Rapid, enantioselective synthesis of the C1-C13 fragment of biselyngbyolide B

Article abstract of DOI:10.1039/c7cc08004b

A rapid synthesis of the C1-C13 fragment of biselynbyolide A and B is reported. The judicious use of catalytic transformations for C-C bond formation and stereocenter generation greatly minimizes the use of protecting groups and oxidation state changes, as compared to previously reported routes to similar fragments.

Full text of DOI:10.1039/c7cc08004b

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DOI: 10.1039/C7CC08004B
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Rapid, enantioselective synthesis of the C1–C13 fragment of
biselyngbyolide B
Rakesh G. Thorata and Andrew M. Harned*,a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A rapid synthesis of the C1–C13 fragment of biselynbyolide A and
B is reported. The judicious use of catalytic transformations for C–
C bond formation and stereocenter generation greatly minimizes
the use of protecting groups and oxidation state changes, as
compared to previously reported routes to similar fragments.
Me
O
Me
27
23
20
17
Me
Me
13
O
O
O
O
9
Me
Me
26
1
5
7
7
Me
Me
25
5
The biselyngbyolides (1, 2) and the biselyngbyasides (3, 4)
represent a small family of structurally related macrolides
produced by the cyanobacterium Lyngbya sp. (Figure 1).1
These compounds demonstrated significant cytotoxic activity
against several cancer cell lines during initial biological assays.
In addition to its anticancer activity, biselyngbyaside (4) was
found to inhibit osteoclastogenesis in mouse monocytic
RAW264 cells and primary bone marrow-derived
macrophages.2 More recently, it was found that
biselyngbyaside (4), biselyngbyolide A (1), and biselyngbyolide
B (2) are potent inhibitors of sarco/endoplasmic reticulum
Ca2+-ATPase (SERCA) with a binding site distinct from other
known SERCA inhibitors.3 SERCA plays a key role in the stress
response mechanism of the cell and its inhibition leads to
induction of caspase activity and, ultimately, apoptotic cell
death.4
OH
OMe
O
OMe
24
R
R
Biselyngbyolide A (1), R = H
Biselyngbyaside B (3)
R = HHO
Biselyngbyolide B (2), R = H
Biselyngbyaside (4)
R = HHO
O
O
HO
MeO
HO
MeO
OH
OH
Figure 1. Structures of the biselyngbyaside family of natural
products.
Given the interesting biological activity associated with
these compounds, and a desire to further their study by the
construction of non-natural analogs, we began a project aimed
at developing a concise synthetic route to both biselyngbyolide
A and biselyngbyolide B (Figure 2). More specifically, we
envisioned both compounds could be constructed from a
common intermediate (5) that would contain appropriate
functionality for late-stage installation of the C5 hydroxyl
The synthetic community has demonstrated some interest
in these natural products. Maier5 and Chandrasekhar6 have
reported the synthesis of fragments related to
biselyngbyaside. More recently, Suenaga and Goswami have
reported total syntheses of biselyngbyolide A (1),7 B (2),8 and
biselyngbyaside (4).9 Extensive use of protecting groups and
numerous oxidation state changes make these synthetic
routes quite lengthy. This is especially true for the C1–C13
portion of these targets. Moreover, different routes were
required to access each of the respective C1–C13 fragments. In
other words, either the C5 hydroxyl group or C4–C5 double
bond is installed during each synthesis. Substantial
modifications to these routes would be required in order to
access the complementary target.
group
(i.e., C7
oxidation/migration of alkene/C5
oxygenation/C7 reduction). Disconnecting intermediate 5 at
the ester linkage and at the C12–C13 diene gives rise to
fragments 6 and 7, which became our immediate targets for
synthesis. Herein we report our synthesis of fragment 7.
The challenge posed by fragment 7 is one of stereocontrol.
In contrast to alcohol 6, which contains a single stereocenter,
fragment 7 contains three rather isolated stereocenters.
Consequently, establishing the correct relative stereochemical
relationships through substrate control would likely be
difficult. However, this same liability can be turned into a
strength by the judicious deployment of catalytic asymmetric
transformations. In this case, the remote nature of the
stereocenters in question will likely minimize any
matched/mismatched interactions during stereocenter
formation. Furthermore, the unsaturation present in fragment
7 offers several possibilities for coupling reactions.
