Total synthesis of distaminolyne A

Article abstract of DOI:10.1016/j.tetlet.2017.02.029

Herein we report the stereoselective total synthesis of first occurrence distaminolyne A via aminolytic kinetic resolution, Corey-Fuch's reaction for alkyne formation and Cardiot-Chodkiewicz cross coupling followed by Wittig olefination as the key steps.

Full text of DOI:10.1016/j.tetlet.2017.02.029

Accepted Manuscript
Total Synthesis of Distaminolyne A
Mohan Dumpala, Theegala Srinivas, Palakodety Radha Krishna
PII:
S0040-4039(17)30205-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.029
TETL 48640
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 December 2016
9 February 2017
9 February 2017
Please cite this article as: Dumpala, M., Srinivas, T., Radha Krishna, P., Total Synthesis of Distaminolyne A,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.029
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
Total Synthesis of Distaminolyne A
Leave this area blank for abstract info.
Mohan Dumpala, Theegala Srinivas and Palakodety Radha Krishna∗

1
Contents lists available at Science Direct
Tetrahedron Letters
journal homepage: www.elsevier.com
Total Synthesis of Distaminolyne A
Mohan Dumpala, Theegala Srinivas and Palakodety Radha Krishna∗
D-211, Discovery Laboratory, Organic & Biomolecular Chemistry Division
CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein we report the stereoselective total synthesis of first occurance
distaminolyne A via aminolytic kinetic resolution, Corey-Fuch’s reaction for
alkyne formation and Cardiot-Chodkiewicz cross coupling followed by Wittig
olefination as the key steps.
Available online
Keywords:
Polyacetylenic,
Amino alcohol,
Aminolytic kinetic resolution,
Corey-Fuch’s reaction,
Cardiot-Chodkiewicz C-C coupling.
———
∗Corresponding author. Tel.: +91-40-27193518; fax: +91-40-27160387; e-mail: prkgenius@iict.res.in

