Synthesis of C1–C11 eribulin fragment and its diastereomeric analogues

Article abstract of DOI:10.1016/j.tetlet.2019.07.006

A practical stereoselective synthesis of the central C1–C10 fragment of eribulin and its two diastereomeric analogues is developed. Our approach relied on the use of L-ascorbic acid as the starting material which allowed accessing a key intermediate with a syn diol moiety (C9 and C10 of eribulin) and a carboxylic ester group. A functionalized six membered lactone having several required hydroxyl groups was then obtained. In a number of steps, the lactone was converted to an intermediate for our key oxa-Michael reaction. A regio- and stereocontrolled intramolecular oxa-Michael reaction completed the synthesis of the C1–11 fragment having a trans-fused tetrahydropyrans with the exact stereochemistry of various hydroxyl groups, as in eribulin.

Full text of DOI:10.1016/j.tetlet.2019.07.006

Accepted Manuscript
Synthesis of C1-C11 Eribulin Fragment and its Diastereomeric Analogues
Mahender Khatravath, Naveen Kumar Mallurwar, Saidulu Konda, Jagan
Gaddam, Pallavi Rao, Javed Iqbal, Prabhat Arya
PII:
S0040-4039(19)30652-5
https://doi.org/10.1016/j.tetlet.2019.07.006
TETL 50915
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 April 2019
1 July 2019
4 July 2019
Please cite this article as: Khatravath, M., Kumar Mallurwar, N., Konda, S., Gaddam, J., Rao, P., Iqbal, J., Arya,
P., Synthesis of C1-C11 Eribulin Fragment and its Diastereomeric Analogues, Tetrahedron Letters (2019), doi:
https://doi.org/10.1016/j.tetlet.2019.07.006
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
Leave this area blank for abstract info.
Synthesis of C1-C11 Eribulin Fragment and its Diastereomeric Analogues
c
Mahender Khatravath,*a,b Naveen Kumar Mallurwar a,b, Saidulu Konda,a,d Pallavi Rao Javed Iqbal and
Prabhat Aryaa,b,c
2
MeO
1
1
3
3
3
31
HO
4
MeO2C
MeO2C
OP1
MeO2C
OP1
5
6
H
O
H
O
H
O
H
O
6
6
6
O
O
H
HO
7
O
H
O
H
O
H
7
7
7
O
35
H
27
10
8
8
10
8
10
8
10
9
OP1
9
O
OP2
OP2
OP2
O
O
Eribulin
B
C
A
O
OP2
OP2
OP2
14
Precise stereochemistry
Diastereomeric eribulin fragments
O

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Synthesis of C1-C11 Eribulin Fragment and its Diastereomeric Analogues
a,c
Mahender Khatravath,a,c,* Naveen Kumar Mallurwar,a,c Saidulu Konda,c,d Jagan Gaddam, Pallavi Rao,c
Javed Iqbalc and Prabhat Aryaa,b,c
a.
Transcell Oncologics, Technology Business Incubator (TBI), University of Hyderabad, Hyderabad, Telangana, 500046, India Transcell Oncologics,
Technology Business Incubator (TBI), University of Hyderabad, Hyderabad, Telangana, 500046, India, Mahender@trans-cell.com
b.SignMod, Science and Technology Park, Pune University, Ganeshkhind Road, Pune, Maharashtra, 411007, India
c. Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, Telangana, 500046, India
d. GVKBiosciences, JP Nagar, Bengaluru, Karnataka 560078, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A practical stereoselective synthesis of the central C1-C10 fragment of eribulin and its two
diastereomeric analogs is developed. Our approach relied on the use of L-ascorbic acid as the
starting material which allowed accessing a key intermediate with a syn diol moiety (C9 and
C10 of eribulin) and a carboxylic ester group. A functionalized six membered lactone having
several required hydroxyl groups was then obtained. In a number of steps, the lactone was
converted to an intermediate for our key oxa-Michael reaction. A regio- and stereocontrolled
intramolecular oxa-Michael reaction completed the synthesis of the C1-11 fragment having a
trans-fused tetrahydropyrans with the exact stereochemistry of various hydroxyl groups, as in
eribulin.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Halichondrin
Eribulin
Macrocycles
Oxy-Micheal addition
led to producing 6 which was converted to scaffold, 7 by an
intramolecular oxa-Michael reaction.36 Further, chemical
transformations completed the total synthesis of the central
fragment, 8. Shown in Scheme 3 are our three targets that
are based on the central C1-C11 fragment of eribulin. The
bicyclic compound 9 has the precise stereochemistry of
several functional groups as in eribulin. For example, it has
a similar trans-fused pyran moiety, two secondary hydroxyl
groups at C9 and C11, one primary hydroxyl group at C11
and a chiral side chain with the carboxyl ester moiety at C3.
