Asymmetric synthesis of epohelmins A, B and 3-epi ent-epohelmin A

Article abstract of DOI:10.1016/j.tet.2016.10.047

An efficient method for asymmetric synthesis of epohelmins A (3), B (4) and their isomer 24 is detailed in this report. The key feature in this divergent synthesis includes the SmI₂-induced cross-coupling of N-tert-butanesulfinyl imine 10 with chiral aldehyde 9 derived from D-malic acid. A cascade cyclization to the pyrrolizidine skeleton is achieved in our synthetic route for epohelmins. In addition, an interesting intramolecular oxa-Michael addition was observed for epohelmin A (3).

Full text of DOI:10.1016/j.tet.2016.10.047

Accepted Manuscript
Asymmetric synthesis of epohelmins A, B and 3-epi ent-epohelmin A
Chang-Mei Si, Yi-Wen Liu, Zhuo-Ya Mao, Pan Han, Zhen-Ting Du, Bang-Guo Wei
PII:
S0040-4020(16)31081-X
10.1016/j.tet.2016.10.047
TET 28188
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 September 2016
Revised Date: 17 October 2016
Accepted Date: 18 October 2016
Please cite this article as: Si C-M, Liu Y-W, Mao Z-Y, Han P, Du Z-T, Wei B-G, Asymmetric synthesis of
epohelmins A, B and 3-epi ent-epohelmin A, Tetrahedron (2016), doi: 10.1016/j.tet.2016.10.047.
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Asymmetric synthesis of epohelmins A, B and
3-epi ent-epohelmin A
Leave this area blank for abstract info.
Chang-Mei Si,a Yi-Wen Liu,a Zhuo-Ya Mao,a,b Pan Han,b Zhen-Ting Du,b Bang-Guo Weia,*
aSchool of Pharmacy Fudan University, 826 Zhangheng Road, Shanghai 201203, China
bCollege of Science, Northwest A&F University, 22 Xinong Road, Shaanxi, Yangling, 712100, China
OH
O
OPMB
O
+
SmI2
H
N
n-C5H10
S
N
TBSO
OPMB
O
Cyclization in cascade
Epohelmins A 3, B 4 and their isomer 24
(S or R)-10
9

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Asymmetric synthesis of epohelmins A, B and 3-epi ent-epohelmin A
Chang-Mei Si,a Yi-Wen Liu,a Zhuo-Ya Mao,a,b Pan Han,a Zhen-Ting Du,b Bang-Guo Weia,
aDepartment of Natural Products Chemistry, School of Pharmacy Fudan University, 826 Zhangheng Road, Shanghai 201203, China
bCollege of Science, Northwest A&F University, 22 Xinong Road, Shaanxi, Yangling, 712100, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient method for asymmetric synthesis of epohelmins A (3), B (4) and their isomer 24 is
detailed in this report. The key feature in this divergent synthesis includes the SmI2-induced
cross-coupling of N-tert-butanesulfinyl imine 10 with chiral aldehyde 9 derived from D-malic
acid. A cascade cyclization to the pyrrolizidine skeleton is achieved in our synthetic route for
epohelmins. In addition, an interesting intramolecular oxa-Michael addition was observed for
epohelmin A (3).
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved
.
Asymmetric Synthesis
Natural Product
Cross-coupling
Spohelmins
Cascade cyclization
1. Introduction
Following the pioneering work of Davis and Ellman, chiral
auxiliaries (e.g. 2-methylpropane-2-sulfinamide and N-
toluenesulfinamide) have been widely used in organic synthesis.7-
Statins, known as 3-hydroxy-3-methylglutaryl coenzyme A
(HMG-CoA) reductase inhibitors, are a class of lipid-lowering
medications, which play a central role in cardiovascular disease
(CVD).1 Due to their significant clinical effect, a number of
statins such as atorvastatin, fluvastatin, lovastatin, pitavastatin,
pravastatin, rosuvastatin and simvastatin are approved for use to
control blood cholesterol level in human.2 Epohelmins A (1) and
B (2), as novel lanosterol synthase inhibitors, were isolated from
a fungal strain FKI-0929.3 Notably, the chemical structures of 3
and 4 were revised from the originally proposed monocyclic core
to a bicyclic skeleton, 3 and 4, by Snider4,5 after their asymmetric
synthesis in 2005, and were further confirmed by Fürstner6 in
2008 (Figure 1).
9
In recent years, one of our research interests is to utilize these
popular chiral auxiliaries in asymmetric synthesis of natural
products.10-12 An interesting tert-butyl migration-addition from
enantioenriched N-tert-butanesulfinyl iminoacetates11 and an
efficient
formation
of
trans-5-hydroxy-6-alkyl/aryl-2-
piperidinone skeleton12 have been discovered in our group. In
continuation of our application of chiral 2-methylpropane-2-
sulfinamide in the divergent synthesis of alkaloids,10a,12,13 herein,
we present the use of such flexible chiral auxiliaries in the
asymmetric synthesis of epohelmins A (3), B (4) and their
isomer 24.
O
O
2. Results and Discussions
O
O
Our synthetic strategy for asymmetric synthesis of epohelmins
A (3) and B (4) is illustrated in Figure 2, with asymmetric
control of stereochemistry and effective formation of the
pyrrolizidine skeleton as our main focus in constructing target
molecule. A SmI2-induced cross-coupling for anti- vicinal β-
amino alcohol, which was established in early years9d and
successfully used in asymmetric synthesis of natural products,10,14
was proposed for the synthesis of a key fragment 15 from
aldehyde 9 and N-sulfinyl imine (S)-10. The enone 16, derived
from 15 using Horner-Wadsworth-Emmons (HWE) reaction, was
subjected to cascade cyclization to form the pyrrolizidine
C5H11-n
C5H11-n
The proposed Epohelmin B 2
OH
N
N
H
H
The proposed Epohelmin A 1
OH
H
O
O
H
n-C5H11
N
n-C5H11
N
The revised Epohelmin B 4
The revised Epohelmin A 3
Figure 1. Structures of epohelmins A and B.
———
Corresponding author. Tel./fax: +86 21 5423 7757 (B.-G.W.); E-mail: bgwei1974@fudan.edu.cn (B.-G. Wei).

2
Tetrahedron
nickel dichloride monohydrate (NiCl2·H2O)21 to give ester 14 in
skeleton.15 The chiral aldehyde 9 could be prepared from D-
ACCEPTED MANUSCRIPT
86% yield.
malic acid.
OH
OH
H
O
OH
O
O
a
H
b
+
(S)-10
MeO
OPMB
9
n-C5H11
N
n-C5H11
N
O
NH
TBSO
S
11
Epohelmin A
Epohelmin B
O
OTBS
OPMB
Cyclization in cascade
O
OTBS
OPMB
O
OH
c
MeO
O
MeO
HO
O
OH OTBS
NHBoc
12
NHBoc
OH
OH
D-malic acid
n-C5H10
OH
13
COOMe
OPMB
NH2
16
O
OTBS
HWE reaction
d
O
MeO
MeOOC
TBSO
NHBoc
OPMB
O
P
O
OP OTBS
OPMB
14
SmI2
9
O
Scheme 2. The preparation of ester 14. Reagents and conditions: a. SmI2,
t-BuOH, THF, -78oC, 76%; b. (1) TBSOTf, 2,6-Lutidine, 0oC; (2)
HCl/dioxane, EtOH, 0oC; (3) Boc2O, TEA, DCM, 3 steps 52%; c. (1) DMP,
DCM; (2) Ph3PCHCOOCH3, DCM, 2 steps 94%; d. NiCl2·H2O, NaBH4,
CH3OH, 86%.
OPMB
Cross Coupling
O
NHBoc
N
S
15 (P =PMB)
O
(S)-10
Figure 2. Retrosynthetic analysis of epohelmins A and B.