2
Introduction
Most of the polyacetylenic compounds are widely spread
Accordingly, our synthetic strategy to access
bromoalkyne derivative 3 (Scheme 2) begun with the
inexpensive 4-pentyn-1-ol (7) as the starting material. Thus,
the primary alcohol8 of 7 was protected as its PMB ether under
PMB-OH/amberlyst-15 conditions to form 8 (90%) and next
the terminal triple bond was converted into its bromoalkyne 3
using N-bromosuccinimide (NBS) and catalytic amount of
silver nitrate in 80% yield.9
in Nature in the form of fatty acids and alcohols, and is
sequestered within a wide range of organisms including plants,
fungi and algae.1 Many of these acetylene derivatives
exhibited various biological activities such as anti-cancer on
binding with DNA (Eg. enediynes), anti-trypanosomal drugs
and anti microbial.2 Distaminolyne A3 (1) (Figure 1) is a first
occurrence diacetylene 1-amino 2- alcohol isolated from the
New Zealand ascidian Pseudodistoma opacum showed a
modest anti-microbial activity toward Escherichia coli,
Staphylococcus aureus and Mycobacterim tuberculosis.
Determination of the absolute configuration i.e. ‘S’ at the lone
stereogenic carbon atom was confirmed by negative Cotton
effect on CD spectra.3 Following our interest in the total
synthesis of natural products containing long chain acetylenic
fatty acid molecules,4 we embarked on the synthesis of
distaminolyne A (1) which possesses structurally impressive
polar long chain amino alcohol carbon framework.
(a)
(b)
HO
PMBO
PMBO
Br
8
3
7
Reagents and conditions: a) PMB-OH, Amberlyst-15, CH2Cl2, reflux, 12 h, 90%; b)
N-Bromosuccinimide (NBS), AgNO3, acetone, 0 oC, 2 h, 80%.
Scheme 2:
3
Synthesis ofcompound
The synthesis of another Cardiot-Chodkiewicz coupling
precursor 4 (Scheme 3) began with the readily available 9-
dacene-1-ol (9) which was protected as PMB ether 10 under
known procedure.8 Later on epoxidation of terminal olefin 10
by treating with meta-chloroperoxybenzoic acid (m-CPBA)
afforded a racemic epoxide 6 in 76% yield.10 Herein we
invoked the asymmetric aminolytic kinetic resolution (AKR)
of racemic terminal epoxides using carbamates as nucleophiles
to generate optically pure 1,2-amino alcohol moiety under the
(Salen)CoIII catalytic conditions developed by Bartoli and co-
workers.6 Thus, compound 6 on AKR using complex (R,R)-
salen-CoII, 4-nitro benzoic acid, tert-butylcarbamate, BuOMe
t
to afford N-Boc protected 1,2-amino alcohol 11 in quantitative
yield 32% in highly enantiopurity (>97% ee, Vide infra Ref.
12), which was determined by chiral HPLC of
enantiomerically pure isomer 11 [by ChiralPak AD-H
250X4.6 mm 5u, 10% i-PrOH-hexane (flow rate: 0.75
mL/min), 225 nm, tR = 13.033 min (1.213%), 14.197 min
(98.787%)]. The absolute stereochemistry of the ‘OH’ bearing
stereogenic carbon was assumed to be ‘S’ based on literature
procedure,6 which was confirmed at a later stage. Next O, N-
protection of 11 as its acetonide using 2,2-dimethoxy propane
in presence of 10-camphorsulfonic acid gave the compound 12
in 73% yield.11
Retrosynthetic analysis
The retrosynthetic analysis of distaminolyne A (1)
(Scheme 1) was mainly conceived by a Cardiot-Chodkiewicz
cross-coupling between terminal alkyne 4 and bromoalkyne 3
to build a crucial acetylenic amino alcohol 2.5 Initially the
formation of precursor 4 with a required configuration was
conceived via aminolytic kinetic resolution6 of racemic
epoxide 6, Next the deprotection of p-methoxy benzyl (PMB)
alcohol ether in 6 would form a primary alcohol 5 which could
be converted into terminal alkyne 4 by Corey-Fuch’s
reaction7 in two consecutive steps. Respectively another
precursor could be obtained by 4-pentyn-1-ol (7), which on
PMB ether protection followed by bromination could yield
bromo alkyne derivative 3. Finally the deprotection of PMB
ether of diacetylenic amino alcohol 2 and the oxidation of the
ensuing alcohol to aldehyde, followed by one carbon Wittig
reaction would furnish the natural product 1.
OH
O
(b)
(c)
NHBoc
(a)
PMBO
HO
PMBO
PMBO
7
7
7
7
6
11
O
7
9
10
O
O
NBoc
(f )
NBoc
NBoc
(e)
(d)
Br
HO
PMBO
7
7
Br
13
12
5
O
PMBO
(g)
OH
NBoc
O
NH2
NBoc
7
7
7
2
4
1
Reagents and conditions: a) para-Methoxy benzyl alcohol (PMB-OH), Amberlyst-15, CH2Cl2,
reflux, 12 h, 87%; b) meta-Chloroperoxybenzoic acid (m-CPBA), CHCl3, 0 oC, 3 h, 76%; c)
(R,R)-salen-CoII, 4-nitro benzoic acid, tert-butylcarbamate, tBuOMe, rt, 24 h, 32%; d) 2,2-
DMP, acetone, 10-CSA, rt 3 h, 73%; e) 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ),
CH2Cl2:H2O (19:1), 0 oC to rt, 1 h, 89%; f ) (i) Des-Martin periodinane (DMP), dry CH2Cl2, 0
oC, 1 h; (ii) CBr4, Triphenyl phosphine (TPP), dry CH2Cl2, TEA, -10 oC, 3 h, 86% (over two
steps); g) n-BuLi, dry THF, -78 oC, 1 h, 90%.
O
O
O
PMBO
NBoc
+
NBoc
HO
PMBO
Br
7
7
7
5
3
4
6
Scheme 1: Retrosynthesis of distaminolyne A
Scheme 3: Synthesis of fragment 4
Next deprotection of p-anisyl group (PMB) in 12 under
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) conditions
Results and Discussion