The second target (10) has an epimeric hydroxyl group at C8
and the rest is the same as in 9. Compound 11 as the third
target has a cis-fused pyran moiety, the reversal of the
stereochemistry of hydroxyl group at C8 and the chiral side
chain at C3 compared to 9. Our first objective was to
develop a practical and scalable stereoselective synthesis of
all the three compounds, i.e. 9, 10 and 11, and preferably, to
use a cheap chiral starting material to make it scalable and
attractive. In continuation of our ongoing efforts to building
Eribulin (1) is a non-taxane drug and first-in-class
microtubule dynamics inhibitor which was approved by
FDA in 2010 for use in patients who previously received at
least two prior chemotherapeutic regiments for the
metastatic breast cancer.1-5 The birth of eribulin originated
from the Kishi group while working on the total synthesis of
halichondrin and its various analogues to search for a better
microtubule binding agent.6-18 Eribulin seems to have a
different binding site compared to other known classes of
tubulin-targeted agents such as taxane (paclitaxel and
docetaxel), vinca alkaloids (vinorelbine and vinblastine),
and epothilones (ixabepilone).19,20 Eribulin binds to an inter-
dimer interface or β-tubulin subunit alone and inhibits the
microtubular growth phase of microtubular dynamics
instability in interphase cells without affecting on the
shortening of microtubule.19,20 It is also known to promote
the centromere spindle relaxation without affecting the rate
of stretching.5 Shown in Scheme 1 is a key central fragment
having trans-fused pyrans and densely populated functional
groups, 2.17 Over the years, Kishi8 and others21-23 have
reported several approaches to the total synthesis of this key
central fragment. One of the plans of the Kishi's synthesis is
shown in Scheme 2. In their approach, L-mannonic lactone,
3 was converted to 4 in three steps and this produced the six
membered derivative 5 easily. C-Alkylation strategy then
a
macrocyclic compound collection having the key
fragments of bioactive natural products and related
compounds,24-26 we plan evaluating them in several
challenging biological targets related to protein-protein
interactions27,28 and pathways in cytoskeleton-based
targets.29-33

2
Allylation
MeO
1
Kishi's one of the key fragments
31
HO
O
3
H
O
6
MeO2C
H
3
O
O
H
HO
HO
7
H
O
6
6
O
7
O
O
H
H
35
7
H
6
O
COOEt
27
10
O
8
8
10
Michael
9
O
O
H
7
OP1
9
10
9
O
10
O
8
10
P2O
OP1
HO
9
O
O
8
OH
P2O
OP1
O
OP2
P1O
12
13
9
OP2
14
1
Eribulin,
2
O
OP1
OH
13
H
O
I
10
O
9
14
L-Ascorbic acid,
HO
OH
Scheme 1. Eribulin (1) and a central key fragment having trans-
fused pyrans with several other functional groups, 2.
Scheme 4. Our synthetic planning for 9.
