Asymmetric Total Synthesis of Bioactive Natural Lipid Mycalol

Article abstract of DOI:10.1021/acs.joc.5b00972

A concise and convergent route for stereoselective total synthesis of promising anticancer natural lipid mycalol has been achieved using cheap and readily available l-arabinose as a chiral pool. The notable features of our synthesis comprised regioselecti

Full text of DOI:10.1021/acs.joc.5b00972

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Article
Asymmetric Total Synthesis of Bioactive Natural Lipid Mycalol
Subhendu Das, Tapan Kumar Kuilya, and Rajib Kumar Goswami
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00972 • Publication Date (Web): 20 May 2015
Downloaded from http://pubs.acs.org on May 23, 2015
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Asymmetric Total Synthesis of Bioactive Natural Lipid Mycalol
Subhendu Das, Tapan Kumar Kuilya, Rajib Kumar Goswami*
Department of Organic Chemistry,
Indian Association for the Cultivation of Science, Jadavpur,
Kolkata-700032, India.
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Email: ocrkg@iacs.res.in
OAc Zipper reaction
Sharpless asymmetric
1
9
dihydroxylation
HO
OH
R
Sonogashira
reaction
HO
O
OH
OH
OH
Regioselective
Wacker oxidation
Wittig
olefination
Julia-Kocienski
olefination
Revised structure of Mycalol
Abstract:
A concise and convergent route for stereoselective total synthesis of promising anticancer
natural lipid mycalol has been achieved using cheap and readily available L-arabinose as a chiral
pool. The notable features of our synthesis comprised regioselective Wacker oxidation, Sharpless
asymmetric dihydroxylation, Julia-Kocienski olefination, Wittig olefination, Zipper reaction and
Sonogashira reaction. Comparison of the spectroscopic data on a series of isomers supports the
revised structure (Org. Lett. 2015, 17, 1652) instead of the one originally proposed.
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Introduction:
Mycalol is a polyoxygenated monoalkyl glyceryl ether lipid which was first isolated by
Fontana and coworkers from chloroform extract of sponge Mycale (Oxymycale) acerata
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Kirkpatrick 1907 collected in the coasts of Terra Nova Bay, Antarctica. It exhibits promising
and selective cytotoxic activity against human anaplastic thyroid carcinoma (ATC), the most
aggressive human thyroid gland malignancy (IC50 against different human ATC-derived cell
lines: FRO-HMGA1as=7.3 µM, ACT1=4.5 µM, 8505c =3.8 µM). It also shows moderate
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cytotoxicity to human colon solid tumor cell line (IC =10.9 µM). The structure of mycalol was
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determined by a combination of spectroscopic methods (NMR, CD, mass) and by functional
group derivatizations. Architecturally mycalol possesses a C-27 linear skeleton embedded with
nine oxygenated carbons and one ether linkage. There are seven hydroxy groups present in the
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molecule among which one remains in its acetylated form [Figure 1, proposed structure (1) and
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(vide infra), 3
4
]. Statistical data revealed that ATC is responsible up to 40% of
revised structure (2)
all deaths from thyroid cancer and most anxiously, there is not a single clinical lead known to
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date to combat against this malignancy. The discovery of mycalol may serve a significant role to
decipher cancer biology and a lead compound for drug development. Mycalol was isolated in
small yields from its natural source. Thus the development of an efficient and scalable synthetic
route is highly desirable to render it readily available for thorough biological investigations. As a
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part of our ongoing program towards synthesis of bioactive natural products, we envisaged the
total synthesis of structurally intriguing and biologically potent natural lipid mycalol. Herein, we
report a convergent stereoselective total synthesis of mycalol (Figure 1, both proposed and
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revised structure) which features the regioselective Wacker oxidation, Sharpless asymmetric
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dihydroxylation, Julia-Kocienski olefination, Wittig olefination, Zipper reaction and
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Sonogashira reaction as the key steps. The spectroscopic data on the synthesized proposed
structure of mycalol indicate discrepancies suggesting that the proposed structure may be
incorrect. To resolve these variation/deviation we have also synthesized a total of twelve
analogues of the proposed structure out of which eight diastereomers and four positional isomers.
The results indicate that the observed data of mycalol is identical to that of a synthetic analogue
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which varies in the configuration in the C-2̍ position (diastereomer) and position of the O-acetyl
group (structural isomer). Our synthetic strategy is quite flexible, as demonstrated by the
synthesis of a wide range of analogues. Our approach, as described above, uses a different set of
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key reactions than the recent report by Reddy and coworkers where they have used Sharpless
epoxidation, a low yielding cross metathesis and opening of chiral epoxide by alkyl Grignard as
the pivotal steps to achieve both the proposed and revised structures of mycalol.
Figure 1: Chemical structure of mycalol.
OAc
2
0
19
OAc
HO
OH
HO
OH
S
R
HO
O
HO
O
OH
1
OH
OH
OH
2
OH
Revised
OH
Proposed
Results and discussion:
Retrosynthetic analysis of proposed structure of mycalol (1) is depicted in Scheme 1. It
could be synthesized from the advanced stage of intermediates 3(a-d) by hydrogenation followed
by global deprotection of acetonides. Intermediates 3(a-d) could be constructed further from the
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vinyl iodides 4(a-d) and alkyne intermediate 5 using Sonogashira reaction as one of the key
coupling steps. Vinyl iodides 4(a-d) could be accessed from compounds 6(a-b) using Wittig
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olefination as one of the pivotal steps. Next Julia-Kocienski olefination would disconnect
compounds 6(a-b) into two coupling partners 7 and 8 which further could be synthesized from a
common precursor 9 derived from the chiral pool L-arabinose.
Scheme 1: Retrosynthetic analysis of proposed structure of mycalol (1).
( )5
0
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OAc
O
O
OAc
HO
OH
O
O
HO
O
O
3(a-d)
O
O
1
OH
OH
OH
O
O
OAc
I
+
O
O
(
)5
O
4(a-d)
O
O
5
O
O
H
O
O
SO PT
2
O
O
OTBDPS
+
O
8
O
O
O
O
7
O
OTBDPS
O
6(a-b)
O
O
O
L-Arabinose
OH
9
O
Our synthetic endeavor began with preparation of a known precursor 9 from L-arabinose
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following a reported procedure (Scheme 2). Compound 9 was then protected as TBDPS ether
2
using TBDPSCl in the presence of imidazole to achieve compound 10. We have tried a number
of hydroborylating reagents like 9-BBN, BH .THF at this stage in variable conditions to obtain
3
compound 11 but none of these were found to afford the desired compound even in moderate
yields. This urged us to adopt a two-step reaction sequence as an alternative. Alkene 10 was first
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subjected to Wacker oxidation using 10 mol% PdCl in the presence of CuCl to produce
2
regioselectively the corresponding aldehyde which concomitantly reduced with NaBH to access
4
alcohol 11 with good overall yield (68% over two steps). To construct the glyceryl ether moiety,
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alcohol 11 was first subjected to react with allyl bromide in the presence of NaH and catalytic
amount of TBAI to afford allyl ether 12 which was further treated with TBAF to deprotect
TBDPS ether and subsequently reacted with commercially available 1-Phenyl-1H-tetrazole-5-
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thiol (PTSH, 13) in the presence of DIAD/Ph P using the Mitsunobu conditions to achieve the
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synthesis of compound 14 in 86% yield over three steps. The terminal olefin of compound 14
was then dihydroxylated using AD-mix-β in the presence of MeSO NH following the Sharpless
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2
asymmetric dihydroxylation protocol to get diols 15a and 15b (dr>3.3:1, please see the HPLC
analysis in Supporting Information) as major and minor isomers, respectively, with 90% overall
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yield. Both the diastereomers were separated cautiously using silica gel column
chromatography. Our effort to reconfirm the absolute configuration of the newly generated
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4
secondary hydroxy center in the major isomer 15a by the modified Mosher method was not
successful at this stage due to the presence of several chemically similar protons in the recorded
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H NMR spectrum. This precluded unambiguous determination of chemical shifts of the protons
shielded or deshielded when the diol moiety of compound 15a was converted to its
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corresponding (R) and (S)-Mosher esters, respectively. However from the literature, it can be
anticipated that the major compound 15a is likely to be the appropriate isomer. Next the diol 15a
was treated with 2,2-DMP in the presence of CSA to afford compound 16 (Scheme 2) which was
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oxidized further using (NH ) Mo O .4H O in the presence of 30% H O to result the sulfone 8
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6
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2
2
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in 85% yield over two steps.
