Ring-closing metathesis based total synthesis of ciliatamides A and B and their structural confirmation

Article abstract of DOI:10.1016/j.tetlet.2016.03.017

Protecting group dependant ring-closing metathesis based approach to the total synthesis of the revised structures of ciliatamides A and B has been described. The current synthetic strategy utilizes the amino acid as starting material to introduce both the stereogenic centers. However, usage of non-racemizing reagents (EDC·HCl, HATU/NMM); for amide coupling and Grubbs' second generation catalyst for caprolactam ring synthesis makes the present approach more convenient to get the correct conclusion on absolute stereochemistry. Thus, on the basis of similar optical rotation values with the Lindsley's reported data, this synthesis further supported for the actual stereochemistry of both ciliatamides A and B is (R,R).

Full text of DOI:10.1016/j.tetlet.2016.03.017

Accepted Manuscript
Ring-closing metathesis based total synthesis of ciliatamides A and B and their
structural confirmation
Krishnakumari Avula, Debendra K. Mohapatra
PII:
S0040-4039(16)30240-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.03.017
TETL 47405
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 November 2015
20 February 2016
6 March 2016
Please cite this article as: Avula, K., Mohapatra, D.K., Ring-closing metathesis based total synthesis of ciliatamides
A and B and their structural confirmation, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.03.017
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Ring-closing metathesis based total synthesis of ciliatamides
A and B and their structural confirmation
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Krishnakumari Avula and Debendra K. Mohapatra*

1
Tetrahedron Letters
Ring-closing metathesis based total synthesis of ciliatamides A and B and their
structural confirmation
Krishnakumari Avula and Debendra K. Mohapatra
aNatural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-5000 007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Protecting group dependant ring-closing metathesis based approach to the total synthesis of the
revised structures of ciliatamides A and B have been described. The current synthetic strategy
utilizes the amino acid as starting material to introduce both the stereogenic centers. However,
usage of non-racemizing reagents (EDC.HCl, HATU/NMM); for amide coupling and Grubbs’
second generation catalyst; for caprolactam ring synthesis makes the present approach more
convenient to get the correct conclusion on absolute stereochemistry. Thus, on the basis of
similar optical rotation values with Lindsley’s reported data, we confirmed that the actual
stereochemistry of both ciliatamides A and B is (R,R).
Available online
Keywords:
Ciliatamides
Antileishmanial activity
Caprolactam
Amide bond formation
Ring-closing metathesis.
2009 Elsevier Ltd. All rights reserved.
Ciliatamides A-D (1-4, Figure 1a) are classified as fused
ketide-amino acid derivatives, which are first isolated by Nakao
and coworkers from the organic extracts of the deep sea sponge
Aaptos cilata.1 These are the rare examples of marine derived
lipopeptides possessing antileishmanial activity. Ciliatamides A-
D (1-4) structurally relate to the bengamides (5), the first
members of a marine derived lipopeptide adorned with a seven
membered caprolactam rings of (2S)-amino caprolactam (Figure
1b).2 The structures of ciliatamides A-C (1-3) were originally
assigned through a combination of spectroscopic methods, and
their absolute stereochemistry was determined through Marfey’s
analysis.3 However, a 2008 synthesis of ciliatamides A (1), B (2)
and C (3) by Lindsley et al. suggested discrepancies in the
relative stereochemistry originally assigned for Ciliatamides A
and B. They concluded that the correct structures of ciliatamides
A and B ( Figure 1a) must be represented by structures 6 and 7
(Figure 1c), originally reported as (S,S) enantiomers. Shortly
after, Matsunga and coworkers reinvestigated the structure of
ciliatamide A (1 or 6) by Merfey’s analysis of its acid
hydrolysate and confirmed that the originally proposed structure
was correct.1b Therefore, we found ciliatamides A and B as an
interesting target to redefine the actual structures, either revised
by Lindsley et al.4 as (R,R) or proposed by Matsunaga et al. as
(S,S) enantiomer.1b
enantiomerically pure isomer of ciliatamides A (6) and B (7) was
described that intersect with the Lindsley’s reported synthesis.4
We envisaged that both ciliatamides A (1) and B (2) could be
synthesized from PMB-protected α-amino lactam 9 and acid
coupling partners 10 and 11 after amide formation and protecting
group cleavage (Scheme 1). In turn, the common lactam
intermediate 9 could be accessed from diene 12 through ring-
closing metathesis reaction. The RCM precursor, diene 12 could
be obtained through coupling of Boc-protected amino acid (+)-13
and mono-protected allyl amine 14. The synthesis of acid units
10 and 11 could be realized through coupling of amine 17 with
suitable acid 15 and acid chloride 16, respectively. While the
common amine coupling partner 17 could be synthesized from
commercially available and optically pure L-phenyl alanine.
In connection with our ongoing research for the synthesis of
large to medium-sized lactone containing natural products
through the formation of C-C bond, particularly by ring-closing
metathesis reaction,5 we thought to utilize the same method for
the construction of α-amino caprolactam ring of potent
antileishmanial agents, ciliatamides A (1) and B (2). In the
Accordingly, the initial objective was to prepare the RCM
cyclization product 9. For a step economy sequence (of two
present report,
a
RCM-based approach to synthesize
———
 Corresponding author. Tel.: +91-40-27193128; fax: +91-40-27160512; e-mail: mohapatra@iict.res.in