Kishi's approach to the central fragment:
OAc
i. Acetone, CuSO4, rt, 24 h
OMe
OH
OH
i. Ag2O, BnBr, Toluene
H
ii. 30% H2O2, K2CO3, H2O
O
HO
O
O
O
10
2 steps
rt, 2 h, 90%
3 steps
6
7
O
rt, 24 h
O
3 steps
10
OH
14
9
8
O
9
8
8
CHO
OEt
9
O
O
O
9
O
9
10
10
ii. LAH, THF, 12 h, rt, 90%
iii. (COCl)2, Et3N, DMSO
DCM, -78oC, 1 h
10
HO
iii. EtI, CH3CN, 70 oC, 24 h
80% 3 steps
HO
O
OH
OH
OBn
O
15
16
OH
O
4
5
L- Mannonic lactone, 3
PhO
O
O
P
i. LiOH, THF-MeOH
rt, 1 h
18
HO
Z:E, 7:3
OsO4,
Acetone-H2O
O
PhO
MeO2C
MeO2C
3
O
O
3
O
10
3
H
H
O
H
9
O
10
6
7
6
7
6
O
O
H
O
7
9
2 steps
DBU, NaI, THF, -78 o
2 h, 69% 2 steps
C
6 steps
ii. TFA-H2O (9:1), 0 oC-rt
7 h, 72% 2 steps
NMO, rt, 2 h, 82%
O
O
10
OBn CO2Et
17a
H
O
H
8
10
8
8
9
10
OBn OH
O
OTBS
9
O
9
OH
OH
+ E-isomer, 17b
TBSO
O
H
H
H
O
O
TBSO
O
O
O
7
6
8
I
HO
AcO
HO
HO
21
O
O
7
O
7
Ac2O, DMAP, Py
rt, 16 h, 48%
8
10
10
8
9
9
HO
AcO
Scheme 2. Kishi's approach to the synthesis of the central fragment.
Our plan to obtain 9 (Scheme 4) starts with L-ascorbic acid (14)
OBn OH
OBn OAc
OBn OH
20
19
34
which is a cheap source to produce 13 in large amounts. This
Scheme 5. Synthesis of a diastereomeric lactone, 20 from L-
ascorbic acid, 14.
can then lead to producing the lactone (12) needed for our next
key steps. Following the literature procedure,34 L-ascorbic acid
(14) gave 16 (Scheme 5) via 15. It was then subjected to Wittig
olefination to obtain the cis-product (17a) as the major isomer
which led to producing a lactone 1835 easily. When subjected to
cis hydroxylation conditions (OsO4), it gave 19 which was fully
characterized following acetylation (20). The details of the
stereochemical assignments are provided in the supporting
material. Failing to reach compound 21 by this approach, we
then developed an alternate path which is shown in Scheme 6.
For obtaining an easy to access to both compounds 21 and 19, we
then tried Sharpless facial selective dihydroxylation on 17a and
this approach produced 22 and 23 (Scheme 6) as two separable
diastereomers in a 7:3 ratio (note: the stereochemistry was
assigned after cyclization). Upon subjection to acidic conditions,
22 produced 21 and 23 gave 19 respectively in high yields
(Scheme 6).
Both of them were thoroughly assigned by 1D and 2D NMR and
MS. Compound 21 was simply transformed to 24. As shown in
Scheme 7, 24 was then converted to 26 in an easy transformation.
In two steps that utilized the Lewis acid catalyzed C-allylation37
at C-6 and further cross metathesis produced 28, a key precursor
to try an intramolecular oxa-Michael reaction. When 28 was
subjected to deacetylation under basic conditions in methanol, it
produced the triol derivative with the trans-esterified product.
This material on exposure to DBU in refluxing toluene gave the
expected Michael product (29, scheme 7) as the
thermodynamically stable isomer (via double bond isomerisation)
having the trans-fused pyran moiety. This product was
thoroughly assigned by 2D NMR (see Scheme 8).