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Scheme 2: Synthesis of glyceryl ether unit 8.
O
O
O
c
ref.12
O
a
b
L-Arabinose
OTBDPS
O
HO
OTBDPS
OH
1
1
O
10
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e
d
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OTBDPS
O
SPT
12
O
14
O
O
N
N
N
SH
O
SPT
+
HO
O
SPT
HO
N
OH
f
O
OH
O
O
PTSH
1
5b (minor)
15a (major)
1
3
O
O
g
O
SPT
SO PT
2
O
O
O 16
O
O
O
8
Reagents and conditions: (a) TBDPSCl, imidazole, CH Cl , 0 ᵒC to rt, 2 h, quantitative; (b) (i)
2
2
PdCl , CuCl, DMF:H O (7:1), rt, 72 h; (ii) NaBH , MeOH, 0 ᵒC, 30 min, 68% after two steps; (c)
2
2
4
allyl bromide, NaH, TBAI, THF, 0 ᵒC to rt, 2 h, 92%; (d) (i) TBAF, THF, 0 ᵒC to rt, 30 min,
t
9
8%; (ii) 13, DIAD, Ph P, THF, 0 ᵒC to rt, 2 h, 88%; (e) AD-mix-β, MeSO NH , BuOH:H O
3
2
2
2
(1:1), 0 ᵒC, 36 h, overall 90% (~69% isolable yield based on compound 15a), (dr>3.3:1); (f) 2,2-
DMP, CSA, CH Cl , 0 ᵒC to rt, 1 h, quantitative; (g) (NH ) Mo O .4H O, 30% aqueous H O ,
2
2
4 6
7
24
2
2
2
EtOH, 0 ᵒC to rt, 1.5 h, 85%.
The synthesis of the intermediates 4(a-d) is summarized in Scheme 3. Alkene 10 was
16
first subjected to oxidative cleavage in the presence of OsO , NMO and NaIO to produce
4
4
aldehyde 7 and concomitantly reacted with sulfone 8 (Scheme 2) in the presence of NaHMDS
8
following the Julia-Kocienski olefination protocol to yield an inseparable mixture of alkenes
6
(a-b) which further were reacted with TBAF to produce another inseparable mixture of alcohols
17(a-b) in good overall yield (59% over three steps). Next the mixture of alcohols 17(a-b) was
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oxidized with IBX to get the corresponding aldehydes which were subjected concomitantly to
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Wittig olefination reaction in presence of Ph PCH I and NaHMDS to provide the mixture of
3
2 2
compounds 4(a-d) in 73% yield after two steps. We did not attempt to separate this mixture of
geometrical isomers 4(a-d) at this stage because the hydrogenation reaction at the pre-final stage
of synthesis would convert them logically to a single saturated compound.
Scheme 3: Synthesis of intermediates 4(a-d).
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O
O
O
O
a
c
b
H
O
OTBDPS
O
OTBDPS
OTBDPS
O
6(a-b)
O
O
O
O
O
O
10
7
O
O
O
d
I
O
OH
O
O
O
O
O
O
4(a-d)
17(a-b)
O
O
O
t
Reagents and conditions: (a) OsO , NMO, NaIO , NaHCO , BuOH:THF:H O(5:5:1), 0 ᵒC to rt,
4
4
3
2
1
2 h, 90%; (b) 8, NaHMDS, THF, -78 ᵒC to rt, 1.5 h, 68%; (c) TBAF, THF, 0 ᵒC to rt, 30 min,
7%; (d) (i) IBX, EtOAc, reflux, 2 h, quantitative; (ii) Ph PCH I , NaHMDS, -78 ᵒC to rt, 4
9
3
2 2
h,73% after two steps.
1
The synthesis of alkyne 5 is summarized in Scheme 4. The known epoxide 18, prepared
8
from its racemic counterpart using Jacobsen hydrolytic kinetic resolution protocol, was subjected
1
to epoxide ring opening reaction with commercially available octyne in the presence of BuLi
9
n
and BF .Et O to afford compound 19 in 83% yield. The internal alkyne in compound 19 was
3
2
10
next translocated to its terminal position using Zipper conditions (KO Bu/ BuLi/1,3-
t
n
diaminopropane) to achieve the synthesis of alkyne 20 in good yield. The free hydroxy of alkyne
2
0 was finally protected as acetate with Ac O/Py to produce the required alkyne intermediate 5
2
quantitatively.
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Scheme 4: Synthesis of alkyne 5.
OH
O
a
( )4
18
19
b
0
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OH
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n
Reagents and conditions: (a) Octyne, BuLi, BF .OEt , THF, -78 to 0 ᵒC, 30 min then -78 ᵒC, 1.5
3
2
t
n
h, 83%; (b) KO Bu, BuLi, 1,3-diaminopropane, THF, 0 ᵒC to rt, 3 h, 73%; (c) Ac O, pyridine, 0
2
ᵒC to rt, 30 min, quantitative.
The final synthetic endeavor for proposed structure of mycalol (1) is outlined in
Scheme 5. The advanced intermediates 4(a-d) and alkyne 5 (Scheme 4) were next coupled
1
1
together in the presence of Pd[(Ph P) Cl ]/CuI/Et N following Sonogashira reaction conditions
3
3
2
2
to produce the mixture of intermediates 3(a-d) which finally was hydrogenated using 10% Pd/C
1 13
to get the single saturated product 21. We have recorded both the H and C NMR spectrum of
pure compound 21 in different solvents like CDCl , d -benzene and d -pyridine and compared
3
6
5
1
with those delineated for the acetonide compound prepared by Fontana et al. The H NMR
1
spectrum of the synthesized compound 21 recorded either in CDCl or in d -benzene or in d -
5
3
6
pyridine although was in agreement with the reported data but there was a significant mismatch
13
1
in C NMR spectrum when compared with the literature values . The signals at δ 31.7 and 25.0
13
1
ppm in the C NMR of the acetonide derivative of isolated mycalol were missing in the C
13
NMR spectrum (recorded in CDCl ) of the synthesized compound 21. Additionally minor
3
13
mismatches were observed in the C NMR signals of the aliphatic carbon centers bearing a
hydroxy group (please see spectra and comparison Table 2 Supporting Information). As there
was no specific rotation documented for that acetonide compound, we were unable to compare
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its specific rotation with the data recorded {observed [α]
= +3.2 (c 1.4, CHCl )} for
3
D
compound 21. However, compound 21 was subjected finally to react with AcOH:H O (4:1) to
2
afford compound 1 by global deprotection of the acetonides in good overall yield (Scheme 5).