3
led to the primary alcohol 5 (89%). Further the alcohol 5 was rotation values between the synthetic 1 and natural product, a
oxidized to aldehyde using Dess-Martin periodinane (DMP), thorough study using modified Mosher esters was undertaken.
and the thus obtained aldehyde was converted into vinyl Their study resulted in stereochemical revision of
dibromide 13 under Corey-Fuch’s reaction conditions using distaminolyne A as ‘R’ instead of ‘S’ (originally proposed by
CBr4/TPP, which on subsequent elimination reaction with n- Copp).
BuLi in THF afforded alkyne 4 (90% over three steps).7
However we are intrigued by dissimilar optical rotational
Having the requisite fragments 3 and 4 in hand, (Scheme values reported by Guo et al since our values matched with
4) we conducted the copper-catalyzed Cardiot-Chodkiewicz the reported one. Also, its equally important to note that we
cross-coupling5 to obtain the long chain diacetylene 1-amino adopted an unambiguous and well established synthetic
1
2-alcohol5 2 in 84% yield. This was supported by H NMR protocols to gather the lone stereogenic center; and the reason
spectrum which revealed the characteristic two sets of for these inconsistencies might be due to the low optical
propargylic methylenic protons at δ 2.37, 2.24 ppm as triplets rotational values.
as well as benzylic protons.12 Simultaneously deprotection of
the PMB group in 2 under 2,3-dichloro-5,6-dicyano-1,4- Acknowledgements
benzoquinone (DDQ) conditions led to the primary alcohol 14
One of the author (M. D) is thankful to the UGC, New Delhi for the
(87%). Next, oxidation of alcohol 14 to aldehyde under Dess-
Martin periodinane (DMP) conditions followed by one-carbon
Wittig olefination (PPh3Me+Br-) gave the terminal alkene 15
in 61% yield over two steps.13 Finally, deprotection of
acetonide 15 under acidic condition furnished natural product
1(as HCL salt) in a 60% yield. The spectral data matched with
the reported values (See the supporting information).12
financial support in the form of fellowship.
References and Notes
1. a) Faulkner, D.; J. Nat. Prod. Rep. 1997, 14, 259. b)
Bohlmann, F.; Burkhardt, T.; Zdero, C. ‘Naturally
Occurring Acetylenes’, Academic Press, London, 1973, p.
1, 32 and 222. c) Hirakura, K.; Morita, M.; Nakajima, K.;
Ikeya, Y.; Mitsuhashi, H. Phytochemistry 1991, 30, 3327-
333; Xu, G.-H.; Choo, S.-J.; Ryoo, I.-J.; Kim, Y.-H.; Paek,
K.-Y.; Yoo, I.-D. Nat. Prod. Sci. 2008, 14, 177-181.
2. a) Barrow, R. A.; Capon, R. J. Aust. J. Chem. 1994, 47,
1901-1918. b) Nishimura, S.; Matsunaga, S.; Shibazaki,
M.; Suzuki, K.; Harada, N.; Naoki, H.; Fusetani, N. J. Nat.
Prod. 2002, 65, 1353-1356. c) Ortega, M. J.; Zubia, E.;
Caraballo, J. L.; Salva, J. J. Nat. Prod. 1996, 59, 1069-
1071. d) Fusteani, N.; Li, H. Y.; Tamura, K.; Matsunga, S.
Tetrahedron 1993, 49, 1203-1210. e) Seo, Y.; Cho, K. W.;
Rho, J. R.; Shin, J. Tetrahedron 1998, 54, 447-462. f)
Patil, A. D.; Kokke, W. C.; Cochran, S.; Francis, T. A.;
Tomszek, T.; Westley, J. W. J. Nat. Prod. 1992, 55, 1170-
1177.
O
NBoc
(a)
PMBO
PMBO
+
O
7
Br
NBoc
2
4
3
7
(c)
(b)
HO
O
O
NBoc
NBoc
7
15
7
14
(d)
OH
NH2
1
7
Reagents and conditions: a) CuCl, 30% n-BuNH2, NH2OH.HCl, rt, 5 h, 84%; b) 2,3-Dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ), CH2Cl2:H2O (19:1), 0 oC to rt, 1 h, 87%; c) (i) Des-
Martin periodinane (DMP), dry CH2Cl2, 0 oC, 1 h; (ii) n-BuLi, PPh3Me+Br-, dry THF, -78 oC
to rt, 1 h, (over two steps) 61%; d) 4M HCl, 1,4-dioxane, 0 oC to rt, 5 h, 60%.
3. Wang, J.; Pearce, A. N.; Chan, S. T. S.; Taylor, R. B.;
Page, M. J.; Valentin, A.;
Bourguet-Kondracki, M. L.;
Dalton, J. P.; Wiles, S.; Copp, B. R. J. Nat. Prod. 2016, 79,
Scheme 4:
1
Synthesis of distaminolyne A ( )
607-610.
In summary, we have accomplished the first total 4. a) Radha Krishna, P.; Raja Sekhar, E.; Kannan, V.
Tetrahedron Lett. 2003, 44, 4973-4975. b) Rama Rao, A.
V.; Radha Krishna, P.; Yadav, J. S. Tetrahedron Lett.
1989, 30, 1669-1670. c) Gurjar, M. K.; Murugaiah, A. M.
S.; Radha Krishna, P.; Ramana, C. V.; Chorghade, M. S.
Tetrahedron: Asymmetry 2003, 14, 1363-1370. d) Radha
Krishna, P.; Anitha, K.; Helv. Chim. Acta 2011, 94, 1246-
1253.
synthesis of distaminolyne A (1) as its HCl salt mainly via
aminolytic kinetic resolution to furnish the amino alcohol
moiety in high enantiomeric purity and the Cardiot-
Chodkiewicz reaction for the construction of
a linear
diacetylene scaffold followed by Wittig olefination to result in
the natural product. The spectral data (1H and 13C NMR) and a
sign of the optical rotation of synthetic 1, [α]D25-5.0 (c 0.1,
methanol), to those reported natural product [α]D20-1.0 (c 0.44,
methanol), were nearly identical.12
While this work was under revision, there appeared a
publication on the synthesis of distaminolyne A14 wherein Guo
et al have observed differences in the NMR spectra and hence
made a TFA salt which then correlated with the reported data.
However the sign of the optical rotation varied which showed
[α]D25 +0.8 (and +1.0 for the TFA salt against -1.0 reported by
Copp) and in order to rationalize the differences in optical
5. a) Chodkiewicz, W.; Cadiot, P. Compt. Rend. 1955, 241,
1055-1057. b) Galler, D. J.; Parker, K. A. Org.
Lett. 2015, 17, 5544-5546. c) Gong, J.-X.; Wang, H.-Y.;
Yao, L.-G.; Li, X.-W.; Guo, Y.-W. Synlett 2016, 27, 391-
394. d) Yun, H.; Chou, T.-C.; Dong, H.; Tian, Y.; Li, Y.-
m.; Danishefsky, S. J. J. Org. Chem. 2005, 70, 10375-
10380. e) Mao, J.; Zhong, J.; Wang, B.; Jin, J.; Li, S.; Gao,
Z.; Yang, H.; Bian, Q. Tetrahedron: Asymmetry 2016, 27,
330-337.
6. a) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.;
Melchiorre, P.; Sambri, L. Org. Lett. 2004, 6, 3973-3975.
b) Hodgson, D. M.; Humphreys, P. G.; Xu, Z.; Ward, J. G.