K3(FeCN)6, OsO4
K2CO3
OH
O
O
OH
O
O
17a
(DHQ2)PHAL, tBuOH
H2O, 0 oC, 36 h, 70%
9
+
O
O
10
O
O
3
3
3
OBn OH
OBn OH
MeO2C
MeO2C
MeO2C
7:3, separable
(based on recovery starting material)
H
O
H
O
H
O
22
23
6
6
6
O
H
O
H
O
H
7
7
7
OH
OH
8
10
8
10
8
10
O
O
OP1
OP1
OP1
O
OH
TFA, H2O
ACN, 70 o
OP2
OP2
OP2
TBSO
H8
HO
C
TBSCl, Im
BnO
6
9
O
O
10
7
7
8
OP2
OP2
OP2
22
O
8
10
OTBS
OH
9
H10 H7
H9
1 h, 70%
DMAP, DMF
55 0C, 70%
TBSO
HO
21
Diastereomeric
11
eribulin fragment,
Diastereomeric
eribulin fragment,
Same as
eribulin fragment,
10
9
OBn
OBn
nOe
24
OH
H7
O
O
O
H8
TFA, H2O
O
Scheme 3. Eribulin central fragment-based three targets and
ACN, 70 o
C
TBSO
TBSO
HO
HO
TBSCl, Im
6
9
O
10
HO
BnO
7
8
7
23
derived macrocyclic compounds.
10
8
OTBS
OH
9
O
1 h, 70%
DMAP, DMF
55 0C, 70%
H10 OH
H9
OBn
OBn
25
19
Scheme 6. Synthesis of the required lactones, 24 and 25.

3
i) DIBAL-H, toluene
-78 oC, 1 h
subjected to C-allylation conditions which gave 37, and
OAc
finally, the cross metathesis led to producing the desired key
starting material, 38 to try our Michael approach. As with two
previous examples, this also produced the expected Michael
product, 39 as a single diastereomer that resulted from the regio-
and stereoselective reaction. As we have done before, 41 (Scheme
12) was thoroughly subjected to nOe studies for the stereochemical
assignment.
AcO
ii) TBAF, THF, rt, 12 h
6
O
7
8
24
10
OAc
9
iii) Ac2O, NaOAc, 90 o
44% 3 steps
C
AcO
OBn
26
13:1 dr
CO2Bn
BF3 OEt2, ACN, 80 o
C
.
AcO
6
O
OAc
Allyltrimethylsilane
12 h, 45%
AcO
27
5 mol% G-II cat. DCM
40 oC, 16 h, 70%
nOe
OBn
OH
3
Ha
H
6
MeO2C
H
10
4
H
O
6
Hb
MeOOC
O
H
H
O
7
BnO2C
34
O
OBn
i) K2CO3, MeOH
16 h, rt, 77%
MeO2C
3
8
3
9
H
O
8
10
7
AcO
AcO
OH
OH
9
6
O
6
O
H
H
H
HO
7
28
29
H
OAc
10
OBn
8
ii) DBU,Toluene
OH
9
HO
100 oC, 18 h, 80%
OBn
Scheme 10. Assignment of 34 by nOe.
OBn
i) DIBAL-H, DCM
-78 oC, 1 h, 70%
ii) OsO4, Acetone
Scheme 7. Synthesis of eribulin central fragment.
13:1 dr
O
OH
6
H2O (1 :1 )
NMO, 0 oC, 2 h, 85%
i) Ac2O, NaOAc
90 oC, 85%
AcO
AcO
HO
HO
6
O
O
O
7
8
7
8
10
10
nOe
OAc
OTBS
OH
9
9
ii) BF3.OEt2, ACN, 80 o
Allyltrimethylsilane
12 h, 55%
C
iii) TBAF, THF, rt
12, h, 80%
OH
Ha
4
H
6
OBn
OBn
35
OBn
MeO2C
HO
10
36
37
H
O
6
Hb
MeOOC
O
H
H
O
7
29
O
OBn
8
BnO2C
3
9
i) K2CO3, MeOH
16 h, rt, 70%
8
10
7
CO2Bn
MeO2C
H
3
OH
9
H
AcO
AcO
6
H
H
H
O
H
HO
6
9
7
O
10
7
8
O
OAc
10
5 mol% G-II cat. DCM
40 oC, 16 h, 70%
8
9
ii) DBU,Toluene
100 oC, 18 h, 70%
OH
OBn
HO
OBn
38
39
OBn
Scheme 8. Assignment of 29 by nOe.
Scheme 11. Synthesis of 39 having 1,2-cis fused pyrans and
isomeric functional groups at C-8 and C-3.