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The spectral data specifically the H NMR (recorded in d -pyridine) and HRMS although were in
5
accordance with the reported values but considerable mismatches (similar to the acetonide
1
3
derivative) were observed when the C NMR (recorded in d -pyridine) data was taken into
5
consideration (please see spectra and comparison Table 1 in Supporting Information). This result
strongly suggests that the structures proposed for isolated mycalol may not be entirely accurate.
Scheme 5: Synthesis of reported structure of mycalol (1).
O
O
O
O
AcO
I
a
O
O
O
O
O
O
4(a-d)
O
O
3(a-d)
O
O
b
OAc
O
c
O
1
O
O
O
O
O
2
1
Reagents and conditions: (a) 5, Pd[(Ph P) Cl ], CuI, Et N, rt, 4 h, 76%; (b) H , Pd/C (10%),
3
2
2
3
2
EtOAc, rt, 12 h, 98%; (c) AcOH:H O(4:1), 0 ᵒC to rt, 6 h, 97%.
2
We next have thought for the possibility that the isolated mycalol is a diastereomer of the
proposed structure. The configuration of the two vicinal diol units (C-3/C-4 and C-7/C-8, Figure
1
, compound 1) was assigned unambiguously as erythro by the isolation group. The C NMR
3
1
study of synthesized acetonide derivative of isolated mycalol exhibited well separated signals
(27.1 and 25.9 ppm; 26.8 and 25.4 ppm) characteristic for the methyl acetals of dioxolane rings
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of cis conformation. Thus the possibility of diastereomers with threo vicinal diol moieties has
been discarded. The absolute configuration of the two erythro diol systems was assigned by the
isolation group as R, S, R and S for C-3, C-4, C-7 and C-8 centers, respectively, by chiroptical
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
approach using the 1 ̍, 2 ̍- dibenzoate-3,4-dipivolyl and 1 ̍, 2 ̍- dibenzoate-7,8-dipivolyl derivatives of
1
mycalol. The preparation, characterization and chiroptical analysis of these compounds were
really challenging and could be the potential sources of complication. We thus have planned to
construct the possible diastereomers 22-24 (Figure 2) where the C-2̍ center is in S configuration.
The stereochemistry of well characterized C-20 center did not alter during the course of the
synthesis.
Figure 2: Diastereomers of compound 21 with C-2
̍
center having S configuration.
O
R
O
S
3
'
1
1
2'
S
R
20
O
O
O
S
O
2
2
1
0
O
O
OAc
2
2
O
S
O
R
3
'
20
2
'
R
S
O
S
10
O
O
O
OAc
2
3
O
O
3
'
1
2
0
2
'
R
R
O
O
S
S
O
S
2
10
O
O
OAc
24
The synthesis of intermediates from D-arabinose is described in Scheme 6. The similar
chemistry as developed for the synthesis of compound 21 was adopted. Alkene 25, prepared
1
from D-arabinose following a reported procedure, was converted to TBDPS ether 26. It was
2
6
next subjected to regioselective Wacker oxidation to get the corresponding aldehyde and
concomitantly reduced to alcohol 27 using NaBH . Alcohol 27 was then treated with allyl
4
bromide in the presence of NaH to access olefin ether 28. Next TBDPS group was deprotected
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and the resultant alcohol was reacted subsequently with PTSH (13) in Mitsunobu conditions to
7
produce compound 29 which finally was dihydroxylated using AD-mix-β to get compounds 30a
and 30b (dr>3.3:1) as major and minor isomers, respectively, in good overall yield. The purified
major isomer 30a was then treated with 2,2-DMP to get acetonide 31 (Scheme 6) and finally
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
5
oxidized with H O in the presence of (NH ) Mo O .4H O to afford required sulfone 32 in
2
2
2
4 6
7
24
8
5% yield over two steps.
Scheme 6: Synthesis of intermediates from D-arabinose.
O
O
O
c
ref.12
O
a
b
D-Arabinose
OTBDPS
HO
OTBDPS
OH
d
27
O
26
O
2
5
O
O
e
O
SPT
O
OTBDPS
28
O
29
O
O
N
N
SH
O
N
N
PTSH
O
SPT +
O
SPT
HO
OH
HO
O
OH
O
1
3
30a (major)
30b (minor)
f
O
O
g
O
SPT
O
SO PT
2
O
O
O
31
O
O
32
O
Reagents and conditions: (a) TBDPSCl, imidazole, CH Cl , 0 ᵒC to rt, 2 h, quantitative; (b) (i)
2
2
PdCl , CuCl, DMF:H O (7:1), rt, 72 h; (ii) NaBH , MeOH, 0 ᵒC, 30 min, 69% after two steps; (c)
2
2
4
allyl bromide, NaH, TBAI, THF, 0 ᵒC to rt, 2 h, 91%; (d) (i) TBAF, THF, 0 ᵒC to rt, 30 min,
t
9
7%; (ii) 13, DIAD, Ph P, THF, 0 ᵒC to rt, 2 h, 88%; (e) AD-mix-β, MeSO NH , BuOH:H O
3
2
2
2
(1:1), 0 ᵒC, 36 h, overall 90% (~69% isolatable yield based on compound 30a), (dr>3.3:1); (f)
,2-DMP, CSA, CH Cl , 0 ᵒC to rt, 1 h, quantitative; (g) (NH ) Mo O .4H O, 30% aqueous
2
2
2
4 6
7
24
2
H O , EtOH, 0 ᵒC to rt, 1.5 h, 85%.
2
2
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2
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The synthesis of advanced stage of intermediates for compounds 22-24 is summarized in
1
Scheme 7. Alkene 26 was subjected to oxidative cleavage using OsO /NMO and NaIO to get
6
4
4
aldehyde 33 and subsequently reacted with sulfone 8 (prepared from L-arabinose, Scheme 2) in
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
the presence of NaHMDS following the Julia-Kocienski olefination protocol to get an
inseparable mixture of compounds 34(a-b). The TBDPS group was next deprotected and the
17
mixture of resulting alcohols was oxidized to the corresponding aldehydes with IBX which
9
concomitantly reacted with Ph PCH I in presence of NaHMDS to get a mixture of inseparable
3
2 2
compounds 35(a-d) in good overall yield (67%, in 3 steps). Similarly, sulfone 32 was subjected
8
separately to the Julia-Kocienski olefination with aldehydes 7 (prepared from L-arabinose,
Scheme 3) and 33 (prepared from D-arabinose, Scheme 7) to get the mixture of compounds
36(a-b) and 38(a-b), respectively, which finally were transformed to their corresponding vinyl
iodides 37(a-d) and 39(a-d), respectively, with good overall yield.
Scheme 7: Synthesis of advanced stage of intermediates for compounds 22-24
O
O
O
O
a
c
H
O
b
O
OTBDPS
O
OTBDPS
OTBDPS
O
33
8
O
34(a-b)
O
O
O
O
O
26
O
I
O
O
O
O
O
3
5(a-d)
O
O
O
O
I
b
c
O
3
2
O
O
OTBDPS
OTBDPS
O
7
O
37(a-d)
O
O
O
O
O
36(a-b)
O
O
O
I
c
b
O
O
O
3
2
O
O
39(a-d)
O
O
3
3
O
O
O
3
8(a-b)
t
Reagents and conditions: (a) OsO , NMO, NaIO , NaHCO , BuOH:THF:H O(5:5:1), 0 ᵒC to rt,
4
4
3
2
1
2 h, 90%; (b) 8 or 7 or 33 NaHMDS, THF, -78 ᵒC to rt, 1.5 h, 68-71%; (c) (i) TBAF, THF, 0 ᵒC
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to rt, 30 min, 93-97%; (ii) IBX, EtOAc, reflux, 2 h, quantitative; (iii) Ph PCH I , NaHMDS, -78
3 2 2
ᵒC to rt, 4 h, 69-72%.