With ester 14 in hand, we turned our attention to synthesize
epohelmin
A
(3). Reaction of 14 and dimethyl
As shown in Scheme 1, aldehyde 9 could be easily prepared
by known method,16 but we could not obtain enough amount for
synthesis of epohelmins. Thus chiral alcohol 5 was prepared from
D-malic acid according to the known procedure.17 Protection of 5
with 3,4-dihydro-2H-pyran (DHP) and subsequent removal of
silyl group with TBAF gave alcohol 6 in 82% overall yield. The
primary alcohol 6 was converted to cyanide 7, through
displacement of the corresponding mesylate with KCN, in 85%
overall yield. After the O-THP protection was switched to O-
TBS, the cyano group was reduced by DIBAL-H18 to afford the
desired chiral aldehyde 9 in 70% yield.
methylphosphonate using n-butyllithium as a base produced
phosphonate 15 in 86% yield (Scheme 3).4 Upon the removal of
both PMB groups by hydrogenolysis (Pd/C, Pd(OH)2, H2), the
crude product was subjected to Horner-Wadsworth-Emmons
reaction with hexanal to give α,β-unsaturated ketone 16 in 54%
yield.22 Finally, mesylation of both hydroxyl groups in 16 with
methanesulfonyl chloride (MsCl) and subsequent selectively
deprotection of NH-Boc with TESOTf/2,6-lutidine resulted in
simultaneous cyclization to pyrrolizidine skeleton, which was
subjected to desilylation with MeOH/HCl at room temperature
for overnight. The crude epohelmin A (3) was purified by flash
chromatography on silica gel (DCM/MeOH/AcOH = 100:10:1)
a
b
HO
D-Malic Acid
THPO
23
to give pure 3·HOAc {[α]D +2.9 (c 0.31, CH3OH)} in 46%
OTBS
OPMB
OH
OPMB
yield over three steps. The spectral data of the synthetic 3·HOAc
were identical to the reported data.4
5
6
THPO
MeO
O
OTBS
c
TBSO
d
TBSO
CN
OPMB
O
a
b
CN
OPMB
14
O
O
OPMB
OPMB
MeO P
OMe
NHBoc
15
7
9
8
Scheme 1. The preparation of aldehyde 9. Reagents and conditions: a. (1)
DHP, PPTS, 100%; (2) TBAF, THF, 82%; b. (1) MsCl, TEA, DCM, 96%; (2)
KCN, DMSO, 89%; c. (1) THF: 3M HCl, 90%; (2) TBSCl, Imidazole, DMF,
99%; d. DIBAL-H, THF, -78oC, 70%.
O
OH OTBS
c
n-C5H11
OH
NHBoc
The SmI2-induced cross-coupling of 9 with (S)-N-(4-(4-
methoxybenzyloxy)butylidene)-2-methylpropane-2-sulfinamide
10, which was readily prepared from chiral 2-methylpropane-2-
sulfinamide, gave desired vicinal β-amino alcohol 11 with high
diastereoselectivity (dr > 99:1) in 76% yield (Scheme 2). Upon
two following sequential steps, regioselective desilylation from
the primary hydroxyl group by tert-butyldimethylsilyl
trifluoromethanesulfonate (TBSOTf) and removal of the chiral
auxiliary using (HCl/dioxane), the resulting amino alcohol was
converted to 12 in 52% overall yield.13a Then oxidation with
Dess-Martin periodinane19 and subsequent Wittig reaction20
generated desired olefin 13 in 94% overall yield, which was
reduced with sodium borohydride (NaBH4) in the presence of
16
OH
H
O
n-C5H10
N
Epohelmin A 3
Scheme 3. The preparation of Epohelmin A 3. Reagents and conditions: a.
n-BuLi, dimethyl methylphosphonate, THF, -78oC, 86%; b. (1) Pd/C,
Pd(OH)2, H2, MeOH; (2) LiCl, DBU, hexanal, 2 steps 54%; c. (1) MsCl, TEA,
DCM; (2) TESOTf, 2,6-lutidine, DCM, -78oC; (3) HCl/CH3OH, 3 steps 46%.

3
Scheme 4. The preparation of Epohelmin B 4. Reagents and conditions: a.
However, our synthetic epohelmin A (3) was relatively
unstable after it was converted to a free base form. As shown in
Figure 3, both olefin protons gradually decreased and a new
signal peak (δ 3.70-3.64) increased in 1H NMR (CDCl3).
Significant changes were also observed in 13C NMR (CDCl3). A
new signal peak (δ = 209.5) appeared and gradually increased.
Although great efforts were devoted to isolate this new structure
by preparative HPLC, we failed to obtain the pure compound. In
consideration of all these changes, the diminished peaks for the
carbon-carbon double bond and carbonyl group, as well as the
emergence and enhancement for new carbonyl group, an
intramolecular oxa-Michael addition23,24 was highly possible,
leading to the formation of tricyclic compound 17. We propose
that there is an equilibrium between epohelmin A (3) and new
skeleton 17, the ipsilateral two corresponding substituents24a and
the basic nitrogen prompted such an addition process in
epohelmin A (3). While the structure of epohelmin A (3) is very
stable in acetic acid condition.3,4
ACCEPTED MANUSCRIPT
(1) (COCl)2, DMSO, DCM, -78oC; (2) L-Selectride, THF, -78oC~rt; (3)
DMP, DCM, 3 steps 63%.
Meantime, another trans-epimer 24 of epohelmin A (3) was also
synthesized. The detailed synthetic sequence was shown in
Scheme 5, Starting from another enantiomeric imine, (R)-N-(4-
(4-methoxybenzyloxy)
butylidene)-2-methylpropane-2-
23
sulfinamide 10, the isomer 24 {[α]D -7.5 (c 0.50, CHCl3)} was
successfully prepared in 7.7% overall yield in 13 linear steps.
The NMR studies also showed that the isomer 24 is more stable
than epohelmin A (3).
O
OH
a
b
MeO
OPMB
(R)-10
+
9
O
NH
TBSO
OPMB
S
18
O
OTBS
O
OTBS
OPMB
C5H11
O
OH
H
MeO
c
MeO
O
O
NHBoc
MeOOC
NHBoc
OH
H
N
n-C5H11
19
20
N
O
OTBS
Epohelmin A 3
17
d
e
MeO
MeOOC
OPMB
NHBoc
21
MeO
O
OTBS
f
O
O
OPMB
MeO
P
NHBoc
OTBS
OMe
22
HO
O
g
n-C5H11
OH
NHBoc
23
OH
H
O
n-C5H11
N
24
Scheme 5. The synthesis of isomer 24. Reagents and conditions: a. SmI2, t-
BuOH, THF, -78oC, 77%; b. (1) TBSOTf, 2,6-lutidine, 0oC; (2) HCl/dioxane,
EtOH, 0oC; (3) Boc2O, TEA, DCM, 3 steps 58%; c. (1) DMP, DCM; (2)
Ph3PCHCOOCH3, DCM, 2 steps 91%; d. NiCl2·H2O, NaBH4, MeOH, 90%;
e. (1) n-BuLi, THF, dimethyl methylphosphonate, -78oC, 86%; f. (1) Pd/C,
Pd(OH)2, MeOH; (2) LiCl, DBU, hexanal, 2 steps 53%; g. (1) MsCl, TEA;
(2) TESOTf, 2,6-lutidine, DCM, -78oC; (3) HCl/MeOH, 3 steps 50%.
Figure 3. The changes observed in 1H NMR and 13C NMR of 3 and 17.
To confirm our speculation of this intramolecular oxa-Michael
addition reaction, we synthesized epohelmin B (4), in which the
two corresponding substituents existed at opposite sides. The
chemistry was straightforward by following the literature
3. Conclusions
23
procedure,4 and epohelmin B (4) {[α]D +4.3 (c 1.00, CH3OH),
In summary, we completed the asymmetric synthesis of
natural epohelmins A (20 steps from 5, 3.0% overall yield), B (23
steps from 5, 1.9% overall yield) and its isomer 24 (20 steps from
5, 4.1% overall yield) using SmI2-induced cross-coupling of N-
tert-butanesulfinyl imine 10 with chiral aldehyde 9 to generate
the required stereocenters. The cascade cyclization to form the
pyrrolizidine skeleton is another feature of our synthetic route for
epohelmins. In addition, we observed epohelmin A (3) could
undergo an intramolecular oxa-Michael process to give a new
skeleton 17. Further efforts on the extension of this strategy are
on-going in our laboratory to synthesize other analogs of
epohelmin A (3). The chemistry and related biological data will
be published in due course.
