A flexible common approach to α-substituted serines and alanines: Diastereoconvergent syntheses of sphingofungins E and F

Article abstract of DOI:10.1002/ejoc.200900772

A flexible common approach for the asymmetric syntheses of sphingofungins E and F is reported, with efficient use of both diastereomers of the Baylis-Hillman adduct in a stereoconvergent manner. Pronounced steric effects of the 2-substituents in diastereo

Full text of DOI:10.1002/ejoc.200900772

FULL PAPER
DOI: 10.1002/ejoc.200900772
A Flexible Common Approach to α-Substituted Serines and Alanines:
Diastereoconvergent Syntheses of Sphingofungins E and F
Bing Wang*[a] and Guo-Qiang Lin*[a,b]
Dedicated to Professor Guo-Bin Rong on the occasion of his retirement
Keywords: Amino acids / Asymmetric synthesis / Epoxides / Natural products / Quaternary stereocenters
A flexible common approach for the asymmetric syntheses of
sphingofungins E and F is reported, with efficient use of both
diastereomers of the Baylis–Hillman adduct in a stereocon-
vergent manner. Pronounced steric effects of the 2-substitu-
also allowed full control over the absolute configurations of
the quaternary stereocenters in α-substituted amino acids
through tunable site-specific adjustment of oxidation states.
ents in diastereoselective dihydroxylations of (E)-2-hy- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
droxymethyl-2,3-alkenoates were observed. This strategy
Germany, 2009)
potent serine palmitoyltransferase (SPT) inhibitors (IC50
=
Introduction
7.2 and 57 n, respectively) with antifungal activities
against several human pathogenic fungi.[4]
There has been enduring interest in asymmetric synthesis
of nonproteinogenic amino acids, due to their versatile roles
in biological studies and drug discovery.[1] Among these un-
natural amino acids, the α,α-disubstituted type occupies a
conspicuous position, because α-quaternary amino acids
possess improved metabolic stability as well as rich struc-
tural features and functions.[2] α-Substituted serines and al-
anines are important representatives of this category; de-
spite their formal similarity, however, they have seldom
shared a common synthetic strategy, due to the limitations
of the “enolate of serine”.[3]
Sphingofungins E (1) and F (2),[4] two highly oxygenated
α-quaternary amino acids, were isolated from the fermenta-
tion broth of Paecilomyces variotii in 1992. Like other mem-
bers of the sphingofungin family, each compound possesses
a polar head bearing four contiguous stereocenters and a
lipophilic tail connected by a trans-olefin (Figure 1). The
two compounds are distinct from congeners 4–7 primarily
in their respective α-substituted serine and alanine struc-
tural motifs. Instead, they bear close resemblance to myri-
ocin (3), an immunosuppressant 10–100 times more potent
than cyclosporine A.[5] As sphingosine[6] analogues, they are
Figure 1. Sphingofungin E and F and related natural products.
The unique structural features and the biological impor-
tance of 1 and 2 have stimulated considerable synthetic ef-
forts. To date, four groups have accomplished the synthesis
of 1,[7] whereas five independent syntheses of 2 have been
reported.[8] The Trost group, for example, developed the
asymmetric allylic alkylation (AAA) of azlactones with
gem-diacetates as electrophiles to construct the requisite
quaternary stereocenters of 1 and 2.[7d] The groups of
Chida[7b,7c] and Shiozaki[7a,7e] both started from -glucose
(chiral pool approach) and applied key rearrangement
transformations to establish the α-quaternary amino acid
unit of 1. Kobayashi utilized the SnII-catalyzed asymmetric
aldol reaction of Schöllkopf’s bislactam for the synthesis
of 2,[8e,8g,8h] whereas Li employed a substrate-directed aza-
Michael addition to introduce the tertiary carbinamine of
[a] Department of Chemistry, Fudan University,
220 Handan Road, Shanghai 200433, P. R. China
Fax: +86-21-54237570
E-mail: wangbing@fudan.edu.cn
[b] Institutes of Biomedical Sciences, Fudan University,
138 Yixueyuan Road, Shanghai 200032, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900772.
5038
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α-Substituted Serines and Alanines
2.[8a] Ham’s approach to 2 depended on a diastereoselective
Pd-catalyzed oxazoline formation and Lewis-acid-pro-
moted allylation.[8b] Of these, only the route described by
Trost, which used a silyl group as a masked hydroxy func-
tion, was applicable to both 1 and 2.
Our previous individual approaches to 1 and 2 had both
focused on the ring-opening of epoxides, using Lewis-acid-
promoted rearrangement of trichloroacetimidates[9] for the
formation of quaternary stereocenters. In our preliminary
report, the synthesis of 1 involved a Baylis–Hillman reac-
tion[10] of an α,β-chiral aldehyde, which produced a pair of
diastereomers in a 7:3 ratio.[7f] Utilization of the minor ad-
duct was proposed but was yet to be validated. On the other
hand, the key asymmetric epoxidation step in our synthesis
of 2 also yielded a moderate dr (3:1), and the minor product
could not be transformed into desired intermediates.[8d]
With these factors in mind, and in continuation of our
interests in the synthesis of chiral amino alcohols,[11] we set
out to develop a common and flexible synthetic strategy
applicable to both α-substituted serine and alanine. Here
we report the full details of this study.
Scheme 1. Retrosynthetic analysis of sphingofungins E (1) and F
(2).
Results and Discussion
catalyst (Bu3P[14b]) or of a different reaction partner (1-
naphthyl acrylate[15]) did accelerate the reaction, but the
yields were compromised by significant side reactions and
the impurities were difficult to separate from the desired
product. A double asymmetric induction protocol had re-
cently been reported to give a high dr for a substrate similar
to 13, but two additional steps of auxiliary removal (74%)
and esterification (60%) were required and lowered the
overall efficiency.[16] On the other hand, reactions involving
functionalized organoaluminum[17] and tantalum[18] rea-
The general retrosynthetic plan of our improved route is
outlined in Scheme 1. For sphingofungin E (1), disconnec-
tion of the trans-double bond (Wittig olefination) led to the
known phosphonium salt 8[12] and the chiral polar “head”
9, which possessed all four requisite stereogenic centers. The
chiral tertiary carbinamine was expected to be installed by
Lewis-acid-promoted rearrangement of trichloroacetimid-
ates derived from the 2,3-epoxy-alcohol 10. However, the
3,4-syn stereochemistry in 10 was a challenge, because it
was the product of an apparent mismatched epoxidation.