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Me
With compound 11 in hand we then turned our attention
20
17
Me
to the formation of the C7 sterocenter. F
D
i
O
rs
I
t:
,
10
s
.
i
1
ly
0
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was
e
/
t
C
h
7
e
C
r
C
1
0
1
80
04
B
v
l
13
hydrolyzed to reveal primary alcohol 13 (Scheme 2). We
attempted to perform a silver-catalyzed allylation12 on the
aldehyde derived from alcohol 13, but poor conversion was
observed with these conditions. Failing this, alcohol 13 was
entered into an Ir-catalyzed, Krische allylation.13 Gratifyingly,
performing the reaction in the presence of (S)-Cl,MeO-BIPHEP
(15) and 3-nitrobenzoic acid provided desired homoallylic
alcohol 14 in 43% yield. Although the yield of 14 was only
moderate, a significant amount of aldehyde 16 was recovered.
Unfortunately, attempts at using aldehyde 16‡ as the starting
material for the Ir-catalyzed allylation were not successful.
O
O
1
2
9
Me
1
6
Me
OAc
OH
common intermediate
(5)
I
l
13
Me
20
Me
O
Ot-Bu
9
+
Me
1
v
14
17
6
2.5 mol% [Ir(COD)Cl]2
5 mol% 15
10 mol% 3-NO2BzOH
20 mol% Cs2CO3
allyl acetate
Me
OH
I
I
OAc
OH
6
7
AcOH
Me
Me
Figure 2. Our synthetic approach to biselyngbyolide A and B.
THF, H2O
82%
THF, 100ºC
14: 43%; 16: 53%
Me
Me
Our synthesis began with an asymmetric cyanomethylation
reaction, first reported by MacMillan and co-workers10
OTBS
OH
11
13
(Scheme 1). Their work employed a catalyst derived from
alanine and resulted in aldehydes with R-configuration. Based
on this, we determined that catalyst 12, prepared from
alanine would generate the correct (S)-configuration at the
C10 stereocenter. The reaction with propionaldehyde, not
reported in MacMillan’s work, proceeded smoothly, but the
low molecular weight of product 8 made its purification
difficult. Fortunately, 1H NMR analysis of the material obtained
L-
I
Cl
I
Me
D
-
MeO
MeO
PPh2
PPh2
Me
Me
Me
Cl
OHC
Me
OHC
Me
OH
(S)-Cl,MeO-BIPHEP (15)
14
16
17
after extractive workup revealed the crude product was Scheme 2.
remarkably clean (see ESI). The major contaminants were
The relative configuration of the stereocenters in 14 was
confirmed by comparing the 13C NMR chemical shifts in our
material to those reported by Maier5 (see ESI). Furthermore,
small amounts of ethyl acetate, DMSO, and 2,6-lutidine.
Consequently, this material was carried directly into a Horner-
Emmons olefination with the indicated phosphorane. Although
sluggish, this reaction furnished unstaturated ester 9 in 60%
yield over the two steps. HPLC analysis of ester 9 revealed an
enantiomeric ratio of 97:3.†
25
the specific rotation of our material ([α]D = +6.1 (c 0.4,
21
CHCl3)) was of the same sign as that reported by Maier ([α]D
= +7.56 (c 1.0, CHCl3)). We have not been able to obtain a good
measure of the enantiopurity of alcohol 14. But, based on the
Horeau principle,14,15,16 which allows the enantiopurity of a
substance to be improved through the formation of
diastereomers, high enantiopurity is expected. In our case, a
full analysis of this phenomenon is complicated by the large
amounts of aldehyde 16 produced during the allylation.
However, Krische and co-workers have found that the Horeau
principle can be applied to other Ir-catalyzed allylation
reactions.17
At this time, it is not clear why aldehyde 16 is such a poor
substrate for the Krische allylation. It is possible that the α-
methyl group facilitates dissociation of the aldehyde from the
catalyst and, once off the metal, prevents it from reentering
the catalytic cycle. It is also plausible that the C10 stereocenter
enforces a conformation of the alkyl chain that discourages
binding of the aldehyde to the catalyst. In an effort to probe
these effects, we attempted to use commercially available
aldehyde 17 as a substrate for the Krische allylation. All
attempts resulted in poor conversion to the desired
homoallylic alcohol; suggesting that the α-methyl group has a
detrimental influence on this reaction.