23
20
[α]D +4.9 (c 0.40, CH2Cl2), lit.6 [α]D +5.3 (c 0.67, CH2Cl2)}
was obtained in 63% yield (Scheme 4). The spectral data of the
synthetic 4·HOAc were identical to the reported data.4,6 Our
NMR studies of epohelmin B (4) as a free base agreed with our
hypothesis, no degradation was observed in CDCl3.
OH
O
H
a
Epohelmin A 3
N
n-C5H11
Epohelmin B 4

4
Tetrahedron
Experimental Section
(S)-3-(4-Methoxybenzyloxy)-5-(tert-butyldimethylsilyloxy)
ACCEPTED MANUSCRIPT
pentanenitrile 8
General: THF was distilled from sodium/benzophenone.
Reactions were monitored by thin layer chromatography (TLC)
on glass plates coated with silica gel with fluorescent indicator.
Flash chromatography was performed on silica gel (300–400)
with petroleum ether/ EtOAc as eluent. Optical rotations were
measured on a polarimeter with a sodium lamp. HRMS were
measured on a LCMS-IT-TOF apparatus. IR spectra were
Compound 7 (4.00 g, 12.52 mmol) was stirred in THF/3 M
HCl (50 mL, V/V=3/1) at room temperature for overnight. Then
the reaction was quenched with a saturated aqueous solution of
NaHCO3 and extracted with EtOAc (50 mL × 3). The combined
organic layers were washed with brine, dried and concentrated.
The residue was purified by flash chromatography on silica gel
(PE/EA = 1/1) to give intermediate as a colorless oil. To a cooled
(0oC) solution of above intermediate (2.60 g, 11.05 mmol),
imidazole (1.50 g, 22.10 mmol) and DMAP (0.14 g, 1.11 mmol)
in DMF (40 mL) was treated with TBSCl (2.49 g, 16.58 mmol)
for 24 h. Then the mixture was quenched with a saturated
aqueous solution of NH4Cl and separated. The aqueous phase
was extracted with EtOAc (60 mL × 4) and the combined organic
layers were washed with water (30 mL × 2) and brine. Dried and
concentrated, the residue was purified by flash chromatography
on silica gel (PE/EA = 10/1) to give 8 (3.89 g, 2 steps 89%) as a
colorless oil. [α]D23 = +29.0 (c 2.50, CHCl3); IR (film): νmax 2954,
2929, 2857, 1616, 1514, 1468, 1304, 1250, 1178, 1095, 1036,
836, 777 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.31-7.25 (m, 2H),
6.91-6.86 (m, 2H), 4.57 (d, J = 11.2 Hz, 1H), 4.51 (d, J = 11.2 Hz,
1H), 3.92-3.84 (m, 1H), 3.80 (s, 3H), 3.74-3.69 (m, 2H), 2.64 (dd,
J = 16.8, 5.2 Hz, 1H), 2.54 (dd, J = 16.8, 5.2 Hz, 1H), 1.91-1.83
(m, 1H), 1.82-1.73 (m, 1H), 0.89 (s, 9H), 0.05 (s, 6H) ppm; 13C
NMR (100 MHz, CDCl3) δ 158.8, 129.1, 128.8, 117.1, 113.3,
71.1, 58.2, 54.7, 36.5, 25.3, 22.8, 17.6, -6.0, -6.1 ppm; HRMS
(ESI) calcd for [C19H31NO3Si+H+]: 350.2146, found: 350.2148.
recorded using film on
a
Fourier Transform Infrared
Spectrometer. NMR spectra were recorded at 400 MHz or 500
MHz, and chemical shifts are reported in δ (ppm) referenced to
1
an internal TMS standard for HNMR and CDCl3 (77.0 ppm) for
13C NMR if not noted otherwise.
(2R)-2-(4-Methoxybenzyloxy)-4-(tetrahydro-2H-pyran-2-
yloxy)butan-1-ol 6
Compound 5 (6.50 g, 19.09 mmol), PPTS (0.48 g, 1.91 mmol)
and DHP (3.5 mL, 38.18 mmol) were stirred in DCM (80 mL)
for overnight. Then the mixture was quenched with a saturated
NH4Cl aqueous solution and extracted with DCM (50 mL × 3).
The combined organic layers were washed with brine. Dried,
filtered and concentrated, the residue was purified by flash
chromatography on silica gel (PE/EA = 10/1) to give alcohol as a
colorless oil. The above oil and TBAF (80 mL, 1 M in THF) was
stirred in THF (80 mL) for overnight and diluted with water. The
resulting mixture was extracted with EtOAc (80 mL × 3) and the
combined organic layers were washed with brine. Dried, filtered
and concentrated, the residue was purified by flash
chromatography on silica gel (PE/EA = 1/1) to give 6 (4.86 g, 2
steps 82%). IR (film): νmax 3441, 2937, 2882, 2858, 1611, 1507,
(R)-3-(4-Methoxybenzyloxy)-5-(tert-butyldimethylsilyloxy)
pentanal 9
1
1249, 1118, 810 cm-1; H NMR (400 MHz, CDCl3) δ 7.29-7.23
(m, 2H), 6.90-6.85 (m, 2H), 4.61-4.46 (m, 3H), 3.89-3.81 (m,
2H), 3.80 (s, 3H), 3.76-3.64 (m, 2H), 3.59-3.41 (m, 3H), 2.37-
2.25 (m, 1H), 1.97-1.63 (m, 4H), 1.60-1.47 (m, 4H) ppm; 13C
NMR (100 MHz, CDCl3) δ 158.7, 129.9, 128.8, 128.7, 113.3,
98.5 (98.4), 76.5 (76.1), 70.6 (70.5), 63.7 (63.6), 63.3, 61.9 (61.8),
54.6, 30.8 (30.7), 30.1 (30.0), 24.8, 19.0 (18.9) ppm; HRMS (ESI)
calcd for [C17H26O5+H+]: 311.1853, found: 311.1854.
To a solution of 8 (3.80 g, 10.87 mmol) in THF (50 mL) was
treated with a solution of DIBAL-H (21.7 mL, 21.74 mmol, 1 M
in hexane) at -78oC for 1 h, and the resulting mixture was
warmed to 0oC for another 1 h. Then the mixture was cooled to -
78oC and EtOAc (25 mL) was added dropwise and stirred for 1 h
-78oC to at room temperature. The mixture was quenched with a
saturated seignette salt solution and extracted with EtOAc (50
mL × 3). The combined organic layers were washed with brine,
dried and concentrated. The residue was purified by flash
chromatography on silica gel (PE/EA = 5/1) to give 9 (2.68 g,
70%) as a light yellow oil.