4
Angew. Chem. Int. Ed. 2007, 46, 2245-2248. c) Kureshy,
R. I.; Prathap, K. J.; Agrawal, S.; Kumar, M.; Khan, N.-u.
H.; Abdi, S. H. R.; Bajaj, H. C. Eur. J. Org. Chem. 2009,
2863-2871. d) Bredihhina, J.; Villo, P.; Andersons, K. R.;
Toom, L.; Vares, L. J. Org. Chem. 2013, 78, 2379-2385.
7. a) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769-
3772. b) Mori, K.; Funaki, Y. Tetrahedron 1985, 41, 2379-
2386. c) Manikanta, G., Nagaraju, T., Radha Krishna, P.;
Synthesis 2016, 48, 4213-4220.
8. a) Radha Krishna, P.; Jagannadha Rao, T. Tetrahedron
Lett. 2010, 51, 4017-4019. b) Gathirwa, J. W.; Maki, T.
Tetrahedron 2012, 68, 370-375. c) Lindsay, K. B.; Pyne, S.
G. J. Org. Chem. 2002, 67, 7774-7780.
9. Kim, S.; Kim, S.; Lee, T.; Ko, H.; Kim, D. Org. Lett. 2004,
6, 3601-3604.
10. Mallula, V. S.; Srinivas, B.; Radha Krishna, P.
Tetrahedron Lett. 2015, 56, 4711-4713.
11. Radha Krishna, P.; Jagannadha Rao, T. Tetrahedron Lett.
2010, 51,4017-4019.
12. Supporting Information.
13. a) Radha Krishna, P.; Anitha, K. Tetrahedron Lett. 2011,
52, 4546-4549. b) Radha Krishna, P.; Jagannadha Rao, T.
Tetrahedron Lett. 2010, 51, 4017-4019. c) Usuki, T.;
Sugimura, T.; Komatsu, A.; Koseki, Y. Org. Lett. 2014,
16, 1672-1675.
14. Sun, D.-Y.; Han, G.-Y.; Gong, J.-X.; Nay, B.; Li, X.-W.;
Guo, Y.-W. Org. Lett. article ASAP. DOI:
10.1021/acs.orglett.6b03892.

*Highlights
HIGHLIGHTS
Title: Total synthesis of Distaminolyne A
 Stereoselective
 Diacetylenic amino alcohol

AKR