2
sole product in 85% yield. Further attempt to cleave the N-
benzyl group in 29 using Pd(OH)2/C also led to the recovery of
the starting material (Scheme 4).
To circumvent the problem faced during hydrogenolysis reaction,
we thought to prepare N-PMB protected α-amino caprolactam 9
and late stage deprotection to achieve the total synthesis. Thus,
by following previous synthetic sequences (Scheme 4) and
simply manipulating the N-Bn-protecting group of 27 to PMB
group, the saturated caprolactam 32 was prepared in an overall
yield of 50% over three steps. The Boc-group was then removed
using TFA in CH2Cl2 to afford the crude lactam 9 in 80% yield
(Scheme 5).
Scheme 1: Retrosynthetic analysis of ciliatamides A (1) and B
(2)
steps) to achieve the synthesis of RCM cyclized product (21
or 22), our first attempt described in Scheme 2 was unsuccessful
during the ring-closing metathesis reaction of the coupled amide
19 using either Grubbs’ I or II catalyst.6 Same result with Boc-
protected amide 20 revealed that the free NH-group of the amide
might be the cause of difficulty for the RCM cyclization to
happen.6e
Scheme 5: Synthesis of α-amino caprolactam 9.
To synthesize the carboxylic acid coupling partners (10 and
11), an amide coupling between L-N,O-dimethyl-L-phenylalanine
(17) and the acid 15 or acid chloride 16 was envisaged. First, N-
Boc-L-phenyl alanine methyl ester 33 was obtained by following
a two steps sequence.7 As the initial attempt for the N-
methylation with NaH/CH3I in DMF led to partial racemization
(roughly 60% of ee was observed from HPLC analysis), the
reagent combinations (Ag2O (4 equiv.)/CH3I (15 equiv) in
DMF)8 gave better results and N-Boc-N-methyl phenyl
Scheme 2: Attempted step economy approach for the
synthesis of α-aminocaprolactams 21 and 22
With this assumption and earlier literature preccedents,6d-e we
prepared the di-Boc-protected diene amide 24 as depicted in
Scheme 3. The synthesis commenced with an amide bond
formation of (S)-N-Boc-allylglycine derivative (S)-13, prepared
from commercially available L-allyl glycine and the mono Boc-
protected allylamine (23) to afford (S)-N'-alkenyl-N-Boc-
allylglycine (24) derivative as a mixture of two rotamers. The
Scheme 3: Attempted RCM cyclization of bis-Boc protected
dienamide 24.
Scheme 6: Synthesis of carboxylic acid coupling partners 10 and
11.
alanine methyl ester 34 was obtained in 93% yield without any
racemization.9 Subsequent,
Boc-deprotection with TFA
furnished 17 in 76% yield. The required acid 15 was obtained
from 9-decen-1-ol via direct oxidation using TPAP,10 while 16
was commercially available. The coupling of amine 17 was
carried out with 15 using EDC.HCl/HOBt.H2O,11 whereas with
octanoyl chloride under Schotten–Baumann reaction conditions12
(aq. NaHCO3, CH2Cl2, room temperature) to afford amides 35
and 36 in 87% and 82% yield, respectively (Scheme 6).
Saponification of the methyl esters13 in 35 and 36 was preceded
smoothly in presence of LiOH to obtain the respective carboxylic
acids (10 and 11).
Scheme 4: An unfruitful approach for the synthesis of saturated
caprolactam 29.
crucial ring-closing metathesis reaction of 24 using the first
generation Grubbs catalyst produced a trace amount of the
required caprolactam 25 and diene 24 was recovered in 89%
yield. Similar outcome in presence of second generation Grubbs
catalyst demonstrated the effect of neighboring protecting groups
in the ring closing metathesis reaction (Scheme 3). Fortunately,
after treatment of Bn-protected (S)-N'-alkenyl-N-Boc-allylglycine
(27) in presence of Grubbs’ II catalyst (c = 0.01 M, CH2Cl2, 45
°C, 6 h) smoothly afforded the required caprolactam 28 in 68%
yield. The attempt to hydrogenolysis of both the olefinic bond
and N-benzylic bond was failed, instead only 29 obtained as the
With both the coupling partners 9 and 10/11 in hand, the final
amide coupling was carried out to append the side diamide chain.
α-Amino caprolactam
9 was subjected to HATU/NMM
conditions14 for the coupling with either acids 10 or 11. The
identical conditions worked well for both the cases to afford the
corresponding amides 37 and 38 (72% and 79% yield,