We reasoned that, to overcome this unfavorable influence,
the trisubstituted oxirane moiety could be established in a
more stereoselective manner through regioselective ring-clo-
sure of diol 11 with inversion at C-3.[11b,11e] Compound 11
was in turn the dihydroxylation product of 12, which was
clearly a Baylis–Hillman adduct. The known aldehyde 13
was conveniently prepared from -(+)-tartaric acid.[13]
The synthesis of the α-substituted alanine 2 diverged
from the above in that deoxygenation at C-1Ј would be re-
quired, and we envisaged that this key transformation could
be achieved en route to 15 from the pivotal compound 10.
Sphingofungins E and F could thus be synthesized by a
common approach converging at the intermediate 10.
Moreover, the mismatched epoxidation with unsatisfactory
dr encountered in our previous approach could be avoided,
because the new route hinged on diol 11, the preparation of
which was highly stereocontrolled in this second-generation
synthesis.
We first attempted to improve the efficiency or the dr of
the Baylis–Hillman reaction (Scheme 2). Initially, the reac-
tion was carried out with DABCO as the catalyst in dioxane
at 0 °C.[14a] This proved very slow, and only a trace yield of
Scheme 2. Attempted optimization of the Baylis–Hillman reaction
12 was obtained. Use either of an alternative Lewis base of 13.
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B. Wang, G.-Q. Lin
FULL PAPER
gents to yield formal Baylis–Hillman adducts were also at- Table 1. Diastereoselective dihydroxylation of 2-substituted acry-
lates.
tempted without success. It thus became clear that the α-
oxygenation of the chiral aldehyde 13 posed considerable
problems, in terms either of reactivity or of stereoselectivity.
Consequently, we adhered to our optimized conditions
[neat methyl acrylate, DABCO (0.5–1.0 equiv.), room temp.,
2–7 days], which provided up to 79% yield and 74:26 dr.
Our focus then shifted to utilization of the minor Baylis–
Hillman adduct 16 (Scheme 3).
Entry Substrate Dihydroxylation conditions Product, yield (%)[a] dr (11/20)
1[b]
12
19
19
19
18
cat. OsO4, NMO, acetone/ 11, 89
H2O (8:1), 20 °C
cat. OsO4, NMO, acetone/ 11 + 20, 92
H2O (8:1), 20 °C
100:0[c]
1.8:1[d]
4.2:1[c]
1.6:1[d]
16.8:1[c]
2
3
AD-mix-β, MsNH2,
11 + 20, 82
11 + 20, 80
11 + 20, 85
tBuOH/H2O (1:1), 20 °C
AD-mix-α, MsNH2,
tBuOH/H2O (1:1), 20 °C
AD-mix-β, MsNH2,
4
5[b]
Scheme 3. Transformations of minor Baylis–Hillman adduct 16.
tBuOH/H2O (1:1), 0 °C
Through the allylic transposition of their hydroxy groups
under Mitsunobu conditions,[19] both 16 and its epimer 12
could be converted into the p-nitrobenzoate 17 in 85–91%
yields (Scheme 3). The configuration of the trisubstituted
olefin was exclusively E, as confirmed by NOE experimen-
tation. Removal of the p-nitrobenzoyl (PNB) group in high
[a] Combined yields of both diastereomers (separable). [b] Dihy-
droxylation followed by selective TBS protection of primary
alcohol. [c] Determined by HPLC. [d] Determined from the yield
of each isomer.
yield was achieved under mild conditions, and the resulting stereocontrol favoring the 3,4-anti product. The unprotec-
alcohol 18 was protected with TBS to prevent possible in- ted compound 18 was hence subjected to the standard AD
tervention of the free hydroxy group in the subsequent dihy- protocol, and excellent dr (16.8:1) and yield were obtained
droxylation reaction.[20] From a practical point of view, (Entry 5).[22] In this manner, the minor Baylis–Hillman ad-
using the crude Baylis–Hillman adducts without the need duct 16 was efficiently transformed into 11 in a short se-
for meticulous separation of diastereomers was a notable quence (56% yield over four steps). The combined yield of
advantage.
pure 11 from 12 and 16 was 80%, and overall diastereocon-
With intermediate 19 to hand, its stereoselective di- vergence was achieved.
hydroxylation was investigated, with the aim of achieving
Then the C-2 and C-3 stereochemistry had to be elabo-
high 3,4-anti selectivity (Table 1). Consistent with Scolas- rated (Scheme 4). The conversion of the diol 11 into the
tico’s excellent study,[21] the dihydroxylation of 12 under epoxide 21 was achieved by regioselective mesylation of the
Upjohn conditions was diastereospecific, producing the de- secondary hydroxy group and base-induced ring-closure,
sired 11 as a single diastereomer after TBS protection of which was reminiscent of our total synthesis of allopumili-
the terminal hydroxy group. The substrate stereoinduction otoxins.[11b,11e] The structure of 21 was confirmed by a
for 19 under the same conditions was not effective, however, NOE between 3-H and 1Ј-H, which corresponded to the
resulting in a poor 3,4-anti/syn ratio of 1.8:1. Because the correct 3,4-syn stereochemistry in 1 and 2. The ester group
asymmetric dihydroxylation of 2-hydroxymethyl crotonates was then subjected to a two-stage reduction, firstly with DI-
has not been studied, we then tested AD-mix-β in order to BAL at –78 °C to afford the aldehyde, and then with
obtain a satisfactory dr by double diastereoselection. The NaBH4 to afford 10. Notably, use of excess DIBAL or rais-
AD reaction was found to be very sluggish under the stan- ing the temperature resulted in complex mixtures, probably
dard conditions (0 °C), whereas running the reaction at due to the stability of the hemiacetal aluminate intermedi-
20 °C for 48 h afforded 11 and the undesired 20 in a moder- ate[23] together with the competing reductive ring-opening
ate ratio of 4.2:1 (Entry 3).
of epoxide. Trichloroacetimidate formation and a Hatakey-
Interestingly, 11 was also the major product when AD- ama reaction[9a] with Et2AlCl as the Lewis acid afforded the
mix-α was used, albeit in a lower dr of 1.5:1 (Entry 4). This oxazoline 22 in almost quantitative yield. Treatment with
suggested that the sterically demanding CH2OTBS substitu- triphosgene and removal of trichloroacetyl under mild con-
ent rendered 19 too bulky to enter the binding pocket of ditions delivered the cyclic carbamate 23, the hydroxy group
the catalytic system, and that the rigid five-membered ace- of which was subsequently protected with MOM in 87%
tonide ring at the γ,δ-position could only afford moderate yield.