The final endeavor of synthesis of compounds 22-24 is described in Scheme 8. Three sets
of vinyl iodides 35(a-d), 37(a-d) and 39(a-d) in hand were coupled separately with common
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1
alkyne 5 following the Sonogashira reaction conditions to afford compounds 40(a-d), 41(a-d)
and 42(a-d), respectively, which were hydrogenated subsequently to produce the corresponding
saturated compounds 22, 23 and 24, respectively, in good overall yield (71-73% in two steps).
1
The H NMR spectra of these compounds were in accordance with the reported data of the
1
13
acetonide compound prepared by Fontana et al. But it was quite embarrassing to see that the C
NMR data of compounds 22-24 deviated significantly from the reported values (please see
spectra and comparison Table 2 in Supporting Information).
Scheme 8: Synthesis of compounds 22-24
O
O
AcO
b
a
O
O
22
3
5(a-d)
O
5
40(a-d)
O
O
O
O
AcO
AcO
b
b
a
O
O
23
37(a-d)
O
5
41(a-d)
O
O
O
O
a
O
O
24
3
9(a-d)
O
5
42(a-d)
O
O
Reagents and conditions: (a) 5, Pd[(Ph P) Cl ], CuI, Et N, rt, 4 h, 75-76%; (b) H , Pd/C (10%),
3
2
2
3
2
EtOAc, rt, 12 h, 94-97%.
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Next, we were keen to see whether the variation of stereochemistry at C-2̍ center would
1
3
provide any insight in to the origin of the aberrant signals in the C NMR data. Thus we have
synthesized all the four possible diastereomers (43-46) of compound 21 (Figure 3) where the C-2
center is in R configuration.
̍
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3: Diastereomers of compound 21 with C-2
̍
center having R configuration.
O
R
O
3
'
1
2'
S
S
20
O
O
R
R
R
OAc
2
1
0
O
O
O
43
O
O
3
'
1
2'
S
R
20
O
O
R
2
R
O
S
R
OAc
1
0
O
O
4
4
O
O
3'
1
20
2
'
R
S
O
O
S
R
R
2
R
OAc
10
O
O
O
4
5
O
S
O
S
3
'
1
2
0
2
'
R
R
O
O
R
R
OAc
2
10
O
O
O
4
6
The synthesis of compounds 43-46 is summarized in Scheme 9. The compounds 15b
Scheme 2) and 30b (Scheme 6) were transformed separately to their corresponding sulfones 47
(
and 48, respectively, following the same chemistry as described for synthesis of compound 8
(
Scheme 2). It is noteworthy that both compounds 15b and 30b were prepared in bigger scale
3.0 gm, please see experimental section) from the corresponding olefins 14 (Scheme 2) and 29
(
(Scheme 6), respectively, using AD-mix-α with similar overall yield (~90%) and
diastereoselectivity (dr>3.3:1, scheme not shown) as observed in AD-mix-β reaction (Scheme 2
and Scheme 6). Next the sulfone 47 was converted separately to intermediates 49(a-d) and 50(a-
d) by reacting with the aldehydes 7 and 33, respectively, following the similar chemistry as
developed above. Similarly sulfone 48 transformed to compounds 51(a-d) and 52(a-d) using the
aldehydes 7 and 33, respectively. All the four sets of intermediates 49(a-d), 50(a-d), 51(a-d) and
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2(a-d) were coupled with alkyne 5 separately and hydrogenated subsequently to get saturated
5
1
compounds 43, 44, 45 and 46, respectively, in good overall yield (73-76% in two steps). Both H
1
3
and C NMR for all these compounds were recorded and compared with those reported for the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
acetonide compound prepared by Fontana et al. The H NMR data of all compounds 43-46 were
1
3
close to the reported values. It was observed that the C NMR signals from the hydroxylated
carbon centers of compounds 44-46 deviated significantly from the reported values. However the
corresponding signals from the synthesized compound 43 were in much better agreement (please
see spectra and comparison Table 3 in Supporting Information). This result urged us to consider
the possibility of other structural/positional isomers for the proposed structure of mycalol.
Scheme 9: Synthesis of compounds 43-46
O
O
R
S
a
O
SO PT
2
O
R
SPT
O
HO
HO
O
O
O
4
7
OH
O
1
5b
O
R
R
a
O
SO PT
2
O
O
S
SPT
O
4
8
O
O
3
0b
OH
O
O
O
c
I
O
b
43
O
5
H
S
7
O
O
O
R
OTBDPS
4
9(a-d)
O
O
O
O
47
7
c
I
4
4
O
O
b
5
O
O
O
5
0(a-d)
O
3
3
H
R
S
OTBDPS
O
O
c
O
O
33
b
I
45
46
O
O
5
7
O
O
O
5
1(a-d)
OAc
48
O
O
c
( )5
I
b
O
O
5
5
3
3
O
5
2(a-d)
O
O
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Reagents and conditions: (a) (i) 2,2-DMP, CSA, CH Cl , 0 ᵒC to rt, 1 h, quantitative; (ii)
2
2
(
NH ) Mo O .4H O, 30% aqueous H O , EtOH, 0 ᵒC to rt, 1.5 h, 85%. (b) (i) 7 or 33,
4 6
7
24
2
2
2
NaHMDS, THF, -78 ᵒC to rt, 1.5 h, 67-69%; (ii) TBAF, THF, 0 ᵒC to rt, 30 min, 96-98%; (iii)
IBX, EtOAc, reflux, 2h, quantitative; (iv) Ph PCH I , NaHMDS, -78 ᵒC to rt, 4 h, 73-76%; (c) (i)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2 2
5, Pd[(Ph P) Cl ], CuI, Et N, rt, 4h, 75-79%; (ii) H , Pd/C (10%), EtOAc, rt, 12h, 94-98%.
3
2
2
3
2
1
3
As the C NMR data of compound 43 matched better the reported values for mycalol
(except the resonances at 31.7 and 25.0 ppm) relative to the other synthesized diastereomers, we
have decided to synthesize its structural isomers by varying the position of hydroxy groups. To
decide which functional group(s) should be varied two issues were considered. First, the two
methylene groups of protons positioned between the erythro vicinal diol moieties in the
deuterated acetonide derivative of isolated mycalol prepared by Fontana et al. have different
1
chemical shifts (δ1.57 and 1.74 ppm) in spite of being in apparently similar chemical
environment. Second, the integration of these protons in the presence of number of other closely
situated methylene groups of protons was arduous. Both of these above facts tempted us to
consider the possibility that there might be more than two methylene groups between the two
erythro vicinal diol moieties. We have thus designed two compounds 53 and 54, as shown in
Figure 4, where the two erythro vicinal diol moieties are separated by three and four methylene
groups, respectively. This would generate eventually almost two non identical environments (H2-
5
/H -7 and H -6 for compound 53; H -5/H -8 and H -6/H -7 for compound 54) for those
2 2 2 2 2 2
methylene protons flanked between the two vicinal diol units.