3
2. (a) Quinoa, E.; Adamczeski, M.; Crews, P.; Bakus, G. J. J. Org.
respectively) without any epimerization. The milder deprotection
conditions15 for the PMB-ether cleavage with cerium(IV)
ammonium nitrate yielded the ciliatamides A (1) and B (2) in
Chem. 1986, 51, 4494; (b) Adamczeski, M.; Quinoa, E.; Crews, P.
J. Am. Chem. Soc. 1989, 111, 647.
3. Marfey, P. Carlsberg Res. Commun. 1984, 49, 591.
4. Lewis, J. A.; Daniels, R. N.; Lindsley, C. W. Org. Lett. 2008, 10,
4545.
5. For contribution of our research group on ring-closing metathesis
reaction, see: (a) Mohapatra, D. K.; Reddy, D. P.; Gajula, S.;
Karthik, P.; Yadav, J. S. Asian J. Org. Chem. 2014, 3, 1210; (b)
Mohapatra, D. K.; Karthik, P.; Reddy, B. E.; Reddy, D. P.; Yadav, J.
S. Asian J. Org. Chem. 2014, 3, 1210; (c) Mohapatra, D. K.; Jena, B.
K. Tetrahedron Lett. 2013, 54, 3415; (d) Mohapatra, D. K.; Reddy,
D. P.; Dash, U.; Yadav, J. S. Tetrahedron Lett. 2011, 52, 151; (e)
Mohapatra, D. K.; Somaiah, R.; Rao, M. M.; Caijo, F.; Mauduit, M.;
Yadav, J. S. Synlett 2010, 1223; (f) Mohapatra, D. K.; Dash, U.;
Naidu, P. R.; Yadav, J. S. Synlett 2009, 2129; (g) Mohapatra, D. K.;
Sahoo, G.; Ramesh, D. K.; Sastry, G. N. Tetrahedron Lett. 2009, 50,
5636; (h) Mohapatra, D. K.; Rahman, H.; Pal, R.; Gurjar, M. K.
Synlett 2008, 1801; (i) Mohapatra, D. K.; Ramesh, D. K.; Giardello,
M. A.; Chorghade, M. S.; Gurjar, M. K.; Grubbs, R. H. Tetrahedron
Lett. 2007, 48, 2621; (j) Gurjar, M. K.; Karmakar, S.; Mohapatra, D.
K. Tetrahedron Lett. 2004, 45, 4525.
6. For the synthesis of seven-membered lactams via ring-closing
metathesis reaction, see: (a) Piscopio, A. D.; Miller, J. F.; Koch, K.
Tetrahedron Lett. 1997, 38, 7143; (b) Piscopio, A. D.; Miller, J. F.;
Koch, K. Tetrahedron Lett. 1998, 39, 2667; (c) Piscopio, A. D.;
Miller, J. F.; Koch, K. Tetrahedron 1999, 55, 8189; (d) Fuhshuku, K.
I.; Asano, Y. Tetrahedron 2012, 68, 6651; (e) Hassan, H. M. A.;
Brown, F. K. Chem. Commun. 2010, 46, 3013.
7. You, J.; Wroblewski, A. E.; Verkade, J. G. Tetrahedron 2004, 60,
7877.
8. For a review, see: Aurelio, L.; Brownlee, R. T. C.; Hughes, A. B.
Chem. Rev. 2004, 104, 5823.
9. The optical purity of N-methyl derivative 17 was assessed by chiral
HPLC, where the ee% of the title compound was obtained as >99%
(see Supporting Information).
10. Schmidt, A. C.; Stark, C. W. Org. Lett. 2011, 13, 4164.
11. Ferrie, L.; Reymond, S.; Capdevielle, P.; Cossy, J. Org. Lett. 2006,
8, 3441.
Scheme 7: Total synthesis of ciliatamides A (1) and B (2).
1
62% and 71% yield, respectively. Although, the H- and 13C-