5040
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Eur. J. Org. Chem. 2009, 5038–5046

α-Substituted Serines and Alanines
A diastereoconvergent synthesis of 1 from the readily
available aldehyde 13 in 22 steps and 11.6% overall yield,
and making use of both diastereomers of the Baylis–Hill-
man product, has thus been achieved. Alternatively, conver-
sion of the free hydroxymethyl group in 23 into an ester
could eventually afford 2-epi-1, providing structural diver-
sity in this route. This also means that the absolute configu-
rations of the quaternary stereocenters in α-substituted
amino acids could be controlled through tunable site-spe-
cific adjustment of oxidation states of the “prochiral” hy-
droxymethyls.
Because this strategy is more stereoselective than our pre-
vious one involving epoxidation,[8d] we further pursued the
synthesis of sphingofungin F from the alcohol 10. Replace-
ment of the free hydroxy group in 10 with hydrogen would
afford 15 (Table 2), the key intermediate for the synthesis
of 2, so we carried out the required deoxygenation in a two-
step approach.[26] The alcohol was first converted into the
iodide in excellent yield by Garegg’s protocol,[27] and appro-
priate reductive dehalogenation conditions were then scre-
ened. Hydrogenolysis in the presence either of Pearlman’s
catalyst or of Raney nickel[28] was first tested, but no con-
version was observed. The mild reductant NaBH3CN[29] in
THF/HMPA (4:1) was also ineffective. Ni-mediated re-
duction[30] resulted in a complex mixture, presumably due
to reductive opening of the adjacent epoxide. NaBH4 in
DMSO[31] offered a moderate yield of 15, but side reactions
were still significant. Fortunately, when we shifted to Super-
Hydride reduction,[32] a satisfactory yield (80%) was ob-
tained. The spectroscopic data for 15 were identical with
those for the product previously obtained by epoxida-
tion.[8d] A formal synthesis of sphingofungin F (2) had thus
been achieved, and a higher overall yield of 2 than in our
previous synthesis could be obtained.
Scheme 4. Elaboration of the polar “head” segment.
As shown in Scheme 5, debenzylation of compound 9
and Swern oxidation gave a crude aldehyde, which was con-
densed with the ylide derived from 8 to afford 24 as a geo-
metric mixture (Z/E ≈ 9:1, separable by silica gel column
chromatography) in 60% yield over three steps. Photoisom-
erization[24] of the Z isomer in the presence of PhSSPh con-
verted it smoothly into the desired (E)-24 in excellent yield.
After routine desilylation and PDC oxidation to carboxylic
acid,[25] the crude product was heated at reflux in aq. etha-
nol under acid catalysis conditions to effect lactonization
and concomitant removal of the MOM, acetonide, and ke-
tal protecting groups. The NOE between 1Ј-H, 3-H, and 4-
H in the bicyclic product 25 corroborated its stereochemis-
try. Finally, saponification of 25 followed by neutralization
with IRC-76 resin completed the total synthesis of sphingo-
fungin E (1), the spectroscopic data of which were consis-
tent with the literature values.
Table 2. De-iodination study.
Entry Conditions
Yield (%)[a]
1
2
3
4
5
6
H2 (1 atm), Pd(OH)2/C, K2CO3, MeOH NR
H2 (1 atm), Raney Ni, MeOH
NaBH3CN, THF/HMPA
NaBH4, NiCl2·6H2O, EtOH
NaBH4, DMSO
NR
NR
complex
56
LiBHEt3, THF, 25 °C, 15 min
80
[a] Isolated yields.
Conclusions
In summary, we have developed a flexible common ap-
proach for the asymmetric syntheses of both sphingofung-
Scheme 5. Synthesis of sphingofungin E (1).
Eur. J. Org. Chem. 2009, 5038–5046
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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B. Wang, G.-Q. Lin
FULL PAPER
(300 MHz, CDCl3): δ = 8.24 (d, J = 8.9 Hz, 2 H), 8.13 (d, J =
8.9 Hz, 2 H), 7.34–7.15 (m, 5 H), 7.02 (d, J = 8.4 Hz, 1 H), 5.20–
5.10 (AB, JAB = 12.0 Hz, 2 H), 4.91 (t, J = 8.2 Hz, 1 H), 4.57–4.48
(AB, JAB = 12.0 Hz, 2 H), 4.04 (dt, J = 8.0, 4.6 Hz, 1 H), 3.81 (s,
3 H), 3.64 (d, J = 4.6 Hz, 2 H), 1.45 (s, 2ϫ3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 166.0, 164.2, 150.6, 144.2, 137.6, 135.3,
130.8 (2 C), 129.8, 128.4 (2 C), 127.8, 127.6 (2 C), 123.5 (2 C),
110.6, 79.7, 74.5, 73.7, 69.0, 59.3, 52.4, 26.9 (2 C) ppm. C25H27NO9
(485.48): calcd. C 61.85, H 5.60, N 2.88; found C 61.87, H 5.75, N
2.62.
ins E and F, representatives of highly oxygenated α-substi-
tuted amino acid natural products. The minor Baylis–Hill-
man adduct 16 has been efficiently utilized in the develop-
ment of a diastereoconvergent route. The dihydroxylation
of (E)-2-hydroxymethyl-2,3-alkenoates was examined and a
pronounced steric effect of the 2-substituent was observed.
Excellent dr and er values could be obtained for 2-
(hydroxymethyl)crotonates under the standard Sharpless
asymmetric dihydroxylation conditions. In addition, our
strategy could provide full control over the absolute config-
urations of the quaternary stereocenters in the α-substituted
amino acids through tunable site-specific adjustment of oxi-
dation states.
Allylic Alcohol 18: K2CO3 (848 mg, 6.14 mmol) was added to a
cooled (0 °C) solution of compound 17 (1.494 g, 3.07 mmol) in
MeOH (30 mL), and the mixture was stirred for 1 h, poured into
brine, and extracted with Et2O (3ϫ30 mL). The combined organic
phase was washed twice with brine, dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (EtOAc/hexanes, 1:6 to 1:3) to
afford 18 (873 mg, 84%) as a colorless oil. [α]2D0 = –31.3 (c = 1.18,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.40–7.26 (m, 5 H), 6.80
(d, J = 8.7 Hz, 1 H), 4.83 (t, J = 8.4 Hz, 1 H), 4.63–4.54 (AB, JAB
= 11.7 Hz, 2 H), 4.41–4.26 (AB, JAB = 12.6 Hz, 2 H), 3.97 (dt, J
= 8.4, 4.5 Hz, 1 H), 3.80 (s, 3 H), 3.66 (dd, J = 4.5, 0.9 Hz, 1 H),
2.66 (br. s, 1 H), 1.46 (s, 3 H), 1.45 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 167.1, 140.4, 137.5, 134.6, 128.4 (2 C), 127.9
(3 C), 110.3, 79.5, 74.4, 73.8, 68.9, 57.2, 52.2, 26.9 (2 C) ppm.
