL), dried (MgSO4), filtered, and concentrated. Purification
of the crude material by flash chromatography (silica gel, EtOAc−
1
hexanes 2:1) afforded the corresponding lactol (20.5 mg, 72%). H
NMR (600 MHz, CDCl3) δ: 5.66 (b, 1H), 5.31 (b, 1H), 5.03 (dd, 1H,
J = 3.7, 7.2 Hz), 4.25 (m, 1H), 4.22 (d, 1H, J = 7.2 Hz), 2.64 (d, 1H, J
= 7.9 Hz), 1.75 (m, 2H), 1.42 (m, 2H), 1.28 (m, 22H), 0.88 (t, 3H, J =
6.8 Hz). 13C NMR (150 MHz, CDCl3) δ: 158.6, 101.0, 80.4, 80.2,
62.5, 31.9, 29.7, 29.6, 29.5, 29.5, 29.4, 29.3, 28.0, 25.9, 22.7, 14.1. IR
(neat): 3341, 2921, 2852, 1736, 1075 cm−1. HRMS: [M + H]+ calcd
for C17H32NO4 314.2300, found 314.2319.
To a cold (−78 °C), stirred solution of lactol (22 mg, 0.064 mmol)
and triethylsilane (0.10 mL, 0.64 mmol) in CH2Cl2 (3.0 mL) was
slowly added BF3·OEt2 (40 μL, 0.32 mmol), and the reaction mixture
was allowed to warm to rt and stir for an additional 16 h. After this
time, the reaction mixture was treated with saturated aqueous
NaHCO3 (5 mL) and diluted with EtOAc (10 mL). The phases
were separated, and the aqueous phase was washed with EtOAc (3 ×
10 mL). The combined organic phases were washed with brine (10
mL), dried (MgSO4), filtered, and concentrated to provide the
tetrahydrofuran carbamate (20 mg, 90%). 1H NMR (500 MHz,
CDCl3) δ: 5.10 (s, 1H), 4.96 (dd, 1H, J = 3.7, 7.5 Hz), 4.37 (dd, 1H, J
= 3.9, 7.5 Hz), 3.93 (d, 1H, J = 10.3 Hz), 3.55−3.50 (m, 2H), 1.77 (m,
2H), 1.47−1.23 (m, 24H), 0.88 (t, 3H, J = 6.8 Hz). 13C NMR (150
MHz, CDCl3) δ: 158.5, 83.3, 80.9, 73.4, 56.9, 31.9, 29.7, 29.6, 29.6,
Preparation of (+)-Pachastrissamine (1). To a stirred solution
of tetrahydrofuran carbamate 37 (7.1 mg, 0.022 mmol) in EtOH (1.5
mL) was added a solution of KOH (1 M in H2O, 1.2 mL), and the
mixture was heated to reflux (85 °C) and maintained at this
temperature for 15 h. The reaction mixture was then cooled to rt and
diluted with EtOAc (10 mL) and H2O (5 mL). The phases were
separated, and the aqueous layer was extracted with EtOAc (4 × 10
mL). The combined organic layers were washed with brine, dried
(MgSO4), and concentrated. Purification of crude product by flash
chromatography (silica gel, CHCl3−CH3OH−NH4OH 95:8:1)
afforded (+)-pachastrissamine (1) as a white solid (5.9 mg, 91%;
mp = 83−85 °C, lit.6c mp = 89−91 °C). [α]20D: +10 (c 0.48, CHCl3).
[α]20D: +16 (c 0.45, EtOH). 1H NMR (600 MHz, CDCl3) δ: 3.92 (dd,
E
dx.doi.org/10.1021/jo4013223 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
29.5, 29.4, 29.3, 28.1, 26.0, 22.7, 14.1. IR (neat): 2923, 2854, 1747,
1718, 1072 cm−1. HRMS: [M + H]+ calcd for C17H32NO3 298.2400,
found 298.2355.
Chem. 2011, 9, 1774. (d) Cruz-Gregorio, S.; Espinoza-Rojas, C.;
Quintero, L.; Sartillo-Piscil, F. Tetrahedron Lett. 2011, 52, 6370.