In another study for developing the synthesis of 34 (Scheme 9)
having an epimeric group at C8, the trans isomer of the Wittig
product, 17b was used as the starting material. The Sharpless
selective dihydroxylation on 17b produced (α-face attack) diol in
85:15 (α:β) diastereomeric ratio. This led to producing the
lactone 30 in two steps having a 1,2-trans relationship between
two hydroxyl groups at C7 and C8. This upon subjection to
DIBAL-H reduction followed by the stereoselective alkylation
led the synthesis of the required intermediate, 32 via compound
31. When subjected to similar conditions, as in the previous
example, compound 32 produced 33, a key material to try our
key intramolecular oxa-Michael reaction.
MeO2C
MeO2C
H
6
H
O
O
7
O
TBSCl, Py
Ac2O, Py, rt
12 h, 90%
O
10
39
H
H
9
DCM, DMAP, 60%
HO
AcO
40
OBn OTBS
41
OBn OTBS
OTBS
H
H
10
9
6
MeO2C
3
H
H
H
O
6
O
OBn
7
nOe
H
8
41
O
10
7
H
OAc
8
OTBS
9
H
O
AcO
3
OBn
COOMe
i) K3(FeCN)6, OsO4, K2CO3
O
Scheme 12. Assignment of 41.
(DHQ2)PHAL, tBuOH, H2O
i) DIBAL-H, toluene
0 oC, 36 h, dr= 85:15(:)
TBSO
-78 oC, 1 h, 70%
O
O
To summarize, a simple and practical synthesis to obtain eribulin
central C1-C11 fragment and its two diastereomeric analogues is
developed. The key steps involved in the synthesis are lewis acid
catalyzed C-glycoside allylation; crass metathesis; alkene
isomerisation and intra molecular oxa-Michael additions. The
key scaffolds (9, 10, 11 Scheme 3) were further utilized in
obtaining a diverse set of 17-membered macrocyclic compounds.
The biological evaluation of all the compounds generated from
this program is ongoing and these studies will be published in a
due course.
7
CO2Et
8
O
OTBS
ii) TFA, H2O, ACN, 70 oC, 2 h
iii) TBSCl, Im, DMAP, DMF
55 oC ,18 h, 44% 3 steps
ii) TBAF, THF, rt, 2 h
iii) Ac2O, NaOAc, 90 oC, 8 h
60%
TBSO
OBn
17b
OBn
30
10:1 dr
OAc
AcO
AcO
AcO
AcO
CO2Bn
BF3 OEt2, ACN, 80 oC
.
6
9
O
O
7
8
10
OAc
OAc
Allyltrimethylsilane
5 mol% G-II cat. DCM
40 oC, 16 h, 70%
OBn
MeO2C
34
OBn
12 h, 45%
31
32
BnO2C
i) K2CO3, MeOH
3
AcO
AcO
H
16 h, rt, 70%
6
6
O
O
O
7
Conflicts of interest
There are no conflicts to declare.
OAc
9
H
ii) DBU,Toluene
8
OH
9
100 oC, 18 h, 60%
33
HO
OBn
OBn
Scheme 9. Synthesis of 34 having 1,2-trans fused pyrans and an
epimeric hydroxyl group at C-8.
Acknowledgment
We thank DST India, DBT India and DRILS for the financial
support. NKM, MK and SK thank CSIR and UGC India for the
award of a Senior Research Fellowship. DRILS analytical
facility is thanked for providing excellent technical support to
this program.
This upon basic conditions gave the expected Michael product
34 in high yields. Once again, as before, the product was well-
characterized by MS, 1D and 2D NMR studies and the key nOe
sites are shown in Scheme 10. Our synthesis for the third target
39 having 1,2-cis fused pyran moiety is shown in Scheme 11.
35, a lactone derivative was obtained from 18 easily, and this
produced 36 in a simple 3 step transformation. This was then
Supplementary data

4
(27)
1001.
(28)
Wells, J. A.; McClendon, C. L. Nature 2007, 450,
Supplementary data (Detailed experimental procedures,
characterization data and copies of NMR spectra for all the new
compounds are provided.) associated with this article can be
found, in the online version, at
Aeluri, M.; Chamakuri, S.; Dasari, B.; Guduru, S. K.;
Jimmidi, R.; Jogula, S.; Arya, P. Chem. Rev. 2014, 114,
4640.