C18H24O6 (336.38): calcd. C 64.27, H 7.19; found C 64.11, H 7.16.
Experimental Section
General Information: All reactions were performed under argon in
1
oven-dried glassware. All H and 13C NMR spectra were recorded
at ambient temperature in CDCl3 unless noted otherwise. Chemical
shifts are reported in parts per million as follows: chemical shift,
multiplicity, coupling constant, and integration. Optical rotations
were measured at ambient temperature, and concentrations are re-
ported in g per 100 mL. HR-MS were recorded on a Kratos Con-
cept 1H apparatus. HR-ESI-MS were recorded on a Shimadzu
LCMS-IT-TOF apparatus. Melting points were not corrected.
THF was distilled from sodium/benzophenone ketyl, dichlorometh-
ane and DMF were distilled from CaH2, and all other solvents and
chemical reagents were used as received.
TBS Ether 19: TBSCl (1.130 g, 7.51 mmol) was added at room
temp. to a solution of compound 18 (1.217 g, 3.62 mmol), Et3N
(1.28 mL, 9.2 mmol), and DMAP (19 mg) in CH2Cl2 (18 mL), and
stirring was continued overnight. The mixture was diluted with
EtOAc, washed successively with HCl (1 ), water, and brine, dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (EtOAc/
Baylis–Hillman Reaction: DABCO (850 mg, 7.6 mmol) was added
under Ar to the crude aldehyde 13 (1.908 g, 7.6 mmol) in methyl
acrylate (5 mL), the solution was stirred for 2 days at room temp.,
and the volatile components were removed under reduced pressure.
The residue was purified by silica gel flash column chromatography
(EtOAc/hexanes, 1:7 to 1:3) to yield 12 (1.403 g, 55%) and 16
(0.631 g, 25%) as colorless oils.
hexanes, 1:10) to afford 19 (1.591 g, 98%) as a colorless oil. [α]2D0
=
1
–25.8 (c = 1.69, CHCl3). H NMR (300 MHz, CDCl3): δ = 7.34–
7.24 (m, 5 H), 6.72 (d, J = 8.9 Hz, 1 H), 4.85 (t, J = 8.6 Hz, 1 H),
4.58 (s, 2 H), 4.46–4.32 (AB, JAB = 11.9 Hz, 2 H), 4.00 (ddd, J =
8.3, 5.5, 3.2 Hz, 1 H), 3.76 (s, 3 H), 3.67 (dd, J = 10.8, 3.3 Hz, 1
H), 3.61 (dd, J = 10.8, 5.5 Hz, 1 H), 1.46 (s, 2ϫ3 H), 0.87 (s, 9 H),
0.06 (s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
166.9, 140.1, 138.0, 135.2, 128.4 (2 C), 127.6 (3 C), 110.3, 80.2,
73.7, 73.6, 69.2, 57.6, 52.0, 27.0 (2 C), 25.9 (3 C), 18.3, –5.4 (2
C) ppm. C24H38O6Si (450.64): calcd. C 63.96, H 8.50; found C
64.29, H 8.70.
Compound 12: [α]2D0 = –10.1 (c = 1.36, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.33–7.20 (m, 5 H), 6.31 (s, 1 H), 5.97 (s, 1 H), 4.62
(t, J = 4.2 Hz, 1 H), 4.56 (s, 2 H), 4.15–4.05 (m, 2 H), 3.72 (s, 3
H), 3.53 (d, J = 4.5 Hz, 2 H), 3.28 (d, J = 4.3 Hz, 1 H), 1.42 (s, 3
H), 1.40 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.5,
138.3, 137.7, 128.3 (2 C), 128.0, 127.6 (2 C), 127.1, 109.6, 78.9,
77.1, 73.4, 71.0, 70.9, 51.9, 27.0, 26.9 ppm. C18H24O6 (336.38):
calcd. C 64.27, H 7.19; found C 64.38, H 7.30.
Diol 11: OsO4/tBuOH (0.1 , 0.7 mL, 0.07 mmol) was added at
room temp. to a solution of compound 12 (202 mg, 0.60 mmol)
and NMO·H2O (270 mg, 2.00 mmol) in acetone/H2O (8:1, 18 mL),
and stirring was continued for 3 h. The mixture was quenched with
Na2SO3 (0.90 g), stirred vigorously for 1 h, and filtered. The filtrate
was concentrated under reduced pressure and the residue was
passed through a short silica gel column (eluted with EtOAc). The
crude triol (245 mg) was dissolved in CH2Cl2 (6 mL) and treated
at room temp. overnight with Et3N (0.10 mL, 0.72 mmol), DMAP
(10 mg), and TBSCl (108 mg, 0.72 mmol). The mixture was diluted
with EtOAc, washed successively with HCl (1 ), water, and brine,
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(EtOAc/hexanes, 1:3) to afford 11 (260 mg, 89%) as a colorless oil.
Compound 16: [α]2D0 = –9.4 (c = 1.32, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.34–7.20 (m, 5 H), 6.34 (s, 1 H), 5.95 (s, 1 H), 4.59
(s, 2 H), 4.55 (d, J = 2.6 Hz, 1 H), 4.23 (dt, J = 8.2, 5.0 Hz, 1 H),
4.03 (dd, J = 8.2, 3.1 Hz, 1 H), 3.73 (s, 3 H), 3.61 (d, J = 1.2 Hz,
1 H), 3.60 (s, 1 H), 2.96 (d, J = 8.8 Hz, 1 H), 1.44 (s, 3 H), 1.41 (s,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.5, 139.8, 137.8,
128.4 (2 C), 128.0, 127.7 (2 C), 126.6, 109.9, 79.8, 76.6, 73.5, 70.3,
69.1, 51.9, 27.1, 26.9 ppm. C18H24O6 (336.38): calcd. C 64.27, H
7.19; found C 64.02, H 7.29.