(3S)-3-(4-Methoxybenzyloxy)-5-(tetrahydro-2H-pyran-2-
yloxy)pentanenitrile 7
Compound 6 (4.75 g, 15.30 mmol) and TEA (16.9 mL, 122.40
mmol) were dissolved in dry DCM (60 mL) and cooled to 0oC,
then MsCl (3.5 mL, 45.90 mmol) was added dropwise. After
being stirred for 1 h at the same temperature, the reaction was
quenched with a saturated aqueous solution of NH4Cl and
extracted with DCM (60 mL × 3). The combined organic layers
were washed with brine, dried and concentrated. The residue was
purified by flash chromatography on silica gel (PE/EA = 2/1) to
give intermediate as a yellow oil. The above yellow oil and KCN
(0.96 g, 14.70 mmol) were stirred in DMSO (60 mL) at 60oC for
overnight. Then the mixture was diluted with water and extracted
with EtOAc (60 mL × 3), the combined organic layers were
washed with brine. Dried and concentrated, the residue was
purified by flash chromatography on silica gel (PE/EA = 2/1) to
give 7 (4.15 g, 2 steps 85%). IR (film): νmax 2941, 2870, 1613,
General procedure for synthesis of (R/S,E)-N-(4-(4-
Methoxybenzyloxy)butylidene)-2-methylpropane-2-
sulfinamide 10
Butane-1,4-diol (20.00 g, 221.92 mmol) was slowly drooped
to a solution of sodium hydride (9.76 g, 244.12 mmol) in dry
DMF (180 mL) at 0oC. After being stirred for 10 min, PMBBr
(32.4 mL, 221.92 mmol) was added dropwise and the resulting
mixture was stirred at room temperature for 24 h. Then the
mixture was quenched with a saturated aqueous solution of
NH4Cl and extracted with EtOAc (20 mL × 3). The combined
organic layers were washed with brine, dried and concentrated.
The residue was purified by flash chromatography on silica gel
(PE/EA = 1/1) to give alcohol (32.70 g, 70%) as a light yellow
oil. (COCl)2 (18.1 mL, 190.24 mmol) was stirred in DCM (350
mL) at -78°C, and then a solution of DMSO (27.0 mL, 380.28
mmol) in DCM (50 mL) was slowly added dropwise. After the
mixture was stirred for 1 h, a solution of the above alcohol (20.00
g, 95.12 mmol) in DCM (120 mL) was added dropwise, and the
resulting mixture was stirred for 3 h. Once TEA (78.9 mL,
570.70 mmol) was added dropwise, the mixture was allowed to
warm to room temperature, and the reaction was quenched with a
saturated aqueous solution of NH4Cl. The organic layer was
1
1514, 1353, 1249, 1075, 1034, 811 cm-1; H NMR (400 MHz,
CDCl3) δ 7.32-7.24 (m, 2H), 6.91-6.86 (m, 2H), 4.70-4.40 (m,
3H), 3.90-3.81 (m, 3H), 3.80-3.78 (m, 3H), 3.54-3.42 (m, 2H),
2.69-2.34 (m, 2H), 1.99-1.63 (m, 4H), 1.62-1.44 (m, 4H) ppm;
13C NMR (100 MHz, CDCl3) δ 159.5 (159.4), 129.6, 129.5, 117.8,
113.9, 99.2 (98.9), 72.1 (71.6), 71.5 (71.4), 63.2 (62.5), 55.3,
34.4 (34.3), 30.7 (30.6), 25.4 (25.3), 23.4 (23.2), 19.7 ppm;
HRMS (ESI) calcd for [C18H25NO4+H+]: 320.1856, found:
320.1856.

5
separated, and the aqueous layer was extracted with DCM (200
mL × 2). The combined organic layers were dried, filtered, and
concentrated to give crude aldehyde without further purification.
Then take half of each, dissolved in DCM (200 mL). R or S 2-
Methyl-2-propanesulfinamide (5.76 g, 47.56 mmol), cupric
sulphate anhydrous (15.20 g, 95.12 mmol) and PPTS (0.60 g,
2.38 mmol) were added to the solution in one portion and the
mixture was stirred for 24 h. The resulting mixture was filtrated
and the filtrate was concentrated to give the crude product, which
was purified by flash chromatography on silica gel (PE/EA = 3/1)
to give (S)-10 (9.70 g, 2 steps 66%) or (R)-10 (8.90 g, 2 steps
60%).
(m, 4H), 3.52-3.44 (m, 3H), 3.18-3.10 (m, 1H), 1.96-1.82 (m,
ACCEPTED MANUSCRIPT
2H), 1.81-1.74 (m, 2H), 1.73-1.61 (m, 4H), 1.21 (s, 9H), 0.91 (s,
9H), 0.08 (s, 3H), 0.07 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
δ 159.3, 159.1, 130.6, 130.1, 129.6, 129.3, 113.9, 113.7, 76.3,
73.8, 72.6, 70.6, 69.7, 61.3, 59.5, 55.9, 55.3, 37.1, 37.0, 26.4,
26.1, 26.0, 22.8, 18.3, -5.3 ppm; HRMS (ESI) calcd for
[C35H59NO7SSi+H+]: 666.3854, found: 666.3855.
General procedure for synthesis of 12, 19.
To a cooled (0°C) solution of 11 or 18 (2.50 g, 3.75 mmol) in
DCM (50 mL) was added dropwise 2,6-lutidine (4.3 mL, 18.75
mmol) followed by TBSOTf (4.3 mL, 7.50 mmol) and stirred for
1 h. Then the mixture was quenched with a saturated aqueous
solution of NH4Cl and extracted with DCM (60 mL × 3). The
combined organic layers were washed with brine, dried and
concentrated. The residue was purified by flash chromatography
on silica gel (PE/EA = 1/1) to give intermediate as a light yellow
oil. To a solution of the above intermediate in EtOH (20 mL) and
added a solution of HCl/1,4-dioxane dropwise at 0°C. After
stirring for 10 min, the mixture was removal of hydrochloric acid
at 0°C by vacuum distillation. Then the mixture was dissolved in
DCM (50 mL). Next, TEA (3.1 mL, 22.50 mmol) and Boc2O (1.3
mL, 5.63 mmol) were added at room temperature and stirred for
overnight. The mixture was quenched with a saturated aqueous
solution of NH4Cl and extracted with DCM (60 mL × 3). The
combined organic layers were washed with brine, dried and
concentrated. The residue was purified by flash chromatography
on silica gel (PE/EA = 2/1) to give title compound.
23
S-10: [α]D = +134.8 (c 2.50, CHCl3); IR (film): νmax 2959,
2921, 2867, 1622, 1513, 1458, 1364, 1247, 1173, 1082, 1035,
822 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.09-8.05 (m, 1H), 7.26-
7.20 (m, 2H), 6.88-6.83 (m, 2H), 4.43-4.40 (m, 2H), 3.77 (s, 3H),
3.50-3.45 (m, 2H), 2.63-2.56 (m, 2H), 1.96-1.87 (m, 2H), 1.15 (s,
9H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.5, 158.6, 129.8,
128.6, 113.2, 72.0, 68.3, 55.9, 54.6, 32.4, 25.0, 21.7 ppm; HRMS
(ESI) calcd for [C16H25NO3S+H+]: 312.1628, found: 312.1627.
23
R-10: [α]D = -119.2 (c 1.00, CHCl3); IR (film): νmax 2956,
2927, 2859, 1622, 1513, 1463, 1363, 1247, 1184, 1082, 1035,
816 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.10-8.06 (m, 1H), 7.27-
7.21 (m, 2H), 6.89-6.84 (m, 2H), 4.43-4.40 (m, 2H), 3.38 (s, 3H),
3.52-3.46 (m, 2H), 2.64-2.57 (m, 2H), 1.97-1.87 (m, 2H), 1.16 (s,
9H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.5, 158.6, 129.8,
128.6, 113.2, 72.0, 68.3, 55.9, 54.6, 32.4, 25.0, 21.7 ppm; HRMS
(ESI) calcd for [C16H25NO3S+H+]: 312.1628, found: 312.1628.
tert-Butyl (4S,5R,7R)-1,7-bis(4-methoxybenzyloxy)-5-(tert-
General procedure for synthesis of 11, 18.
butyldimethylsilyloxy)-9-hydroxynonan-4-ylcarbamate 12
To a mixture of 9 (1.92 g, 5.44 mmol), imine S-10 or R-10
(1.70 g, 5.44 mmol) and t-BuOH (2.1 mL, 21.74 mmol) in THF
(110 mL) was treated with a solution of freshly prepared SmI2
(109 mL, 21.74 mmol, 0.2 M in THF) at -78oC under an argon
atmosphere. After being vigorously stirred for overnight, the
reaction mixture was quenched with a saturated aqueous solution
of Na2S2O3. The mixture was separated, and aqueous layer was
extracted with EtOAc (100 mL × 3). The combined organic
layers were washed with brine, dried and concentrated. The
residue was purified by flash chromatography on silica gel
(PE/EA = 1/2) to give title compound.