(29)
(30)
Schmidt, A.; Hall, M. N. Annu. Rev. Cell Dev. Biol. 1998,
14, 305.
Yeung, K. S.; Paterson, I. Angew. Chem. Int. Ed. 2002, 41,
4632.
Fenteany, G.; Zhu, S. Curr. Top. Med. Chem. 2003, 3, 593.
Gourlay, C. W.; Ayscough, K. R. Nat. Rev. Mol. Cell
Biol.2005, 6, 583.
Altmann, K.-H. Bioorg. Med. Chem. 2014, 22,
5038.
Ermolenko, L.; Sasaki, N. A. J. Org. Chem. 2006, 71, 693.
a) Lorenz, K.; Lichtenthaler, F. W. Tetrahedron Lett.
1987, 28, 6437. (b) Valverde, S.; Herradon, B.;
Martin-Lomas, M. Tetrahedron Lett. 1985, 26, 3731.
a) Hu, J.; Bian, M.; Ding, H. Tetrahedron Lett. 2016,
57, 5519. (b) Nasir, N. M.; Ermanis, K.; Clarke, P.
A. Org. Biomol. Chem. 2014, 12, 3323. (c) Fuwa, H.
Heterocycles 2012, 85, 1255. (d) Nising, C. F.;
Bräse, S. Chem. Soc. Rev. 2008, 37, 1218
Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem.
Soc. 1982, 104, 4976.
References and notes
(1)
(2)
(3)
(4)
Newman, S. Curr. Opin. Investig. Drugs, 2007, 8, 1057.
Jimeno, A. Clin. Cancer Res. 2009, 15, 3903.
Morris, P. G. Anticancer Drugs. 2010, 21, 885.
El Saghir, N. S.; Tfayli, A.; Hatoum, H. A.; Nachef, Z.;
Dinh, P.; Awada, A. Crit. Rev. Oncol. Hematol. 2011, 80,
433.
(31)
(32)
(33)
(5)
(6)
(7)
(8)
(9)
Menis, J.; Twelves, C. Breast Cancer (Dove Med Press)
2011, 3, 101.
Yan, W.; Li, Z.; Kishi, Y. J. Am. Chem. Soc. 2015, 137,
6219.
Li, J.; Yan, W.; Kishi, Y. J. Am. Chem. Soc. 2015, 137,
6226.
Aicher, T. D.; Kishi, Y. Tetrahedron Lett. 1987, 28,
3463.
Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.;
Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.;
Spero, D.M.; Yoon, S. K. J. Am. Chem. Soc. 1992, 114,
3162.
(34)
(35)
(36)
(37)
(10)
(11)
Fang, F. G.; Forsyth, C. J.; Kishi, Y.; Scola,
Yoon, S. K.; US5436238A, 1995 .
Choi, H.-w.; Demeke, D.; Kang, F.-A.; Kishi, Y.;
Nakajima, K.; Nowak, P.; Wan, Z.-K.; Xie, C. Pure Appl.
Chem. 2003, 75, 1.
P.
M.;
(12)
(13)
Seletsky, B. M.; Wang, Y.; Hawkins, L. D.; Palme, M. H.;
Habgood, G. J.; DiPietro, L. V.; Towle, M. J.; Salvato, K.
A.; Wels, B. F.; Aalfs, K. K.; Kishi, Y.; Littlefield, B. A.;
Yu, M. J. Bioorg. Med. Chem. Lett. 2004, 14, 5547.
Zheng, W.; Seletsky, B. M.; Palme, M. H.; Lydon, P. J.;
Singer, L. A.; Chase, C. E.; Lemelin, C. A.; Shen, Y.;
Davis, H.; Tremblay, L.; Towle, M. J.; Salvato, K. A.;
Wels, B. F.; Aalfs, K. K.; Kishi, Y.; Littlefield, B. A.;
Yu, M. J. Bioorg. Med. Chem. Lett. 2004, 14, 5551.