20 mol% 12•TfOH
1 mol% Ru(bpy)3Cl2
BrCH2CN
Me
EtO2C
Me
O
O
CN
CN
EtO2C
PPh3
H
H
H
2,6-lutidine, DMSO
blue LEDs
CH2Cl2
60% (2 steps)
97:3 er
Me
Me
Me
(S)-8
9
OTBS
OTBS
I
1. LiAlH4
THF, 0 ºC, 97%
1. DIBAL-H, THF
–78 ºC to rt, 72%
Me
Me
Me
CN
9
2. TBSCl, DMAP
imidazole
CH2Cl2, 80%
2. CrCl2, CHΙ3, THF
59%, 8:1 E/Z
H
H
Me
11
10
O
Me
N
Me
Me
Me
Me
N
H
12
Scheme 1.
Ester 9 was reduced with LiAlH4 to give a primary alcohol,
which was protected to give silly ether 10. The nitrile was then
elaborated to vinyl iodide 11. This was accomplished by
reduction to the aldehyde and chain extension by Takai
olefination.11
Finally, with alcohol 14 in hand, we were in a position to
complete the C1–C13 fragment. Based on success by others,18
we planned to forge the C4–C5 alkene by performing a cross
metathesis reaction between allylic acetate 18 and homoallylic
alcohol 14 (Scheme 3). To this end, known acetate (S)-18 was
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prepared by enzymatic resolution of the corresponding
alcohol.19 Treating alcohol 14 with two equivalents of acetate
18 and Hoveyda-Grubbs catalyst 19 led to the formation of
desired product 7 in moderate yield. Potential intramolecular
coordination of the homoallylic alcohol to the ruthenium
alkylidene may contribute to the moderate yield of this
transformation.20 The importance of such chelation has been
debated.21
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DOI: 10.1039/C7CC08004B
K. Suenaga, Chem. Lett. 2012, 41, 165. (c) M. Morita, O. Ohno, T.
Teruya, T. Yamori, T. Inuzuka, and K. Suenaga, Tetrahedron
2012, 68, 5984. (d) O. Ohno, A. Watanabe, M. Morita, and K.
Suenaga, Chem. Lett. 2014, 43, 287.
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Cha, K. Yagasaki, K. Suenaga, K. Nagai, and J.-T. Woo, J. Cell.
Biochem. 2012, 113, 440.
2
I
3
4
M. Morita, H. Ogawa, O. Ohno, T. Yamori, K. Suenaga, and C.
Toyoshima, FEBS Lett. 2015, 589, 1406.
(a) H. Liu, R. C. Bowes, 3rd, B. van de Water, C. Sillence, J. F.
Nagelkerke, and J. L. Stevens, J. Biol. Chem. 1997, 272, 21751.
(b) C. Caspersen, P. S. Pedersen, and M. Treiman, J. Biol. Chem.
2000, 275, 22363.
P. Sawant, and M. E. Maier, Synlett 2011, 3002.
S. Chandrasekhar, G. Rajesh, and T. Naresh, Tetrahedron Lett.
2013, 54, 252.
O
OAc
Me
5 mol% 19
+
t-BuO
CH2Cl2, 40 ºC
Me
(S)-18
(2 equiv)
42%
OH
14
I
5
6
N
N
Mes
Mes
O
Ot-Bu
Cl
Me
Ru
7
8
Y. Tanabe, E. Sato, N. Nakajima, A. Ohkubo, O. Ohno, and K.
Suenaga, Org. Lett. 2014, 16, 2858.
(a) E. Sato, Y. Tanabe, N. Nakajima, A. Ohkubo, and K. Suenaga,
Org. Lett. 2016, 18, 2047. (b) S. Das, D. Paul, and R. K. Goswami,
Org. Lett. 2016, 18, 1908.
Cl
Me
19
i-PrO
OAc
OH
7
Scheme 3.
9
E. Sato, M. Sato, Y. Tanabe, N. Nakajima, A. Ohkubo, and K.
Suenaga, J. Org. Chem. 2017, 82, 6770.