(1.29 g, 52%) as a colorless oil. [α]D23 = +17.5 (c 2.50, CHCl3);
IR (film): νmax 3447, 2952, 2931, 2856, 1710, 1605, 1513, 1458,
1
1364, 1248, 1172, 1096, 1037, 838, 778 cm-1; H NMR (400
MHz, CDCl3) δ 7.29-7.24 (m, 4H), 6.91-6.84 (m, 4H), 4.62-4.40
(m, 5H), 3.93-3.85 (m, 1H), 3.85-3.67 (m, 3H), 3.80 (s, 3H), 3.79
(s, 3H), 3.56-3.42 (m, 3H), 2.02-1.88 (m, 2H), 1.80-1.68 (m, 2H),
1.67-1.53 (m, 3H), 1.45 (s, 9H), 1.43-1.37 (m, 1H), 0.91 (s, 9H),
0.07 (s, 3H), 0.06 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
δ159.2, 159.1, 155.6, 130.6, 130.2, 129.5, 129.2, 113.9, 113.8,
79.1, 74.8, 72.5, 71.9, 70.4, 69.7, 60.2, 55.2, 53.6, 38.6, 36.1,
28.5, 26.3, 25.9, 24.3, 18.1, -4.4, -4.6 ppm; HRMS (ESI) calcd
for [C36H59NO8Si+H+]: 662.4083, found: 662.4092.
(S)-N-((4S,5R,7R)-1,7-bis(4-methoxybenzyloxy)-9-(tert-
butyldimethylsilyloxy)-5-hydroxynonan-4-yl)-2-
methylpropane-2-sulfinamide 11
tert-Butyl (4R,5S,7R)-1,7-bis(4-methoxybenzyloxy)-5-(tert-
butyldimethylsilyloxy)-9-hydroxynonan-4-ylcarbamate 19
23
(2.72 g, 76%) as a yellow oil. [α]D = +17.2 (c 2.50, CHCl3);
(1.45 g, 58%) as a colorless oil. [α]D23 = -5.7 (c 1.00, CHCl3);
IR (film): νmax 3452, 2953, 2931, 2856, 1712, 1611, 1514, 1359,
1249, 1173, 1099, 1038, 837 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.33-7.25 (m, 4H), 6.91-6.85 (m, 4H), 4.62-4.51 (m, 2H), 4.49-
4.42 (m, 3H), 3.94-3.87 (m, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.80-
3.69 (m, 3H), 3.66-3.58 (m, 1H), 3.52-3.45 (m, 2H), 2.52-2.45
(m, 1H), 1.93-1.82 (m, 2H), 1.77-1.70 (m, 2H), 1.68-1.58 (m,
3H), 1.46 (s, 9H), 0.91 (s, 9H), 0.08 (s, 3H), 0.04 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ159.2, 159.1, 155.6, 130.6, 130.4,
129.6, 129.3, 113.8, 113.7, 79.0, 75.5, 72.5, 71.6, 71.1, 69.7, 60.3,
55.3, 54.3, 38.7, 36.1, 28.5, 27.4, 26.4, 25.9, 24.9, 18.1, -4.3, -4.5
ppm; HRMS (ESI) calcd for [C36H59NO8Si+H+]: 662.4083, found:
662.4086.
IR (film): νmax 3403, 2953, 2929, 2856, 1611, 1514, 1463, 1359,
1299, 1248, 1167, 1091, 1037, 836, 773 cm-1; H NMR (400
1
MHz, CDCl3) δ 7.29-7.24 (m, 4H), 6.90-6.85 (m, 4H), 4.57-4.40
(m, 4H), 3.94-3.78 (m, 8H), 3.77-3.66 (m, 2H), 3.53-3.37 (m,
4H), 3.25-3.15 (m, 1H), 1.94-1.53 (m, 8H), 1.23 (s, 9H), 0.91 (s,
9H), 0.08-0.05 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ
159.3, 159.1, 130.6, 129.6, 129.5, 129.3, 113.8, 113.7, 73.9, 72.6,
71.5, 71.3, 69.7, 61.6, 59.6, 55.9, 55.3, 37.3, 36.7, 26.1, 26.0,
22.8, 18.3, -5.3 ppm; HRMS (ESI) calcd for [C35H59NO7SSi+H+]:
666.3854, found: 666.3856.
(R)-N-((4R,5S,7R)-1,7-bis(4-Methoxybenzyloxy)-9-(tert-
butyldimethylsilyloxy)-5-hydroxynonan-4-yl)-2-
methylpropane-2-sulfinamide 18
General procedure for synthesis of 13, 20.
(2.76 g, 77%) as yellow oil. [α]D23 = -27.5 (c 2.50, CHCl3); IR
(film): νmax 3048, 2953, 2929, 2856, 1611, 1514, 1458, 1353,
To a solution of 12 or 19 (1.25 g, 1.89 mmol) in dry DCM (20
mL) was treated with DMP (1.60 g, 3.78 mmol) at room
temperature for 0.5 h. The reaction was carefully quenched with
a saturated aqueous solution of NaHCO3 and solid Na2S2O3, then
the resulting mixture was separated and the aqueous layer was
1
1293, 1248, 1173, 1090, 1036, 835, 773 cm-1; H NMR (400
MHz, CDCl3) δ 7.30-7.24 (m, 4H), 6.90-6.85 (m, 4H), 4.56 (dd, J
= 10.8 Hz, 1H), 4.45-4.38 (m, 3H), 3.83-3.79 (m, 7H), 3.76-3.66

6
Tetrahedron
extracted with DCM (30 mL × 3). The combined organic layers
75.0, 72.5, 72.1, 69.9, 69.8, 55.2, 54.4, 51.5, 38.6, 34.1, 32.9,
ACCEPTED MANUSCRIPT
were washed with brine, dried and concentrated to give crude
product without further purification. The crude product and
Ph3PCHCOOCH3 (758 mg, 2.27 mmol) were stirred in DCM (20
ml) at room temperature for overnight and concentrated. The
residue was purified by flash chromatography on silica gel
(PE/EA = 4/1) to give title compound.
28.5, 26.4, 25.9, 25.2, 20.1, 18.1, -4.4, -4.5 ppm; HRMS (ESI)
calcd for [C39H63NO9Si+H+]: 718.4345, found: 718.4345.
(5R,7S,8R)-Methyl 5,11-bis(4-methoxybenzyloxy)-8-(tert-
butoxycarbonyl)-7-(tert-butyldimethylsilyloxy)undecanoate
21
23
(1.08 g, 90%) as a light yellow oil. [α]D = -11.6 (c 1.00,
(5R,7R,8S,E)-Methyl 5,11-bis(4-methoxybenzyloxy)-8-(tert-
CHCl3); IR (film): νmax 2952, 2930, 2855, 1737, 1712, 1605,
butoxycarbonyl)-7-(tert-butyldimethylsilyloxy)undec-2-enoate
13
1513, 1458, 1365, 1248, 1171, 1100, 1037, 835, 775 cm-1; H
1
NMR (400 MHz, CDCl3) δ 7.34-7.25 (m, 4H), 6.91-6.85 (m, 4H),
4.63 (d, J = 9.2 Hz, 1H), 4.52-4.41 (m, 4H), 3.96-3.90 (m, 1H),
3.82 (s, 3H), 3.81 (s, 3H), 3.69 (s, 3H), 3.67-3.59 (m, 1H), 3.53-
3.44 (m, 3H), 2.39-2.25 (m, 2H), 1.82-1.66 (m, 4H), 1.65-1.53
(m, 5H), 1.46 (s, 9H), 1,43-1.35 (m, 1H), 0.90 (s, 9H), 0.07 (s,
3H), 0.04 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ173.9,
159.1, 155.6, 130.9, 130.7, 129.5, 129.2, 113.8, 113.7, 78.9, 75.6,
72.5, 71.8, 71.0, 69.8, 55.3, 54.0, 51.5, 39.0, 34.1, 33.6, 28.5,
26.4, 25.9, 24.9, 20.6, 18.1, -4.4, -4.6 ppm; HRMS (ESI) calcd
for [C39H63NO9Si+H+]: 718.4345, found: 718.4344.