p-Nitrobenzoate 17: DEAD (2.2 mL, 40% in toluene, 4.84 mmol)
was added dropwise to a cooled (0 °C) solution of compound 16
(628 mg, 1.87 mmol), Ph3P (740 mg, 2.82 mmol), and p-nitroben-
zoic acid (470 mg, 2.81 mmol) in THF (18 mL), and the solution
was allowed to warm to room temp. and stirred for 3 h. The solvent
was removed, and the residue was purified by silica gel column
chromatography (EtOAc/hexanes, 1:12 to 1:6) to afford 17 (828 mg,
91%) as a yellow oil. [α]1D8 = –11.3 (c = 1.33, CHCl3). 1H NMR
1
[α]2D0 = +1.1 (c = 1.08, CHCl3). H NMR (300 MHz, CDCl3): δ =
7.33–7.24 (m, 5 H), 4.64–4.54 (AB, JAB = 12.2 Hz, 2 H), 4.22 (dt,
J = 7.5, 5.2 Hz, 1 H), 3.92–3.84 (AB, JAB = 10.6 Hz, 2 H), 3.86–
3.82 (m, 1 H), 3.80 (s, 3 H), 3.68 (dd, J = 9.8, 5.1 Hz, 1 H), 3.66
5042
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5038–5046

α-Substituted Serines and Alanines
(br. s, 1 H), 3.60 (dd, J = 9.8, 5.2 Hz, 1 H), 3.04 (br. d, J = 8.1 Hz,
1 H), 1.38 (s, 2ϫ3 H), 0.95 (s, 9 H), 0.04 (s, 3 H), 0.03 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 173.8, 137.5, 128.4 (2 C), 127.8
(3 C), 109.6, 81.9, 78.6, 77.2, 74.1, 73.5, 70.6, 66.0, 52.7, 26.9, 26.8,
25.7 (3 C), 18.1, –5.5, –5.7 ppm. C24H40O8Si (484.66): calcd. C
59.48, H 8.32; found C 59.27, H 8.31.
was added dropwise. The solution was allowed to warm to room
temp., stirring was continued for 30 min, and the reaction mixture
was quenched with aq. NaHCO3, followed by extraction with Et2O.
The combined organic phase was washed with brine, dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (EtOAc/
hexanes, 1:6) to afford 22 (780 mg, 97%) as a colorless oil.
Epoxide 21: MsCl (0.15 mL, 1.94 mmol) was added dropwise to a
cooled (0 °C) solution of compound 11 (470 mg, 0.97 mmol) and
Py (1.2 mL, 14.9 mmol) in CH2Cl2 (10 mL), and stirring was con-
tinued for 48 h at room temp. The solvent was removed under re-
duced pressure, and the residue was diluted with MeOH (6 mL),
treated with K2CO3 (1.45 g, 10.5 mmol) at room temp. for 1 h, and
diluted with Et2O. The organic layer was washed successively with
satd. aq. CuSO4 and brine, dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography (EtOAc/hexanes, 1:10) to afford 21
(411 mg, 91%) as a colorless oil. [α]2D0 = –22.2 (c = 2.34, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.34–7.26 (m, 5 H), 4.56 (s, 2
A solution of triphosgene in CH2Cl2 (0.67 , 0.85 mL, 0.57 mmol)
was added to a cooled (–35 °C) solution of 22 (780 mg, 1.34 mmol)
and pyridine (0.14 mL, 1.73 mmol) in CH2Cl2 (10 mL), the mixture
was stirred at room temp. for 4 h, and water (0.072 mL, 4.0 mmol)
was added. After having been stirred for an additional 1 h, the mix-
ture was diluted with EtOAc, dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The residue was taken up in MeOH
(24 mL) and treated with K2CO3 (146 mg, 1.06 mmol) for 30 min
at room temp., filtered through celite, concentrated under reduced
pressure, and purified by silica gel column chromatography
(EtOAc/hexanes, 1:1) to afford 23 (520 mg, 81%) as a pale yellow
1
H), 4.21–3.76 (AB, JAB = 11.8 Hz, 2 H), 4.12 (dt, J = 8.0, 4.7 Hz, oil. [α]2D0 = –48.4 (c = 1.64, CHCl3). H NMR (300 MHz, CDCl3):
1 H), 3.96 (dd, J = 7.8, 6.7 Hz, 1 H), 3.62 (s, 3 H), 3.55 (dd, J = δ = 7.38–7.24 (m, 5 H), 6.34 (br. s, 1 H), 4.55 (s, 2 H), 4.38 (s, 1
10.6, 4.9 Hz, 1 H), 3.52 (dd, J = 10.6, 4.5 Hz, 1 H), 3.24 (d, J =
H), 4.31–4.23 (m, 1 H), 4.20 (d, J = 8.5 Hz, 1 H), 4.06–3.77 (AB,
6.6 Hz, 1 H), 1.43 (s, 3 H), 1.40 (s, 3 H), 0.87 (s, 9 H), 0.06 (s, 3 JAB = 9.8 Hz, 2 H), 3.74–3.60 (m, 3 H), 3.60–3.44 (m, 2 H), 1.42
H), 0.05 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.3,
137.9, 128.5 (2 C), 127.8, 127.7 (2 C), 110.6, 77.4, 75.8, 73.7, 69.5,
(s, 2ϫ3 H), 0.86 (s, 9 H), 0.05 (s, 2ϫ3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 159.4, 137.8, 128.4 (2 C), 127.7, 127.6 (2 C),
62.6, 59.0, 52.3, 27.1, 26.8, 25.8, 18.3, –5.4 (2 C) ppm. C24H38O7Si 110.3, 77.9, 76.9, 75.4, 73.6, 70.0, 65.5, 63.5, 62.2, 27.4, 26.2, 25.7
(466.64): calcd. C 61.77, H 8.21; found C 62.08, H 8.29.
(3 C), 18.0, –5.7, –5.8 ppm. C24H39NO7Si (481.65): calcd. C 59.85,
H 8.16, N 2.91; found C 59.55, H 8.44, N 2.64.