Conclusions
10 E. R. Welin, A. A. Warkentin, J. C. Conrad, and D. W. C.
MacMillan, Angew. Chem. Int. Ed. 2015, 54, 9668.
11 K. Takai, K. Nitta, and K. Utimoto, J. Am. Chem. Soc. 1986, 108,
7408.
12 A. Yanagisawa, H. Nakashima, A. Ishiba, and H. Yamamoto, J.
Am. Chem. Soc. 1996, 118, 4723.
13 I. S. Kim, M.-Y. Ngai, and M. J. Krische, J. Am. Chem. Soc. 2008,
130, 14891.
14 J. P. Vigneron, M. Dhaenens, and A. Horeau, Tetrahedron 1973,
29, 1055.
In conclusion, we have successfully synthesized the C1–C13
fragment (7) of biselyngbyolides A and B in only 9 steps from
propionaldehyde. Our route relies on catalyst control for the
formation of the C3, C7, and C10 stereocenters, as well as the
C4–C5 double bond. This reliance on catalytic transformations
has allowed us to greatly minimize the use of protecting
groups and reduce the number of oxidation state changes.
Efforts are underway to use fragment 7 for the construction of
non-natural analogs of the biselyngbyolides. This will be
reported in due course.
15 For a thorough discussion of the mathematical basis behind the
Horeau principle, see: V. Rautenstrauch, Bull. Chim. Soc. Fr.
1994, 131, 515.
16 Selected examples of the Horeau principle applied to complex
molecule synthesis. (a) S. M. Canham, B. D. Hafensteiner, A. D.
Lebsack, T. L. May-Dracka, S. Nam, B. A. Stearns, and L. E.
Overman, Tetrahedron 2015, 71, 6424. (b) X. Han, and P. E.
Floreancig, Angew. Chem. Int. Ed. 2014, 53, 11075. (c) M. Burns,
S. Essafi, J. R. Bame, S. P. Bull, M. P. Webster, S. Balieu, J. W.
Dale, C. P. Butts, J. N. Harvey, and V. K. Aggarwal, Nature 2014,
513, 183. (d) Z. (A.) Fang, G. J. Clarkson, and M. Wills,
Tetrahedron Lett. 2013, 54, 6834. (e) J. A. Enquist, Jr., and B. M.
Stoltz, Nature 2008, 453, 1228.
17 For other examples of the Horeau principle being applied to Ir-
catalyzed allylations, see: (a) Z. A. Kasun, X. Gao, R. M. Lipinski,
and M. J. Krische, J. Am. Chem. Soc. 2015, 137, 8900. (b) I. Shin,
and M. J. Krische, Org. Lett. 2015, 17, 4686. (c) S. W. Kim, W.
Lee, and M. J. Krische, Org. Lett. 2017, 19, 1252.
18 (a) A. Wohlrab, R. Lamer, and M. S. VanNieuwenhze, J. Am.
Chem. Soc. 2007, 129, 4175. (b) A. K. Ghosh, and S. Kulkarni, S.
Org. Lett. 2008, 10, 3907.
Acknowledgements
We thank Texas Tech University for financial support of this project
and Materia, Inc. for generous donation of olefin metathesis
catalysts. NMR data was collected using instruments supported by
the NSF CRIF Program (CHE-1048553). We thank Prof. Michael
Krische (UT Austin) and Prof. David MacMillan (Princeton) for
helpful discussions and suggestions.
Conflicts of interest
There are no conflicts to declare.
Notes and references
† The diastereomeric purity of catalyst 12 was critical for
achieving high enantioselectivity. When we used catalyst 12 with
a 7.3:1 dr, we obtained 9 with ~85:15 er.
‡ We were unable to assign the configuration of the recovered
aldehyde.
19 S. Vrielynck, M. Vandewalle, A. M. García, J. L. Mascareñas, and
A. Mouriño, Tetrahedron Lett. 1995, 36, 9023.
20 For example: P. E. Standen and M. C. Kimber, Tetrahedron Lett.
2013, 54, 4098–4101.
1
(a) T. Teruya, H. Sasaki, K. Kitamura, T. Nakayama, and K.
21 M. Lautens and M. L. Maddess, Org. Lett. 2004, 6, 1883.
Suenaga, Org. Lett. 2009, 11, 2421. (b) M. Morita, O. Ohno, and
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