(1.27 g, 94%) as a colorless oil. [α]D23 = -0.5 (c 2.50, CHCl3);
IR (film): νmax 2952, 2931, 2856, 1716, 1611, 1514, 1364, 1248,
1
1172, 1098, 1037, 844, 777 cm-1; H NMR (400 MHz, CDCl3) δ
7.30-7.23 (m, 4H), 7.02 (ddd, J = 15.6, 7.6, 6.8 Hz, 1H), 6.91-
6.85 (m, 4H), 5.93 (d, J = 15.6 Hz, 1H), 4.58-4.47 (m, 2H), 4.45-
4.38 (m, 3H), 3.94-3.88 (m, 1H), 3.82-3.79 (m, 6H), 3.75 (s, 3H),
3.69-3.62 (m, 1H), 3.59-3.49 (m, 1H), 3.47-3.41 (m, 2H), 2.63-
2.40 (m, 2H), 1.83-1.64 (m, 2H), 1.63-1.50 (m, 3H), 1.46 (s, 9H),
1.43-1.34 (m, 1H), 0.89 (s, 9H), 0.06 (s, 3H), 0.02 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ 166.6, 159.2, 159.1, 155.6, 145.0,
130.7, 130.4, 129.3, 129.2, 123.5, 113.8, 113.7, 78.9, 74.3, 72.5,
71.8, 70.3, 69.8, 55.2, 54.2, 51.4, 38.8, 36.5, 28.5, 26.4, 25.9,
24.9, 18.1, -4.4, -4.5 ppm; HRMS (ESI) calcd for
[C39H61NO9Si+H+]: 716.4188, found: 716.4189.
General procedure for synthesis of 15, 22.
To a solution of dimethyl methylphosphonate (0.94 mL, 8.77
mmol) in dry THF (20 mL) was treated with a solution of n-BuLi
(3.6 mL, 8.77 mmol, 2.4 M in hexane) at -78oC for 1 h. Then a
solution of compound 14 or 21(900 mg, 1.25 mmol) in THF (5
mL) was added dropwise, and the reaction was warmed to -50oC
and stirred for 2 h. The resulting mixture was quenched with a
saturated aqueous solution of NH4Cl and extracted with EtOAc
(50 mL × 3). The combined organic layers were washed with
brine, dried and concentrated. The residue was purified by flash
chromatography on silica gel (PE/EA = 1/2) to give title
compound.
(5R,7S,8R,E)-Methyl 5,11-bis(4-methoxybenzyloxy)-8-(tert-
butoxycarbonyl)-7-(tert-butyldimethylsilyloxy)undec-2-enoate
20
(1.23 g, 91%) as a colorless oil. [α]D23 = -13.0 (c 2.50, CHCl3);
IR (film): νmax 2952, 2930, 2856, 1713, 1514, 1365, 1248, 1171,
1
1099, 1037, 836, 777 cm-1; H NMR (400 MHz, CDCl3) δ 7.33-
7.25 (m, 4H), 6.98 (ddd, J = 15.6, 8.0, 7.2 Hz, 1H), 6.91-6.85 (m,
4H), 5.91 (d, J = 15.6 Hz, 1H), 4.63 (d, J = 9.2 Hz, 1H), 4.52-
4.42 (m, 4H), 3.97-3.89 (m, 1H), 3.83-3.80 (m, 6H), 3.75 (s, 3H),
3.69-3.58 (m, 2H), 3.50-3.44 (m, 2H), 2.54-2.36 (m, 2H), 1.82-
1.68 (m, 2H), 1.65-1.54 (m, 3H), 1.46 (s, 9H), 1.42-1.34 (m, 1H),
0.90 (s, 9H), 0.07 (s, 3H), 0.02 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 166.7, 159.2, 159.1, 155.6, 145.3, 130.7, 130.4, 129.6,
129.2, 123.3, 113.8, 78.9, 74.7, 72.5, 71.5, 71.3, 69.8, 55.3, 54.0,
51.5, 39.1, 37.1, 28.5, 26.4, 25.9, 24.8, 18.1, -4.4, -4.6 ppm;
HRMS (ESI) calcd for [C39H61NO9Si+H+]: 716.4188, found:
716.4188.
tert-Butyl (4S,5R,7R)-1,7-bis(4-methoxybenzyloxy)-5-(tert-
butyldimethylsilyloxy)-12-(dimethoxyphosphoryl)-11-
oxododecan-4-ylcarbamate 15
(875 mg, 86%) as a colorless oil. [α]D23 = +1.9 (c 2.50, CHCl3);
IR (film): νmax 2954, 2930, 2855, 1712, 1605, 1514, 1364, 1249,
1
1173, 1035, 835, 777 cm-1; H NMR (400 MHz, CDCl3) δ 7.30-
7.23 (m, 4H), 6.89-6.84 (m, 4H), 4.59-4.33 (m, 5H), 3.93-3.86
(m, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H),
3.60-3.47 (m, 2H), 3.46-3.39 (m, 2H), 3.12 (s, 1H), 3.06 (s, 1H),
2.69-2.60 (m, 2H), 1.80-1.63 (m, 4H), 1.61-1.48 (m, 5H), 1.45 (s,
9H), 1.41-1.33 (m, 1H), 0.89 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H)
pm; 13C NMR (100 MHz, CDCl3) δ 201.6, 201.5, 159.1, 155.6,
130.8, 130.7, 129.3, 129.2, 113.7, 78.8, 75.1, 72.5, 72.0, 69.8,
55.2, 54.3, 53.1, 53.0, 44.1, 41.9, 40.6, 38.6, 32.7, 28.5, 26.4,
25.9, 25.2, 18.6, 18.1, -4.4, -4.5 ppm; HRMS (ESI) calcd for
[C41H68NO11PSi+H+]: 810.4372, found: 810.4374.
General procedure for synthesis of 14, 21.
To a solution of 13 or 20 (1.20 g, 1.68 mmol) in CH3OH (12
mL) was added NiCl2•6H2O (199 mg, 0.84 mmol) at 0°C. Then
NaBH4 (127 mg, 3.36 mmol) was added in batches and stirred for
40 min. The reaction was carefully filtered and concentrated. The
residue added water and extracted with EtOAc (30 mL × 3). The
combined organic layers were washed with brine. Dried and
concentrated, the residue was purified by flash chromatography
on silica gel (PE/EA = 4/1) to give title compound.