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Figure 4: Positional isomers of compound 43
O
R
O
3
'
1
2
'
S
R
20
6
6
O
O
O
5
5
7
7
S
R
2
2
12
12
O
O
O
OAc
5
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
R
O
3'
1
2
'
S
20
8
S
O
R
R
O
O
O
OAc
5
4
The synthesis of advanced stage of intermediates for compounds 53 and 54 is outlined in
17
Scheme 10. Alcohol 11 (Scheme 2) was oxidized with IBX to get the corresponding aldehyde
8
and subsequently subjected to Julia-Kocienski olefination with sulfone 47 (Scheme 9) to afford
mixture of compounds 55(a-b) which finally was converted to mixture of compounds 56(a-d)
following the same chemistry as described for compound 21. For preparation of higher
homologue of alcohol 11, the aldehyde 7 (Scheme 3) was subjected to Wittig olefinations with
2
0
Ph P=CHCO Et to get the corresponding α, β-unsaturated ester which finally was reduced with
3
2
LiBH to yield alcohol 57. Next this alcohol was transformed to advance stage of intermediates
4
59(a-d) through intermediates 58(a-b) following the identical chemistry as mentioned above.
Scheme 10: Synthesis of advanced stage of intermediates for compounds 53-54
O
O
O
O
a
OTBDPS
c
O
O
I
O
O
1
1
7
b, 47
O
O
O
56(a-d)
O
O
O
5
5(a-b)
O
O
O
d
b, 47
HO
O
O
OTBDPS
OTBDPS
O
O
58(a-b)
O
O
5
7
O
O
I
c
O
O
O
59(a-d)
O
O
O
O
O
O
SO PT
2
O
OHC
OTBDPS
HO
OTBDPS
O
O
4
7
7
O
11
O
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Reagents and conditions: (a) IBX, EtOAc, reflux, 2 h, quantitative; (b) 47, NaHMDS, THF, -78
ᵒC to rt, 1.5 h, 68-69%; (c) (i) TBAF, THF, 0 ᵒC to rt, 30 min, 97-98%; (ii) IBX, EtOAc, reflux, 2
h, quantitative; (iii) Ph PCH I , NaHMDS, -78 ᵒC to rt, 4 h, 74-76%; (d) (i) Ph P=CHCO Et,
3
2 2
3
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CH Cl , rt, 12 h, 98% (ii) LiBH , THF, 0 ᵒC to rt, 12 h, 97%.
2
2
4
The synthesis of alkyne fragments for compounds 53 and 54 is depicted in Scheme 11.
Following the identical chemistry of alkyne 5 (Scheme 4), we treated epoxide 18 separately with
1-heptyne and 1-hexyne to produce compounds 60a and 60b, respectively, which was subjected
10
further to Zipper reaction to access the corresponding alkynes 61a and 61b. Finally the free
hydroxy groups in both alkynes were protected separately as acetate to yield protected alkynes
62a and 62b, respectively.
Scheme 11: Synthesis of alkynes intermediates for compounds 53-54
OH
O
a
( )n
1
8
60a, n=3
60b, n=2
b
OAc
OH
c
(
)n
( )n
62a, n=4
62b, n=3
61a, n=4
61b, n=3
n
Reagents and conditions: (a) 1-Heptyne or 1-hexyne, BuLi, BF .OEt , THF, -78 to 0 ᵒC, 30 min
3
2
t
n
then -78 ᵒC, 1.5 h, 84-86%; (b) KO Bu, BuLi, 1,3-diaminopropane, THF, 0 ᵒC to rt, 3 h, 72-
7
6%; (c) Ac O, pyridine, 0 ᵒC to rt, 30 min, 98-99%.
2
The final endeavor of synthesis of compounds 53 and 54 is described in Scheme 12.
Following the same synthetic strategy as developed for compound 21, the mixture of compounds
1
6(a-d) and 59(a-d) were subjected to the Sonogashira reaction with the alkynes 62a and 62b,
1
5
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respectively, to yield mixture of compounds 63(a-d) and 64(a-d), respectively, which finally
1 13
were hydrogenate to afford compounds 53 and 54, respectively. Both the H and C NMR
1
spectra of compounds 53 and 54 were recorded and compared with those data reported for
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
acetonide compound synthesized by Fontana et al. Disappointingly, all the spectra deviated
significantly (please see the spectra and comparison Table 4 in Supporting Information) from the
1
3
reported spectra and no C NMR signals at δ 31.7 and 25.0 ppm were observed in both the
cases. Thus the possibility of existence of more than two methylene groups between the two
erythro vicinal diol moieties has been discarded.
Scheme 12: Synthesis of compounds 53-54
OAc
O
O
O
O
b
b
5
3
a
O
O
O
5
6(a-d)
( )4
6
2a
O
63(a-d)
O
O
O
( )3
AcO
5
4
a
5
9(a-d)
O
6
2b
64(a-d)
O
O
Reagents and conditions: (a) 62a or 62b, Pd[(Ph P) Cl ], CuI, Et N, rt, 4 h, 76-77%; (b) H , Pd/C
3
2
2
3
2
(10%), EtOAc, rt, 12 h, 97-98%.
Finally we considered the possibility that the position of the OAc group in the
hydrophobic chain might be different in mycalol from its proposed structure. As it was reported
that the terminal methyl group (C-24) has HMBC correlation with C-23, C-22 and C-21
methylene groups of protons, we planned to synthesize isomers where the OAc group is
1
positioned elsewhere in the hydrophobic chain. As the C NMR data of compound 43 was more
3
compatible with reported data (except the signals at 31.7 and 25.0 ppm), we have prepared two
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
of its structural isomers 65 and 66 (Figure 5) where the OAc group is at C-18 and C-19 position,
respectively.
Figure 5: Other positional isomers of compound 43
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
R
O
3'
1
21
2
'
S
S
18
O
O
R
R
2
R
1
0
24
O
O
O
OAc
6
5
O
R
O
OAc
R
3
'
1
21
2
'
S
S
O
O
R
19
R
2
24
10
O
O
O
6
6
The synthesis of alkyne intermediates for compounds 65 and 66 is summarized in
Scheme 13. The epoxides 67a and 67b prepared from their racemic counterpart using Jacobsen
hydrolytic kinetic resolution protocol were subjected to epoxide opening reaction separately with
1
-hexyne and1-heptyne, respectively, to afford compounds 68a and 68b, respectively. Finally
both the alkynes 68a and 68b were transformed to other alkynes 70a and 70b, respectively, via
the intermediate alkynes 69a and 69b, respectively, following the same chemistry as followed in
synthesis of alkyne 5.
Scheme 13: Synthesis of alkyne intermediates for compounds 65-66
OH
O
a
( )m
(
)n
( )n
6
7a, n=3
68a, n=3, m=2
68b, n=2, m=3
67b, n=2
b
OAc
OH
c
(
)n
( )m
( )n
( )m
7
7
0a, n=3, m=3
0b, n=2, m=4
69a, n=3, m=3
69b, n=2, m=4
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n
Reagents and conditions: (a) 1-Hexyne or 1-heptyne , BuLi, BF .OEt , THF, -78 to 0 ᵒC, 30 min
3
2
t
n
then -78 ᵒC, 1.5 h, 83-84%; (b) KO Bu, BuLi, 1,3-diaminopropane, THF, 0 ᵒC to rt, 3 h, 73-
7
4%; (c) Ac O, pyridine, 0 ᵒC to rt, 30 min, 98-99%.