Alcohol 10: DIBAL/hexane (1.0 , 6.8 mL, 6.8 mmol) was added
dropwise to a cooled (–78 °C) solution of 21 (749 mg, 1.61 mmol)
in CH2Cl2 (7 mL), and stirring was continued for 2 h. The reaction
mixture was quenched with satd. aq. NH4Cl, allowed to warm to
room temp., and stirred for another 30 min. The mixture was fil-
tered through celite, the filter cake was washed with CH2Cl2, and
the combined filtrate was dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The residue was taken up in MeOH
(7 mL) and cooled to 0 °C, NaBH4 (67 mg, 1.81 mmol) was added,
and the mixture was stirred for 30 min at room temp., diluted with
water, and extracted with Et2O. The combined organic phase was
washed with brine, dried (Na2SO4), filtered, and concentrated un-
der reduced pressure. The residue was purified by silica gel column
chromatography (EtOAc/hexanes, 1:3) to afford 10 (616 mg, 90%)
as a colorless oil. [α]2D0 = –18.2 (c = 2.04, CHCl3). 1H NMR
MOM Ether 9: A solution of compound 23 (224 mg, 0.46 mmol),
DIPEA (0.72 mL, 4.36 mmol), and MOMCl (0.17 mL, 2.1 mmol)
in CH2Cl2 (10 mL) was heated at reflux for 4 h, cooled, poured
into water, and extracted with EtOAc (2ϫ20 mL). The combined
organic layer was washed with brine, dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (EtOAc/hexanes, 1:6) to afford 9
(213 mg, 87%) as a colorless oil. [α]1D8 = –40.4 (c = 1.77, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.38–7.26 (m, 5 H), 5.39 (br. s,
1 H), 4.59 (s, 2 H), 4.55 (s, 2 H), 4.33 (s, 1 H), 4.31 (dt, J = 6.2,
4.5 Hz, 1 H), 4.06 (d, J = 8.4 Hz, 1 H), 3.99–3.87 (AB, JAB
=
9.6 Hz, 2 H), 3.72 (part of AB-d, JAB = 9.9, J = 4.7 Hz, 1 H), 3.63–
3.54 (AB, JAB = 9.5 Hz, 2 H), 3.53 (part of AB-d, JAB = 9.9, J =
6.1 Hz, 1 H), 3.30 (s, 3 H), 1.44 (s, 3 H), 1.42 (s, 3 H), 0.87 (s, 9
H), 0.06 (s, 2ϫ3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 157.9,
137.8, 128.4 (2 C), 127.8, 127.6 (2 C), 110.5, 96.9, 77.9, 77.4, 75.1,
73.7, 70.2, 69.4, 62.4, 61.2, 55.5, 27.4, 26.1, 25.7 (3 C), 18.1, –5.7,
–5.8 ppm. C26H43NO8Si (525.71): calcd. C 59.40, H 8.24, N 2.66;
found C 59.43, H 8.34, N 2.81.
(500 MHz, CDCl3): δ = 7.35–7.28 (m, 5 H), 4.62–4.55 (AB, JAB
=
12.0 Hz, 2 H), 4.12–4.08 (m, 1 H), 4.01 (t, J = 7.5 Hz, 1 H), 3.86
(dd, J = 12.0, 7.5 Hz, 1 H), 3.83–3.72 (AB, JAB = 12.0 Hz, 2 H),
3.69 (dd, J = 9.5, 4.5 Hz, 1 H), 3.63 (dd, J = 11.0, 6.0 Hz, 1 H),
3.58 (dd, J = 12.0, 4.5 Hz, 1 H), 3.09 (d, J = 8.5 Hz, 1 H), 2.76
(br. t, J = 6.0 Hz, 1 H), 1.46 (s, 3 H), 1.40 (s, 3 H), 0.89 (s, 9 H),
0.06 (s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
136.8, 128.3 (2 C), 127.9, 127.8 (2 C), 110.0, 77.1, 77.0, 73.7, 69.5,
63.9, 63.3, 60.6, 60.1, 26.9, 26.8, 25.6 (3 C), 18.0, –5.7 (2 C) ppm.
C23H38O6Si (438.63): calcd. C 62.98, H 8.73; found C 63.32, H
8.80.
Synthesis of 24: A suspension of compound 9 (114 mg, 0.22 mmol)
and Pd(OH)2/C (20%, 18 mg) in EtOAc/MeOH (4:1, 2.4 mL) was
stirred under hydrogen at room temp. for 2 h, filtered through ce-
lite, and concentrated to afford the crude alcohol (95 mg) as a col-
orless oil. DMSO (0.046 mL, 0.65 mmol) was added to a cooled
(–78 °C) solution of (COCl)2 (0.039 mL, 0.45 mmol) in CH2Cl2
(2.5 mL), the mixture was stirred for 5 min, and a solution of the
above alcohol in CH2Cl2 (2.0 mL) was added. After the system had
been stirred for 30 min, Et3N (0.31 mL, 2.2 mmol) was added, and
the mixture was stirred at –78 °C for an additional 30 min, allowed
to warm gradually to 0 °C, poured into water, and extracted with
CH2Cl2. The combined organic layer was washed with water and
brine, dried (Na2SO4), filtered, and concentrated under reduced
pressure to afford the crude aldehyde (98 mg) as a pale yellow oil.
Carbamate 23: Cl3CCN (0.18 mL, 1.8 mmol) was added to a cooled
(0 °C) solution of compound 10 (603 mg, 1.38 mmol) in CH2Cl2
(12 mL), followed by DBU (0.038 mL, 0.25 mmol). The mixture
was stirred for 30 min, diluted with EtOAc, washed with water and
brine, dried (Na2SO4), filtered, and concentrated under reduced
pressure. The residue was passed through a short silica gel column
(eluted with EtOAc/hexanes, 1:6) to afford the crude trichloroaceti-
midate (823 mg) as a colorless oil.
The above intermediate was dissolved in CH2Cl2 (12 mL) and co-
A
cooled (0 °C) solution of phosphonium salt
8 (450 mg,
oled (0 °C), and Et2AlCl (1.0  in hexane, 0.69 mL, 0.69 mmol)
0.75 mmol) in THF (4 mL) was treated with BuLi (1.6  in hexane,
Eur. J. Org. Chem. 2009, 5038–5046
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5043

B. Wang, G.-Q. Lin
FULL PAPER
0.41 mL, 0.66 mmol), stirred at room temp. for 10 min, and cooled
to –78 °C, and a solution of the above aldehyde in THF (1.6 mL)
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
was added dropwise. The mixture was stirred at this temperature (EtOAc/hexanes, 2:1) to afford 25 (53 mg, 77%) as a colorless oil.
for 1 h, allowed to warm to room temp., and quenched with satd.
aq. NH4Cl. The aq. phase was extracted with Et2O, and the com-
[α]1D8 = –11.9 (c = 0.50, CHCl3). NMR peaks were broadened, due
to the presence of rotamers. 1H NMR (300 MHz, CDCl3): δ = 7.44
bined organic layer was washed with brine, dried (Na2SO4), fil- (br. s, 1 H), 5.95 (dt, J = 15.4, 6.9 Hz, 1 H), 5.54 (dd, J = 15.4,
tered, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (EtOAc/hexanes, 1:6
to 1:3) to afford (Z)-24 (77 mg, 53%) and (E)-24 (9 mg, 6%) as
colorless oils.