Dong, C. G.; Henderson, J. A.; Kaburagi, Y.; Sasaki, T.;
Kim, D. S.; Kim, J. T.; Urabe, D.; Guo, H.; Kishi, Y. J.
Am. Chem. Soc. 2009, 131, 15642.
(14)
(15)
(16)
(17)
(18)
Yang, Y. R.; Kim, D. S.; Kishi, Y. Org. Lett. 2009, 11,
4516.
Yamamoto, A.; Ueda, A.; Brémond, P.; Tiseni, P. S.;
Kishi, Y. J. Am. Chem. Soc. 2012, 134, 893.
Yu, M. J.; Zheng, W.; Seletsky, B. M. Nat. Prod. Rep.
2013, 30, 1158.
a) Ueda, A.; Yamamoto, A.; Kato, D.; Kishi, Y. J. Am.
Chem. Soc. 2014, 136, 5171. (b) Časar, Z. Synthesis of
heterocycles in contemporary medicinal chemistry;
Springer, 2016, pp. 209-270.
(19)
(20)
Smith, J. A.; Wilson, L.; Azarenko, O.; Zhu, X.; Lewis, B.
M.; Littlefield, B. A.; Jordan, M. A. Biochemistry. 2010,
49, 1331.
Bai, R.; Nguyen, T. L.; Burnett, J. C.; Atasoylu, O.;
Munro, M. H.; Pettit, G. R.; Smith, A. B., 3rd; Gussio, R.;
Hamel, E. J. Chem. Inf. Model. 2011, 51, 1393.
Burke, S. D.; Jung, K. W.; Lambert, W. T.; Phillips, J. R.;
Klovning, J. J. J. Org. Chem. 2000, 65, 4070.
Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips,
A. J. Angew. Chem. Int. Ed. 2009, 48, 2346.
Jackson, K. L.; Henderson, J. A.; Phillips, A. J. Chem. Rev.
2009, 109, 3044.
Jimmidi, R.; Guduru, S. K. R.; Arya, P. Org. Lett. 2015,
17, 468.
Guduru, S. K. R.; Jimmidi, R.; Deora, G. S.; Arya, P. Org.
Lett. 2015, 17, 480.
Aeluri, M.; Dasari, B.; Arya, P. Org. Lett. 2015, 17, 472.
(21)
(22)
(23)
(24)
(25)
(26)

5
Graphical Abstract
 Synthesized precise C1-C11 eribulin
fragment from L-ascorbic acid.
 Synthesized two diastereomeric analogs of
precise eribulin fragment.
 Dihydroxylation;
C-allylation;
crass
Leave this area blank for abstract info.
Synthesis of C1-C11 Eribulin Fragment and its Analogs for Building A Diverse Set of
Macrocycles
c
Mahender Khatravath,*a,b Naveen Kumar Mallurwar a,b, Saidulu Konda,a,d Pallavi Rao Javed Iqbal and
Prabhat Aryaa,b,c
2
MeO
1
1
3
3
3
31
HO
4
MeO2C
MeO2C
OP1
MeO2C
OP1
5
6
H
O
H
O
H
O
H
O
6
6
6
O
O
H
HO
7
O
H
O
H
O
H
7
7
7
O
35
H
27
10
8
8
10
8
10
8
10
9
OP1
9
O
OP2
OP2
OP2
O
O
Eribulin
B
C
A
O
OP2
OP2
OP2
14
Precise stereochemistry
Diastereomeric eribulin fragments
O
OH
H
OH
10
6
H
6
H
O
OH
O
10
8
9
O
7
9
7
O
OH
O
O
8
3
O
B
C
H
O
O
O
H
3
H
HN
R1
O
N
O
O
O
O
O
R1
metathesis and oxa-Michael are key
reactions.
 All the synthesized compounds are fully
characterized by 1D and 2D NMR
techniques.
Should you require further information related
to this manuscript, please do let us know.
Following points are the justification for
publication in this journal.
With my best wishes,

6
Tetrahedron
Mahender Khatravath, PhD
Transcell Oncologics
Technology Business Incubator (TBI)
University of Hyderabad Campus
Hyderabad, Telangana, 500046, India