tert-Butyl (4R,5S,7R)-1,7-bis(4-methoxybenzyloxy)-5-(tert-
butyldimethylsilyloxy)-12-(dimethoxyphosphoryl)-11-
oxododecan-4-ylcarbamate 22
(5R,7R,8S)-Methyl 5,11-bis(4-methoxybenzyloxy)-8-(tert-
butoxycarbonyl)-7-(tert-butyldimethylsilyloxy)undecanoate
23
(875 mg, 86%) as a colorless oil. [α]D = -11.7 (c 1.00,
CHCl3); IR (film): νmax 2952, 2928, 2855, 1712, 1605, 1513,
14
1359, 1248, 1173, 1034, 833, 767 cm-1; H NMR (400 MHz,
1
23
(1.03 g, 86%) as a light yellow oil. [α]D = +1.4 (c 2.50,
CDCl3) δ 7.33-7.24 (m, 4H), 6.91-6.84 (m, 4H), 4.63 (d, J = 9.2
Hz, 1H), 4.52-4.39 (m, 4H), 3.95-3.88 (m, 1H), 3.83-3.79 (m,
9H), 3.78 (s, 1H), 3.65-3.57 (m, 1H), 3.53-3.43 (m, 3H), 3.10 (s,
1H), 3.05 (s, 1H), 2.65-2.58 (m, 2H), 1.78-1.66 (m, 3H), 1.66-
1.47 (m, 6H), 1.45 (s, 9H), 1.43-1.37 (m, 1H), 0.90 (s, 9H), 0.07
(s, 3H), 0.03 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 201.6,
201.5, 159.1, 155.6, 130.9, 130.7, 129.5, 129.2, 113.7, 113.6,
78.8, 75.7, 72.5, 71.8, 71.0, 69.8, 55.3, 54.1, 53.1, 53.0, 44.1,
41.9, 40.6, 38.9, 33.3, 28.5, 26.4, 25.9, 24.9, 19.0, 18.1, -4.3, -4.6
CHCl3); IR (film): νmax 2952, 2931, 2856, 1738, 1712, 1611,
1
1514, 1365, 1248, 1172, 1097, 1037, 835, 776 cm-1; H NMR
(400 MHz, CDCl3) δ 7.31-7.24 (m, 4H), 6.90-6.85 (m, 4H), 4.58-
4.35 (m, 5H), 3.96-3.87 (m, 1H), 3.81-3.79 (m, 6H), 3.69 (s, 3H),
3.61-3.49 (m, 2H), 3.47-3.40 (m, 2H), 2.42-2.31 (m, 2H), 1.82-
1.67 (m, 4H)1.65-1.49 (m, 5H), 1.45 (s, 9H), 1.42-1.32 (m, 1H),
0.90 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 173.9, 159.1, 155.6, 130.8, 130.7, 129.2, 113.7, 78.8,

7
ppm; HRMS (ESI) calcd for [C41H68NO11PSi+H+]: 810.4372,
found: 810.4373.
without further purification, which was stirred in mixture of
ACCEPTED MANUSCRIPT
MeOH/HCl (3 mL, V : V = 50 : 50) for overnight. Then the
mixture was concentrated to give crude salt, which was dissolved
in water (10 mL) and treated with potassium carbonate. The
resulting mixture was extracted with DCM (15 mL × 5). The
combined organic layers were dried, concentrated. The residue
was purified by flash chromatography on silica gel
(DCM/CH3OH/HOAc = 100/10/1) to give title compound.
General procedure for synthesis of 16, 23.
Compound 15 or 22 (300 mg, 0.37 mmol), 10% Pd/C (300 mg)
and 20% Pd(OH)2 (300 mg) were stirred under hydrogen
atmosphere for 4 h. Then the mixture was filtrated and
concentrated. The residue, LiCl (19 mg, 0.44 mmol), DBU (56
mg, 0.37 mmol) and hexaldehyde (37 mg, 0.37 mmol) were
stirred in CH3CN (5 mL) at 0oC for 1 h. Then the reaction was
quenched with a saturated aqueous solution of NH4Cl and
extracted with EtOAc (20 mL × 3). The combined organic layers
were washed with brine, dried and concentrated. The residue was
purified by flash chromatography on silica gel (PE/EA = 1/2) to
give title compound.
Epohelmin A•HOAc (3•HOAc)
23
(23 mg, 46%) as a yellow oil. [α]D = +2.9 (c 0.31, CH3OH);
IR (film): νmax 3340, 2950, 2928, 2859, 1674, 1630, 1473, 1390,
1085 cm-1; H NMR (600 MHz, CDCl3) δ 6.90-6.83 (m, 1H),
1
6.08 (d, J = 15.6 Hz, 1H), 4.33-4.27 (m, 1H), 4.14-4.02 (m, 2H),
3.61-3.55 (m, 1H), 2.93-2.86 (m, 1H), 2.71-2.63 (m, 2H), 2.51-
2.45 (m, 1H), 2.27-2.19 (m, 3H), 2.12-2.07 (m, 1H), 2.03-1.97
(m, 1H), 1.86-1.78 (m, 3H), 1.70-1.62 (m, 2H), 1.53-1.44 (m,
3H), 1.34-1.28 (m, 4H), 0.92-0.88 (m, 3H) ppm; 13C NMR (150
MHz, CDCl3) δ 199.7, 148.5, 130.0, 73.3, 63.1, 48.0, 38.6, 36.7,
32.5, 31.4, 29.3, 28.1, 27.7, 25.7, 22.4, 20.8, 14.0 ppm; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C18H32NO2: 294.2428, found:
294.2430.
tert-Butyl (4S,5R,7R,E)-5-(tert-butyldimethylsilyloxy)-1,7-
dihydroxy-11-oxooctadec-12-en-4-ylcarbamate 16
(109 mg, 54%) as a colorless oil. [α]D23 = +3.2 (c 1.00, CHCl3);
IR (film): νmax 3456, 2954, 2928, 2856, 1692, 1496, 1370, 1255,
1
1172, 1063, 838, 773 cm-1; H NMR (400 MHz, CDCl3) δ 6.87
(ddd, J = 15.6, 7.2, 6.4 Hz, 1H), 6.11 (ddd, J = 15.6, 1.6, 0.8 Hz,
1H), 4.58 (d, J = 8.8 Hz, 1H), 4.05-3.90 (m, 1H), 3.80-3.60 (m,
4H), 2.89 (brs, 1H), 2.68-2.50 (m, 2H), 2.30-2.17 (m, 3H), 1.94
(brs, 1H), 1.77-1.66 (m, 4H), 1.62-1.54 (m, 3H), 1.51-1.46 (m,
3H), 1.45 (s, 9H), 1.37-1.28 (m, 5H), 0.94-0.91 (m, 3H), 0.90 (s,
9H), 0.10 (s, 3H), 0.08 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
δ 200.9, 156.0, 147.9, 130.2, 79.2, 72.6, 67.8, 62.3, 54.2, 40.7,
39.7, 38.0, 32.5, 31.4, 28.8, 28.4, 27.8, 25.9, 25.6, 22.4, 19.6,
18.1, 14.0, -4.5, -4.6 ppm; HRMS (ESI) calcd for
[C29H57NO6Si+H+-H2O]: 526.3922, found: 526.3908.
3-epi ent-Epohelmin A 24
(30 mg, 50%) as a yellow oil. [α]D23 = -7.5 (c 0.50, CHCl3); IR
(film): νmax 3345, 2955, 2929, 2870, 1670, 1632, 1463, 1389,
1085 cm-1; 1H NMR (600 MHz, CDCl3) δ 6.83 (ddd, J = 15.6, 7.2,
6.0 Hz, 1H), 6.08 (ddd, J = 15.6, 1.8, 0.6 Hz, 1H), 3.97-3.92 (m,
1H), 3.52-3.46 (m, 1H), 3.06-3.01 (m, 1H), 2.72-2.66 (m, 2H),
2.64-2.52 (m, 2H), 2.38-2.33 (m, 1H), 2.23-2.18 (m, 2H), 2.02-
1.96 (m, 1H), 1.83-1.78 (m, 2H), 1.70-1.61 (m, 5H), 1.57-1.52
(m, 1H), 1.49-1.44 (m, 2H), 1.36-1.24 (m, 5H), 0.91-0.88 (m, 3H)
ppm; 13C NMR (150 MHz, CDCl3) δ 200.4, 147.7, 130.3, 76.5,
72.5, 65.6, 54.3, 41.6, 39.9, 35.8, 32.4, 31.4, 29.8, 27.8, 25.0,
22.4, 21.6, 13.9 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C18H32NO2: 294.2428, found: 294.2428.