6.0 Hz, 1 H), 5.16 (d, J = 4.1 Hz, 1 H), 4.65–4.40 (m, 3 H), 4.15–
3.80 (br. m, 1 H), 4.02–3.87 (AB, JAB = 11.3 Hz, 2 H), 2.38 (t-like,
J = 7.1 Hz, 2ϫ2 H), 2.14–1.93 (m, 2 H), 1.62–1.45 (m, 4 H), 1.45–
1.10 (m, 12 H), 0.87 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 212.5, 174.8, 157.6, 136.2, 125.7, 84.4, 78.9, 69.9, 66.8,
61.3, 42.8, 42.7, 32.2, 31.5, 28.9 (3 C), 28.5, 23.8, 23.7, 22.4,
14.0 ppm. HR-MS: calcd. for C21H39NO7 [M]+ 425.2387; found
425.2361.
Compound (Z)-24: [α]1D8 = –25.6 (c = 0.92, CHCl3). NMR peaks
were broadened, due to the presence of rotamers. 1H NMR
(300 MHz, CDCl3): δ = 5.74 (dt, J = 10.7, 7.1 Hz, 1 H), 5.40 (br.
s, 1 H), 5.31 (dd, J = 10.7, 9.1 Hz, 1 H), 4.88 (t, J = 9.1 Hz, 1 H),
4.62 (s, 2 H), 4.09 (s, 1 H), 3.98–3.86 (AB, JAB = 9.6 Hz, 2 H), 3.92
Sphingofungin E (1): Aq. NaOH (1 , 1.0 mL) was added to a solu-
(s, 4 H), 3.76 (d, J = 8.8 Hz, 1 H), 3.64–3.56 (AB, JAB = 9.6 Hz, 2 tion of 25 (34 mg, 0.08 mmol) in MeOH (1.0 mL) and the mixture
H), 3.34 (s, 3 H), 2.26–1.97 (m, 2 H), 1.63–1.50 (m, 4 H), 1.44 (s, was heated at reflux for 2 h, allowed to cool, and neutralized with
3 H), 1.43 (s, 3 H), 1.42–1.16 (m, 16 H), 0.89 (s, 9 H), 0.87 (t, J =
6.9 Hz, 3 H), 0.07 (s, 3 H), 0.06 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 158.0, 137.8, 124.7, 111.8, 110.0, 96.8, 78.6, 76.4, 72.7,
69.4, 64.8 (2 C), 62.4, 61.1, 55.5, 37.1, 37.0, 31.8, 29.7, 29.5 (2 C),
IRC-76 resin. The resin was filtered off and washed with MeOH,
and the combined filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(CHCl3/MeOH/H2O 10:3:1) to afford 1 (25 mg, 75%) as a white
29.1, 27.8, 27.5, 26.1, 25.7 (3 C), 23.7 (2 C), 22.5, 18.0, 14.0, –5.7, solid. M.p. 147–149 °C. [α]1D8 = –13.0 (c = 0.30, MeOH). H NMR
–5.8 ppm. HR-MS: calcd. for C34H62NO9Si [M – CH3]+ 656.4220; (500 MHz, CD3OD): δ = 5.76 (dt, J = 15.4, 6.6 Hz, 1 H), 5.45 (dd,
1
found 656.4247.
J = 15.4, 7.7 Hz, 1 H), 4.10 (t, J = 7.3 Hz, 1 H), 3.98–3.83 (AB,
JAB = 10.9 Hz, 2 H), 3.95 (s, 1 H), 3.63 (d, J = 6.8 Hz, 1 H), 2.44
(t, J = 7.2 Hz, 4 H), 2.05 (q-like, 2 H), 1.60–1.47 (m, 4 H), 1.46–
1.21 (m, 12 H), 0.89 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (125 MHz,
CD3OD): δ = 214.4, 173.0, 135.7, 130.2, 76.2, 75.6, 71.2, 70.2, 64.9,
43.5 (2 C), 33.4, 32.8, 30.2, 30.1, 30.0 (2 C), 24.9, 24.7, 23.6,
14.3 ppm. HR-ESI-MS: calcd. for C21H40NO7 [M + H]+ 418.2799;
found 418.2799.
Compound (E)-24: A solution of (Z)-24 (33 mg, 0.049 mmol) and
PhSSPh (21 mg, 0.096 mmol) in cyclohexane/dioxane (19:1, 8 mL)
was irradiated with a high-pressure mercury lamp for 9 h at room
temp. The mixture was poured into satd. aq. NaHCO3 (10 mL) and
extracted with EtOAc (3ϫ15 mL). The combined organic layer was
washed with brine, dried (Na2SO4), filtered, and concentrated un-
der reduced pressure. The residue was purified by silica gel column
chromatography (EtOAc/hexanes, 1:3) to afford (E)-24 [21 mg,
95% based on reacted (Z)-24] as a colorless oil, together with unre-
acted (Z)-24 (12 mg). [α]1D8 = –38.2 (c = 1.01, CHCl3). NMR peaks
were broadened, due to the presence of rotamers. 1H NMR
Iodide 26: I2 (240 mg, 0.94 mmol) was added at room temp. to a
solution of compound 10 (236 mg, 0.54 mmol), Ph3P (212 mg,
0.82 mmol), and imidazole (55 mg, 0.81 mmol) in Et2O/MeCN
(3:1, 6 mL), and stirring was continued for 3 h. The mixture was
(300 MHz, CDCl3): δ = 5.90 (dt, J = 15.4, 6.9 Hz, 1 H), 5.38 (dd, quenched with satd. aq. Na2S2O3 and extracted with CH2Cl2
J = 15.4, 8.0 Hz, 1 H), 5.24 (br. s, 1 H), 4.64 (s, 2 H), 4.47 (t, J = (2ϫ15 mL), and the combined organic layer was washed with
8.5 Hz, 1 H), 4.14 (s, 1 H), 3.97–3.87 (AB, JAB = 9.6 Hz, 2 H), 3.93 water and brine, dried (Na2SO4), filtered, and concentrated under
(s, 4 H), 3.80 (d, J = 8.8 Hz, 1 H), 3.67–3.58 (AB, JAB = 9.3 Hz, 2 reduced pressure. The residue was purified by silica gel column
H), 3.35 (s, 3 H), 2.10–1.95 (m, 2 H), 1.75–1.45 (m, 4 H), 1.44 (s, chromatography (EtOAc/hexanes, 1:15) to afford 26 (288 mg, 97%)
3 H), 1.43 (s, 3 H), 1.42–1.10 (m, 16 H), 0.90 (s, 9 H), 0.88 (t, J =
6.9 Hz, 3 H), 0.08 (s, 3 H), 0.07 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 157.8, 138.5, 125.4, 111.8, 109.9, 96.9, 78.5, 78.4, 76.4,
69.4, 64.9 (2 C), 62.3, 61.1, 55.5, 37.1 (2 C), 32.3, 31.8, 29.8, 29.6,
29.2, 28.8, 27.5, 26.1, 25.7 (3 C), 23.8, 23.7, 22.6, 18.1, 14.1, –5.7
as a colorless oil. [α]2D3 = –12.2 (c = 1.55, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 7.38–7.26 (m, 5 H), 4.62–4.54 (AB, JAB
12.0 Hz, 2 H), 4.16 (dt, J = 8.5, 2.7 Hz, 1 H), 4.01 (dd, J = 8.0,
5.0 Hz, 1 H), 3.83–3.70 (AB, JAB = 11.0 Hz, 2 H), 3.67 (part of
=
AB-d, JAB = 10.5, J = 4.5 Hz, 1 H), 3.64 (part of AB-d, JAB
=
(2 C) ppm. HR-MS: calcd. for C31H56NO9Si [M
614.3698; found 614.3672.