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The final steps of construction of compounds 65 and 66 are outlined in Scheme 14. The
mixture of intermediates 49(a-d) (Scheme 9) was coupled separately with alkynes 70a and 70b,
11
respectively following Sonogashira conditions to achieve compounds 71(a-d) and 72(a-d),
respectively, in good yield. Both these mixture of products finally hydrogenated to get single
1 13
saturated compounds 65 and 66, respectively. The H and C NMR spectra of both these
1
compounds were recorded and it was observed that the H NMR data of both the compounds was
1
13
compatible with the literature values. Comparison of C NMR data of both compounds 65 and
6
6 with the reported data (please see spectra and comparison Table 5 in Supporting Information)
confirmed unambiguously that compound 66 is the actual structure of acetonide derivative of
isolated mycalol reported by Fontana et al.
Scheme 14: Synthesis of compounds 65-66
b
O
1
8
65
O
O
O
OAc
O
a
71(a-d)
O
O
7
0a
4
9(a-d)
O
b
O
19
66
a
O
O
OAc
O
7
0b
72(a-d)
O
O
Reagents and conditions: (a) 70a or 70b, Pd[(Ph P) Cl ], CuI, Et N, rt, 4 h, 74-76%; (b) H , Pd/C
3
2
2
3
2
(
10%), EtOAc, rt, 12 h, 97-98%.
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1
1
1
1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The final endeavor of synthesis mycalol is depicted in Scheme 15. The prefinal
compound 66 was finally subjected to AcOH:H O (4:1) for global deprotection of the acetonides
2
to achieve the compound 2 in very good yield. The spectral data and specific rotation [reported
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
20
22
[
α] = +3.45 (c 0.1, MeOH); observed [α]
= +4.00 (c 0.4, MeOH)] of present synthesized
D
D
1
compound 2 were in good agreement with those reported for isolated natural product (For
1
13
comparison of H and C NMR between isolated mycalol and synthetic mycalol please see
Table 6 in supporting Information) which unambiguously confirms the asymmetric total
synthesis of isolated mycalol. While we engaged in resolving the differences between the NMR
data of mycalol and that of the synthesized compound 1 (i.e. its proposed structure, by
synthesizing isomers where both chiral centers and positions of functional groups were
3
systematically varied), Reddy and coworkers used elegant NMR techniques (HMBC at 700
MHz) to resolve the same problem and have arrived at the same conclusion i.e. the proposed
structure of mycalol varies from its actual structure in the position of the OAc group and the
chirality of the C-2
̍ center.
Scheme 15: Synthesis of revised structure of mycalol (2)
OAc
1
9
a
HO
OH
66
R
HO
O
OH
2
OH
OH
Reagents and conditions: (a) AcOH:H O(4:1), 0 ᵒC to rt, 6 h, 98%.
2
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Conclusion:
In summary, we have developed a convergent and flexible synthetic strategy to
accomplish the stereoselective total synthesis of biologically promising anticancer natural lipid
mycalol from known precursor 9 with good overall yield [(16 linear steps, 10% for proposed
structure (1) and 11.1% for revised/actual structure (2)]. Out of seven hydroxy groups, four have
been installed from the chiral pool L-arabinose. The key steps like regioselective Wacker
oxidation, Sharpless asymmetric dihydroxylation, Julia-Kocienski olefination, Wittig olefination,
Zipper reaction and Sonogashira reaction have been employed logically to construct efficiently
the complete architecture of mycalol. In our effort to resolve the differences in the NMR data of
the isolate structure and the synthesized proposed structure we have developed convenient
synthetic strategies for several configurational and positional isomers for mycalol. The
availability of a large number of isomers of the anticancer natural lipid mycalol (analogues) are
ideally suited for developing structure activity relationships and their comparative biological
activity is currently under investigation.
10
11
12
13
14
15
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17
18
19
20
21
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23
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29
30
31
32
33
34
35
36
37
38
39
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental section:
tert-Butyl(((4S,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)methoxy)diphenylsilane (10): To
an ice cold solution of compound 9 (1.98 g, 12.50 mmol) in anhydrous CH Cl (30 mL) under
2
2
argon atmosphere, imidazole (2.5 g, 37.50 mmol) and TBDPSCl (4.0 mL, 16.25 mmol) were
added sequentially. The reaction mixture was warmed to ambient temperature and stirred further
for 2 h prior to quench it with saturated aqueous NH Cl solution (10 mL). The resultant mixture
4
was extracted with CH Cl (30 mL), washed with water, brine, dried (Na SO ) and concentrated
2
2
2
4
under reduced pressure. Flash column chromatographic purification (SiO , 60-120 mesh, 2%
2
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
EtOAc in hexane as eluant) of the resultant crude residue furnished pure TBDPS protected
2
7
compound 10 (4.95 g, quantitative) as a colorless liquid. R =0.6 (5% EtOAc in hexane); [α]
=
D
f
1
-
6.5 (c 1.5, CHCl ); H NMR (CDCl , 300 MHz) δ 7.69-7.65 (m, 4H), 7.43-7.35 (m, 6H), 5.99-
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
.88 (m, 1H), 5.36 (dt, J=16.8, 1.5 Hz, 1H), 5.21 (dq, J =10.2, 1.2 Hz, 1H), 4.65 (t, J = 6.6, 1H),
1
4.28 (q, J =6.6 Hz, 1H), 3.73-3.64 (m, 2H), 1.44 (s, 3H), 1.37 (s, 3H), 1.05 (s, 9H); C NMR
3
1
,2
(
CDCl , 75 MHz) δ 134.8, 134.8, 132.8, 128.8, 126.8, 117.2, 107.7, 77.9, 77.6, 61.9, 26.9, 25.9,
3
-
1
2
4.5, 18.4 ppm; IR (neat) νmax 2931, 1215 cm ; HRMS (ESI) m/z calculated for C H O SiNa
24
32
3
+
[M + Na] 419.2018, found 419.2016.
2
-((4R,5S)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethanol
(11): To a stirred solution of compound 10 (2 g, 5.04 mmol) in mixture of DMF (35 mL) and
water (5 mL) at ambient temperature, PdCl (100 mg, 0.1 mmol, 10 mol%) and CuCl (740 mg,
2
7
.47 mmol) were added. The reaction mixture was stirred for 30 min prior to start bubbling
oxygen gas though it for 72h at room temperature. The mixture was then filtered using a small
pad of celite and washed with EtOAc. The filtrate was washed with water, brine, dried (Na SO )
2
4
and concentrated in vacuo to afford the corresponding aldehyde as a yellowish liquid which was
used directly in the next reaction without further purification and characterization.