tert-Butyl (4R,5S,7R,E)-5-(tert-butyldimethylsilyloxy)-1,7-
dihydroxy-11-oxooctadec-12-en-4-ylcarbamate 23
23
(107 mg, 53%) as a colorless oil. [α]D = -21.3 (c 1.00,
CHCl3); IR (film): νmax 3453, 2955, 2928, 2856, 1690, 1501,
1
1452, 1366, 1252, 1172, 1096, 1058, 837, 773 cm-1; H NMR
Epohelmin B 4
(400 MHz, CDCl3) δ 6.86 (ddd, J = 16.0, 7.2, 6.4 Hz, 1H), 6.11
(ddd, J = 16.0, 1.6, 0.8 Hz, 1H), 4.72 (dd, J = 8.4, 1H), 4.02-3.98
(m, 1H), 3.80-3.73 (m, 1H), 3.72-3.65 (m, 3H), 3.40-3.12 (m,
1H), 2.65-2.55 (m, 2H), 2.26-2.18 (m, 2H), 2.00-1.88 (m, 1H),
1.82-1.68 (m, 4H), 1.67-1.55 (m, 5H), 1.51-1.47 (m, 3H), 1.45 (s,
9H), 1.51-1.47 (m, 3H), 1.45 (s, 9H), 1.35-1.31 (m, 4H), 0.94-
0.91 (m, 3H), 0.91 (s, 9H) 0.11 (s, 1H), 0.10 (s, 3H) ; 13C NMR
(100 MHz, CDCl3) δ 200.8, 156.2, 147.8, 130.2, 79.5, 73.0, 68.5,
62.5, 53.6, 40.3, 39.8, 37.3,32.5, 31.4, 29.1, 28.4, 27.8, 25.9, 25.5,
22.4, 20.1, 18.0, 14.0, -4.5, -4.6 ppm; HRMS (ESI) calcd for
[C29H57NO6Si+H+-H2O]: 526.3922, found: 526.3910.
To a stirred solution of oxalyl chloride (27 µL, 0.28 mmol) in
DCM (5 mL) was added DMSO (40 µL, 0.56 mmol) at -78oC.
The resulting mixture was stirred at -78oC for 30 min and a
solution of 3 (41 mg, 0.14 mmol) in DCM (1 mL) was added
followed by TEA (116 µL, 0.84 mmol). The reaction mixture
was stirred at -78oC for 3 h and poured into water. The organic
layer was separated and the aqueous layer was extracted with
DCM (10 mL× 3). The combined organic layers were washed
with brine, dried and concentrated. The residue was dissolved in
THF (3 mL) and added L-Selectride (1.0 M in THF, 1.4 mL, 1.4
mmol) dropwise at -78oC. The reaction was stirred at -78oC for 1
h, warmed to room temperature and stirred for another 3 h. Then
the resulting mixture was quenched with 10% NH4OH. The
organic layer was separated and the aqueous layer was extracted
with DCM (10 mL× 3). The combined organic layers were
washed with brine, dried and concentrated to give intermediate as
a yellow oil. Then to a stirred solution of the yellow oil in CHCl3
(5 mL) was added DMP (72 mg, 0.17 mmol) in one portion. The
resulting mixture was stirred at room temperature for 1 h and
poured into a mixture of saturated aqueous Na2S2O3 solution and
saturated aqueous NaHCO3 solution (5 mL/5 mL). The organic
layer was separated and the aqueous layer was extracted with
CHCl3 (10 mL× 3). The combined organic layers were dried,
concentrated. The residue was purified by flash chromatography
on silica gel (DCM/CH3OH/HOAc = 100/10/1) to give 4•HOAc
General procedure for synthesis of Epohelmin A 3 and 3-epi
ent-Epohelmin A 24.
To a solution of alcohol 16 or 23 (93 mg, 0.17 mmol) and
TEA (0.19 mL, 1.37 mmol) in dry DCM (5 mL) was cooled to
0oC. Then MsCl (40 ꢀL, 0.51 mmol) was added dropwise and the
mixture was stirred for 30 min. The reaction was quenched with a
saturated NH4Cl solution (20 mL) and extracted with DCM (25
mL × 3). The combined organic layers were washed with brine
for two times, dried and concentrated to give crude product
without further purification. The above crude product and 2,6-
lutidine (96 ꢀL, 0.82 mmol) were dissolved in DCM (5 mL) and
cooled to -78oC. The reaction was treated with TESOTf (0.18 mL,
0.78 mmol) and the mixture was allowed to warm to room
temperature and stirred for overnight. The mixture was diluted
with water and extracted with DCM (30 mL × 3) and the
combined organic layers were washed with brine. The resulting
organic layer was dried and concentrated to give crude product
23
(26 mg, 63%) as a yellow oil. [α]D23 +4.3 (c 1.00, CH3OH), [α]D
+4.9 (c 0.40, CH2Cl2), lit.6 [α]D20 +5.3 (c 0.67, CH2Cl2); IR (film):
νmax 3341, 2954, 2928, 2869, 1667, 1627, 1463, 1386, 1085 cm-1;

8
Tetrahedron
ACCEPTED MANUSCRIPT
1H NMR (400 MHz, CDCl3) δ 6.85 (ddd, J = 16.0, 7.2, 6.4 Hz,
5824-5833; (c) Si, C.-M.; Mao, Z.-Y.; Liu, Y.-W.; Du, Z.-T.; Wei,
B.-G.; Lin, G.-Q. Org. Chem. Front., 2015, 2, 1485-1499.
13. (a) Zhou, Q.-R.; Wei, X.-Y.; Li, Y.-Q.; Huang, D.; Wei, B.-G.
Tetrahedron 2014, 70, 4799-4808; (b) Si, C.-M.; Mao, Z.-Y.;
Zhou, Z.; Du, Z.-T.; Wei, B.-G. Tetrahedron 2015, 71, 9396-9402.
14. (a) Lin, X.; Bentley, P. A.; Xie, H. Tetrahedron Lett. 2005, 46,
7849-7852; (b) Liu, R-H., Fang, K., Wang, B., Xu, M-H., Lin, G-
Q. J. Org. Chem. 2008, 73, 3307-3310; (c) Wang, B., Liu, R-H.
Eur. J. Org. Chem. 2009, 2845-2851.
1H), 6.08 (d, J = 16.0 Hz, 1H), 4.56-4.48 (m, 1H), 4.27-4.19 (m,
1H), 3.70-3.60 (m, 1H), 3.48-3.43 (m, 1H), 2.99-2.91 (m, 1H),
2.67-2.61 (m, 2H), 2.55-2.44 (m, 2H), 2.24-2.18 (m, 3H), 2.14-
2.04 (m, 4H), 1.85-1.76 (m, 3H), 1.75-1.65 (m, 4H), 1.50-1.43
(m, 2H), 1.35-1.27 (m, 5H), 0.92-0.87 (m, 3H) ppm; 13C NMR
(150 MHz, CDCl3) δ 199.1, 147.8, 129.4, 68.3, 58.8, 46.8, 38.1,
36.8, 31.9, 30.7, 29.1, 28.7, 27.1, 25.1, 23.1, 21.8, 20.4, 13.3 ppm;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H32NO2: 294.2428,
found: 294.2427.
15. (a) Rajender, A.; Rao, J. P.; Rao, B. V. Eur. J. Org. Chem. 2013,
1749-1757; (b) Tang, S.; Xiong, D.-C.; Jiang, S.; Ye, X.-S. Org.
Lett. 2016, 18, 568-571; (c) Chabaud, L.; Landais, Y.; Renaud, P.
Org. Lett. 2005, 7, 2587-2590.
16. Flowers, C. L.; Vogel, P. Chem. Eur. J. 2010, 16, 14074-14082.
17. Paterson, I.; De Savi, C.; Tudge, M. Org. Lett. 2001, 3, 3149-
3152.
18. Boyd, D. R.; Sharma, N. D.; Acaru, C. A.; Malone, J. F.; O’Dowd,
C. R.; Allen, C. C. R.; Stevenson, P. J. Org. Lett. 2010, 12, 2206-
2209.
Acknowledgements
We thank the National Natural Science Foundation of China
(21472022, 21272041, 21072034) for financial support. The
authors also thank Dr. Han-Qing Dong (Arvinas, Inc.) for helpful
suggestions and thank Yu Tang for the purification of epohelmin
A by Prep-HPLC.
19. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156;
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
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(b) Wittig, G.; Haag, W. Chem. Ber. 1955, 88, 1654-1666; (c)
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