–
C4H9]+
10.5, J = 5.5 Hz, 1 H), 3.46–3.32 (AB, JAB = 10.5 Hz, 2 H), 3.20
(d, J = 7.0 Hz, 1 H), 1.44 (s, 3 H), 1.43 (s, 3 H), 0.89 (s, 9 H), 0.08
(s, 3 H), 0.06 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
137.6, 128.5 (2 C), 127.9 (3 C), 110.4, 77.8, 75.7, 73.7, 69.4, 65.0,
63.6, 63.0, 27.0, 26.8, 25.8 (3 C), 18.2, 3.3, –5.4 (2 C) ppm. HR-
ESI-MS: calcd. for C23H37IO5SiNa [M + Na]+ 571.1353; found
571.1370.
Lactone 25: A solution of (E)-24 (140 mg, 0.21 mmol) in THF
(2.6 mL) was treated with TBAF/THF (1 , 0.31 mL, 0.31 mmol)
for 15 min at room temp., diluted with EtOAc, washed with water
and brine, dried (Na2SO4), filtered, and concentrated under re-
duced pressure. The residue was passed through a short silica gel
column (eluted with EtOAc) to afford a colorless oil (108 mg,
93%). The above crude alcohol (87 mg, 0.17 mmol) was dissolved
in DMF (1.0 mL), PDC (535 mg, 1.42 mmol) was added in one
portion, and stirring was continued for 24 h. The mixture was di-
luted with water and extracted with Et2O (6ϫ10 mL), and the
combined organic layer was washed with water and brine, dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
crude acid (85 mg, 0.16 mmol) was dissolved in EtOH/H2O (7:3,
Epoxide 15: LiBHEt3/THF (1.0 , 0.26 mL, 0.26 mmol) was added
dropwise at room temp. to a solution of compound 26 (69 mg,
0.13 mmol) in THF (1.2 mL), stirring was continued for 15–20 min,
and the solution was then cooled to 0 °C and quenched with aq.
H2O2 (30%). After the system had been stirred for 5 min, satd.
aq. Na2S2O3 was added and the mixture was extracted with Et2O
(3ϫ15 mL). The combined organic phase was washed with aq.
FeSO4 and brine, dried (Na2SO4), filtered, and concentrated under
4.5 mL), TsOH·H2O (134 mg, 0.70 mmol) was added, and the sys- reduced pressure. The residue was purified by silica gel column
tem was heated at reflux for 8 h, allowed to cool, diluted with Et2O, chromatography (EtOAc/hexanes, 1:15) to afford 15 (42 mg, 80%)
5044
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5038–5046

α-Substituted Serines and Alanines
as a colorless oil. [α]2D4 = –22.7 (c = 0.42, CHCl3). 1H NMR
Chida, Org. Lett. 2002, 4, 151–154; d) B. M. Trost, C. Lee, J.
Am. Chem. Soc. 2001, 123, 12191–12201; e) T. Nakamura, M.
Shiozaki, Tetrahedron Lett. 2001, 42, 2701–2704; f) B. Wang,
X.-M. Yu, G.-Q. Lin, Synlett 2001, 904–906.
Total synthesis of 2: a) M. Li, A. Wu, Synlett 2006, 2985–2988;
b) K.-Y. Lee, C.-Y. Oh, W.-H. Ham, Org. Lett. 2002, 4, 4403–
4405; c) Reference 7d; d) D.-G. Liu, B. Wang, G.-Q. Lin, J.
Org. Chem. 2000, 65, 9114–9119; e) S. Kobayashi, T. Furuta,
Tetrahedron 1998, 54, 10275–10294; f) B. M. Trost, C. B. Lee,
J. Am. Chem. Soc. 1998, 120, 6818–6819; g) S. Kobayashi, T.
Furuta, T. Hayashi, M. Nishijima, K. Hanada, J. Am. Chem.
Soc. 1998, 120, 908–919; h) S. Kobayashi, M. Matsumura, T.
Furuta, T. Hayashi, S. Iwamoto, Synlett 1997, 301–303.
(600 MHz, CDCl3): δ = 7.36–7.26 (m, 5 H), 4.61–4.54 (AB, JAB
=
12.1 Hz, 2 H), 4.07 (dt, J = 8.1, 4.2 Hz, 1 H), 3.86 (t, J = 8.0 Hz,
1 H), 3.63 (part of AB-d, JAB = 10.5, J = 4.0 Hz, 1 H), 3.58 (part
[8]
of AB-d, JAB = 10.5, J = 4.8 Hz, 1 H), 3.56–3.48 (AB, JAB
11.2 Hz, 2 H), 2.95 (d, J = 8.0 Hz, 1 H), 1.47 (s, 3 H), 1.43 (s, 3
H), 1.24 (s, 3 H), 0.88 (s, 9 H), 0.05 (s, 3 H), 0.03 (s, 3 H) ppm. 13
=
C
NMR (150 MHz, CDCl3): δ = 137.7, 128.4 (2 C), 127.7 (3 C),
110.1, 77.7, 73.67, 69.2, 67.3, 60.7, 60.5, 27.1, 26.9, 25.8 (3 C), 18.3,
14.8, –5.4 (2 C) ppm. HR-ESI-MS: calcd. for C23H39O5Si [M +
Na]+ 445.2386; found 445.2380.
Supporting Information (see also the footnote on the first page of
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Acknowledgments
We thank the National Natural Science Foundation of China for
Major Program Funding (20832005, in part) and Youth Funding
(20602008). Financial support from Fudan University (Startup
Grants EYH1615003 and EYH1615004) is also gratefully acknowl-
edged.
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