The crude aldehyde from the above step was taken in anhydrous MeOH (15 mL) under
ᵒ
argon, cooled to 0 C and NaBH (720 mg, 20.0 mmol) was added cautiously into it. The mixture
4
was warmed slowly at room temperature and stirred further for 30 min. The reaction was then
quenched with saturated aqueous NH Cl solution (5 mL), extracted with EtOAc (3×30 mL),
4
washed with brine, dried over Na SO and finally concentrated in vacuo. Purification of the
2
4
resultant crude residue by column chromatography (SiO , 60-120 mesh, 20% EtOAc in hexane
2
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as eluant) afforded pure alcohol 11 (1.42 g, 68%) as a colorless oil. R =0.4 (20% EtOAc in
f
3
0
1
hexane); [α] = +0.5 (c 0.6, CHCl ); H NMR (CDCl , 300 MHz) δ 7.68-7.61 (m, 4H), 7.47-
D
3
3
7
.35 (m, 6H), 4.41-4.35 (m, 1H), 4.26-4.19 (m,1H), 3.89-3.82 (m, 2H), 3.76-3.63 (m, 2H), 2.35
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
br s, 1H), 1.93-1.86 (m, 2H), 1.37 (s, 3H), 1.33 (s, 3H), 1.05 (s, 9H); C NMR (CDCl , 75
(
3
MHz) δ 135.7, 133.3, 133.2, 129.9, 127.9, 127.9, 108.3, 77.9, 62.6, 61.6, 31.6, 28.2, 26.9, 25.7,
-
1
1
9.3 ppm; IR (neat) νmax 3446, 2929, 1112 cm ; HRMS (ESI) m/z calculated for C H O SiNa
24
34
4
+
M + Na] 437.2124, found 437.2122.
[
(((4S,5R)-5-(2-(Allyloxy)ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)(tert-butyl)
diphenylsilane (12): To a stirred solution of alcohol 11 (1.5 g, 3.62 mmol) in anhydrous THF
(10 mL) at 0 ᵒC under argon, NaH (174 mg, 60% dispersion in mineral oil, 4.34
mmol) was added portion wise. The reaction mixture was warmed to room temperature and
stirred for 30 min. The mixture was cooled again to 0 ᵒC and allyl bromide (0.4 mL, 4.34 mmol)
followed by TBAI (67 mg, 0.2 mmol) were added into it. The reaction mixture was warmed
again to room temperature and stirred further for 1.5 h prior to quench it with saturated aqueous
NH Cl solution (3 mL). The resulting mixture was extracted with EtOAc (2×30 mL), washed
4
with water, brine, dried over Na SO and concentrated in vacuo. Purification of the resultant
2
4
crude residue by flash column chromatography (SiO , 60-120 mesh, 5% EtOAc in hexane as
2
eluant) provided allyl ether 12 (1.5 g, 92%) as a colorless oil. R =0.7 (10% EtOAc in hexane);
f
28
1
[
α] = +4.3 (c 1.45, CHCl ); H NMR (CDCl , 300 MHz) δ 7.69-7.65 (m, 4H), 7.45-7.34 (m,
D
3
3
6
4
1
H), 5.96-5.87 (m, 1H), 5.27 (dq, J = 17.1, 1.8 Hz, 1H), 5.17 (dq, J = 10.2, 1.8 Hz, 1H), 4.38-
.31 (m, 1H), 4.22-4.16 (m, 1H), 3.98 (dt, J = 2.7, 1.5 Hz, 2H), 3.77-3.56 (m, 4H), 1.99-1.96 (m,
13
H), 1.86-1.81 (m, 1H), 1.37 (s, 3H), 1.33 (s, 3H), 1.05 (s, 9H); C NMR (CDCl , 75 MHz) δ
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1
1
1
1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
2
35.8, 135.7, 135.1, 129.9, 127.8, 116.9, 108.0, 77.9, 74.5, 72.0, 67.6, 62.9, 29.8, 28.3, 27.0,
-1
5.7, 19.3 ppm; IR (neat) νmax 2931, 1587, 1109 cm ; HRMS (ESI) m/z calculated for
+
C H O SiNa [M + Na] 477.2437, found 477.2439.
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5-((((4R,5R)-5-(2-(Allyloxy)ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)thio)-2-phenyl-2H-
tetrazole (14): To a stirred solution of allyl ether 12 (1.45 g, 3.2 mmol) in anhydrous THF (10
ᵒ
mL) at 0 C under argon, TBAF (1 M in THF, 4.16 mL, 4.16 mmol) was added. The reaction
mixture was warmed to room temperature and stirred for 30 min prior to quench it with saturated
aqueous NH Cl solution (5 mL). The resultant mixture was extracted with EtOAc (2×30 mL),
4
washed with water, brine, dried (Na SO ), and concentrated under vacuum. Flash column
2
4
chromatographic purification (SiO , 60-120 mesh, 10% EtOAc in hexane as eluant) of the
2
resultant crude residue afforded the corresponding alcohol (995 mg, 98%) as colorless oil. Rf
2
7
1
=
0.4 (20% EtOAc in hexane); [α] = -3.0 (c 1.6, CHCl ); H NMR (CDCl , 300 MHz) δ 5.95-
D
3
3
5
.82 (m, 1H), 5.26 (dq, J = 16.8, 1.5 Hz, 1H), 5.19 (dq, J = 10.5, 1.5 Hz, 1H), 4.33-4.27 (m, 1H),
.19-4.14 (m, 1H), 3.39 (dt, J = 5.7, 1.5 Hz, 2H), 3.79-3.49 (m, 4H), 2.27 (t, J = 5.4 Hz, 1H),
4
1
3
1.92-1.81 (m, 2H), 1.44 (s, 3H), 1.35 (s, 3H); C NMR (CDCl , 75 MHz) δ 134.6, 117.4, 108.0,
3
-1
7
8.1, 74.8, 72.2, 67.5, 61.8, 29.6, 28.3, 25.6 ppm; IR (neat) νmax 3444, 2933 cm ; HRMS (ESI)
+
m/z calculated for C H O Na [M + Na] 239.1259, found 239.1256.
1
1
20
4
To an ice cold solution of above alcohol (650 mg, 3.0 mmol) in anhydrous THF (10 mL)
under argon, Ph P (870 mg, 3.3 mmol) and 1-phenyl-1H-tetrazole-5-thiol (13) (590 mg, 3.3
3
mmol) were added sequentially. After stirring for 30 min at same temperature, DIAD (0.65 mL,
3
.3 mmol) was added in drop wise manner. The mixture was warmed slowly to room
temperature and stirred for 1.5 h prior to quench it with brine (3 mL). The mixture was extracted
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with EtOAc (2×30 mL), washed with brine, dried (Na SO ), and concentrated in vacuo. Flash
2
4
column chromatography (SiO , 100-200 mesh, 5% EtOAc in hexane as eluant) of the resultant
2
crude residue afforded pure compound 14 (990 mg, 88%) as a colorless oil. R =0.5 (10% EtOAc
f
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
30
1
in hexane); [α]
= -31.9 (c 0.91, CHCl ); H NMR (CDCl , 300 MHz) δ 7.62-7.52 (m, 5H),
D
3
3
5.96-5.87 (m, 1H), 5.27 (dq, J =16.5, 1.5 Hz, 1H), 5.18 (dq, J =10.2, 1.5 Hz, 1H), 4.49-4.37 (m,
2
H), 4.01 (dt, J = 2.7, 1.5 Hz, 2H), 3.73 (dd, J =13.2, 3.0 Hz, 1H), 3.65-3.58 (m, 2H), 3.34 (dd, J
13
=
12.9, 9.9 Hz, 1H), 1.97-1.88 (m, 2H), 1.45 (s, 3H), 1.35 (s, 3H); C NMR (CDCl , 75 MHz) δ
3
154.3, 134.8, 133.8, 130.3, 129.5, 123.9, 117.2, 108.8, 75.9, 75.2, 72.2, 67.1, 35.3, 29.9, 28.5,
-1
2
5.8 ppm; IR (neat) νmax 2927, 1217 cm ; HRMS (ESI) m/z calculated for C H N O SNa
18
24
4
3
+
M+Na] 399.1467, found 399.1465.