(e) Zhao, M.-L.; Zhang, E.; Gao, J.; Zhang, Z.; Zhao, Y.-T.; Qu, W.;
Liu, H.-M. Carbohydr. Res. 2012, 351, 126.
(8) For a review on the isolation and total syntheses of
pachastrissamine, see: Abraham, E.; Davies, S. G.; Roberts, P. M.;
Russell, A. J.; Thomson, J. E. Tetrahedron: Asymmetry 2008, 19, 1027.
(9) Kikuchi, H.; Saito, Y.; Komiya, J.; Takaya, Y.; Honma, S.;
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(d) Britton, R.; Kang, B. Nat. Prod. Rep. 2013, 30, 227.
To a stirred solution of tetrahydrofuran carbamate (12 mg, 0.037
mmol) in EtOH (1.7 mL) was added a solution of KOH (1 M in H2O,
1.7 mL), and the mixture was heated to reflux and maintained at this
temperature for an additional 12 h. The reaction mixture was then
cooled to rt and concentrated. Purification of the crude product by
flash chromatography (silica gel, CHCl3−CH3OH−NH4OH 95:6:1)
afforded ( )-dodecyl analogue of pachastrissamine (39) as a white
solid (9.0 mg, 82%; mp = 74−76 °C). 1H NMR (400 MHz, CDCl3) δ:
3.92 (dd, 1H, J = 7.3, 8.4 Hz), 3.86 (dd, 1H, J = 3.5, 5.0 Hz), 3.73 (m,
1H), 3.66 (m, 1H), 3.51 (dd, 1H, J = 6.6, 8.4 Hz), 2.02 (br s, 2H),
1.69−1.61 (m, 2H), 1.42−1.22 (m, 24H), 0.88 (t, 3H, J = 6.8 Hz). 13C
NMR (150 MHz, CDCl3) δ: 83.2, 72.4, 71.7, 54.2, 31.9, 29.8, 29.7,
29.6, 29.6, 29.5, 29.5, 29.4, 29.3, 26.3, 22.7, 14.1. IR (neat): 3675,
3157, 2918, 2850, 1469, 1054 cm−1. HRMS: [M + H]+ calcd for
C16H34NO2 272.2600, found 272.2575.
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(12) For the asymmetric α-chlorination of aldehydes, see: (a) Hal-
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ASSOCIATED CONTENT
■
S
* Supporting Information
General experimental methods and copies of 1H and 13C NMR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
(14) (a) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957,
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Madsen, U. Org. Lett. 2001, 3, 433. (b) Bew, S. P.; Bull, S. D.; Davies,
S. G.; Savory, E. D.; Watkin, D. J. Tetrahedron 2002, 58, 9387.
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(18) Halperin, S. D.; Britton, R. Org. Biomol. Chem. 2013, 11, 1702.
(19) For cross-metathesis approaches to pachastrissamine and its
epimers, see: (a) Salma, Y.; Ballereau, S.; Maaliki, C.; Ladeira, S.;
AUTHOR INFORMATION
Corresponding Author
*E-mail: rbritton@sfu.ca.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by an NSERC Discovery Grant for
R.B., a Michael Smith Foundation for Health Research Career
Investigator Award for R.B., a NSERC Postgraduate Scholar-
ship for S.C., and SFU Graduate Fellowships for S.C. and V.D.
The authors thank R. Gries for assistance with chiral GC
analysis.
́
Andrieu-Abadie, N.; Genisson, Y. Org. Biomol. Chem. 2010, 8, 3227.
(b) Lee, D. Synlett 2012, 23, 2840. (c) Mu, Y.; Kim, J.-Y.; Jin, X.; Park,
S.-H.; Joo, J.-E.; Ham, W.-H. Synthesis 2012, 44, 2340. (d) Yoshimitsu,
Y.; Miyagaki, J.; Oishi, S.; Fujii, N.; Ohno, H. Tetrahedron 2013, 69,
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Am. Chem. Soc. 2000, 122, 8168. (b) Gessler, S.; Randl, S.; Blechert, S.
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dx.doi.org/10.1021/jo4013223 | J. Org. Chem. XXXX, XXX, XXX−XXX