[
5
-((((4R,5R)-5-(2-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)ethyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)methyl)thio)-2-phenyl-2H-tetrazole (16): AD mix-β (3.5 g, 1.4 g for 1 mmol of
t
olefin) and MeSO NH (475 mg, 5.0 mmol) were dissolved in a mixture of BuOH (9 mL) and
2
2
water (10 mL) and stirred for 30 min at room temperature. The reaction mixture was cooled to 0
ᵒ
t
C and compound 14 (990 mg, 2.5 mmol, dissolved in 1 mL BuOH) was added into it. The
mixture was stirred vigorously for 36 h at the same temperature and finally quenched with
Na SO (1.0 g). The resulting mixture was stirred for another 1 h and extracted with EtOAc
2
3
(3×30 mL). The organic layer was washed with water, brine, dried (Na SO ) and concentrated in
2
4
vacuo. Column chromatographic purification (SiO , 230-400 mesh, 50% EtOAc in hexane as
2
eluant) of the resultant crude residue yielded the pure diols 15a (709 mg, 69%) and 15b (214 mg,
2
1%) as colorless oil.
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Data for compound 15a: R =0.5 (60% EtOAc in hexane); [α]
= -10.3 (c 1.2, CHCl ); H
3
f
D
NMR (CDCl , 300 MHz) δ 7.60-7.53 (m, 5H), 4.93 (br s, 1H), 4.52-4.49 (m, 1H), 4.39-4.32 (m,
3
1
1
H), 3.94-3.83 (m, 2H), 3.72-3.61 (m, 4H), 3.56-3.46 (m, 2H), 3.27-3.19 (m, 1H), 2.54 (br s,
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4
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6
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9
0
13
H), 2.04-1.95 (m, 2H), 1.44 (s, 3H), 1.35 (s, 3H); C NMR (CDCl , 75 MHz) δ 154.5, 133.7,
3
130.4, 130.0, 124.0, 108.6, 76.5, 75.9, 73.2, 70.7, 68.8, 64.2, 35.5, 29.5, 28.5, 25.8 ppm; IR
-1
+
(
neat) νmax 3409, 2927, 1218 cm ; HRMS (ESI) m/z calculated for C H N O SNa [M + Na]
18
26
4
5
4
33.1522, found 433.1523.
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1
Data for compound 15b: R =0.5 (60% EtOAc in hexane); [α]
= +4.9 (c 0.6, CHCl ); H
3
f
D
NMR (CDCl , 300 MHz) δ 7.60-7.52 (m, 5H), 4.53-4.45 (m, 1H), 4.38-4.31 (m, 1H), 4.00-3.79
3
(
m, 2H), 3.74-3.58 (m, 4H), 3.55-3.47 (m, 2H), 3.27-3.19 (m, 1H), 2.00-1.92 (m, 2H), 1.43 (s,
1
3
3H), 1.33 (s, 3H); C NMR (CDCl , 75 MHz) δ 154.5, 133.6, 130.4, 129.9, 124.0, 108.6, 76.5,
3
-1
7
5.9, 73.1, 70.7, 68.8, 64.1, 35.5, 29.5, 28.5, 25.7 ppm. IR (neat) νmax 3421, 2920, 1216 cm ;
+
HRMS (ESI) m/z calculated for C H N O SNa [M + Na] 433.1522, found 433.1519.
18 26
4
5
To an ice cold solution of the diol 15a (700 mg, 1.7 mmol) in anhydrous CH Cl (10 mL)
2
2
under argon, 2,2-DMP (0.63 mL, 5.1 mmol) and CSA (20 mg, 0.08 mmol) were added
sequentially. The reaction mixture was stirred for 1 h at room temperature prior to quench it with
Et N (1 mL). The mixture was concentrated and purified by flash column chromatography to get
3
(
SiO , 60-120 mesh, 10% EtOAc in hexane as elutant) compound 16 (762 mg, quantitative) as
2
27
1
colorless oil. R = 0.3 (20% EtOAc in hexane); [α] = -44.9 (c 0.8, CHCl ); H NMR (CDCl ,
f
D
3
3
3
00 MHz) δ 7.62-7.53 (m, 5H), 4.47-4.43 (m, 1H), 4.40-4.36 (m, 1H), 4.31-4.26 (m, 1H), 4.08-
.03 (m, 1H), 3.75-3.57 (m, 4H), 3.56-3.44 (m, 2H), 3.31 (dd, J = 12.9, 10.2 Hz, 1H), 1.95-1.87
4
1
3
(
m, 2H), 1.44 (s, 3H), 1.42 (s, 3H), 1.35 (s, 3H), 1.34 (s, 3H); C NMR (CDCl , 300 MHz) δ
3
1
54.3, 133.8, 130.3, 129.9, 123.9, 109.6, 108.8, 75.9, 75.1, 74.8, 72.4, 68.5, 66.9, 35.3, 29.8,
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8.5, 26.9, 25.8, 25.5; IR (neat) νmax 2931, 1218 cm ; HRMS (ESI) m/z calculated for
+
C H N O SNa [M + Na] 473.1835, found 473.1837.
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5
-((((4R,5R)-5-(2-(((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)ethyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)methyl)sulfonyl)-2-phenyl-2H-tetrazole (8): To an ice cold solution of
compounds 16 (750 mg, 1.7 mmol) in EtOH (5 mL), (NH ) Mo O .4H O (105 mg, 0.09 mmol)
4
6
7
24
2
and 30% H O (3 mL) were added sequentially. The reaction mixture was warmed slowly to
2
2
room temperature and stirred further for 1.5 h. The mixture was extracted with EtOAc (2×30
mL), washed with water, brine, dried over Na SO , and concentrated in vacuo. Flash column
2
4
chromatography (SiO , 100-200 mesh, 20% EtOAc in hexane as eluant) of the resultant crude
2
residue provided sulfone 8 (694 mg, 85%) as colorless oil. R = 0.3 (30% EtOAc in hexane);
f
27
1
[
α] = -66.3 (c 0.52, CHCl ); H NMR (CDCl , 300 MHz) δ 7.65-7.54 (m, 5H), 4.69-4.60 (m,
D
3
3
1
3
H), 4.33 (q, J = 6.6 Hz, 1H), 4.28-4.18 (m, 1H), 4.04-3.98 (m, 1H), 3.86-3.83 (m, 2H), 3.70-
1,2
.57 (m, 2H), 3.55-3.39 (m, 3H), 1.87-1.81 (m, 2H), 1.40 (s, 3H), 1.32 (s, 3H), 1.26 (s, 3H), 1.21
13
(s, 3H); C NMR (CDCl , 75 MHz) δ 154.4, 133.4, 131.5, 129.5, 126.0, 109.7, 109.4, 75.9,
3
74.6, 72.7, 72.7, 68.3, 66.8, 58.5, 29.8, 27.7, 26.9, 25.6, 25.4 ppm; IR (neat) νmax 2926, 1219
-1
+
cm ; HRMS (ESI) m/z calculated for C H N O SK [M + K] 521.1472, found 521.1474.
2
1
30
4
7
(4S,5S)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolane-4-
carbaldehyde (7): To an ice cold solution of compound 10 (815 mg, 2.05 mmol) in a mixture of
t
THF (3 mL), BuOH (3 mL), and water (0.6 mL), OsO (5% solution in BuOH, 100 µL) and
t
4
NMO (481 mg, 4.1 mmol) was added and stirred for 30 min at the same temperature. NaHCO3
(515 mg, 6.15 mmol) followed by NaIO (875 mg, 4.1 mmol) was added into it. The reaction
4
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