NMR spectra of the synthesized compounds 1 and 2 (see SI),
were identical with those reported by Matsunaga1a and Lindsley
24
group,4 the optical rotation values {[α]D = −33.4 (c = 0.05,
MeOH) for 1 and −40.2 (c = 0.1, MeOH) for 2} are
20
contradictory with the Matsunaga’s report {[α]D = +40 (c =
0.05, MeOH) for 1 and +55 (c = 0.05, MeOH) for 2} and
20
comparable with Lindsley’s synthetic values {[α]D = −35 (c =
0.05, MeOH) for 6 and −44 (c = 0.05, MeOH) for 7}. On the
basis of these comparisons, our result was in alignment with the
Lindsley’s reported data.
12. Kaul, R.; S. Surprenant, W. D. Lubell, J. Org. Chem. 2005, 70, 3838.
13. K. X. Chen, F. G. Njoroge, J. Pichardo, A. Progay, N. Butkiewicz,
N. Yao, V. Madison, V. Girijavallabhan, J. Med. Chem. 2005, 48,
6229.
14. R. Kaul, S. Simon, W. D. Lubell, J. Org. Chem. 2005, 70, 3838.
15. Y. Brouillette, J. Martinez, V. Lisowski, J. Org. Chem. 2009, 74,
4975.
In summary, a convergent total synthesis of the revised
structure of ciliatamides A and B via protecting group directed
ring-closing metathesis reaction has been described. Since the
stereogenic centers were directly derived from the amino acids,
the current synthetic route has further supported the absolute
stereochemistry revision by Lindsley et al. Moreover, the
protecting groups dependant ring-closing metathesis reaction for
the construction of caprolactam core has left an accessible route
to synthesize the other ciliatamides (C and D), so also the related
analogue for SAR studies. A similar synthetic route to assign the
actual stereochemistry of ciliatamides C and D is underway and
will be reported in due course.
Acknowledgments
The authors thank Council of Scientific and Industrial
Research (CSIR), New Delhi, India, for financial support as part
of XII Five Year plan programme under title ORIGIN (CSC-
0108). D.S.R and J.G thank Council of Scientific and Industrial
Research, New Delhi, India for financial assistance in the form of
fellowships.
Supporting Information
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi/xxxxxx.
References and notes
1. (a) Nakao, Y.; Kawatsu, S.; Okamoto, C.; Okamoto, M.; Matsumoto,
Y.; Matsunaga, S.; van Soest, R. W. M.; Fusetani, N. J. Nat. Prod.
2008, 71, 469; (b) Imae, Y.; Takada, K.; Okada, S.; Ise, Y.;
Yoshimura, H.; Morii, Y.; Matsunaga, S. J. Nat. Prod. 2013, 76,
755.

HIGHLIGHTS
1. Small protecting groups are suitable for ring-closing metathesis reaction.
2. Epimerization during N-methylation was prevented using Ag2O/CH3I conditions.
3. Our synthesis of ciliatamides A and B further confirmed the stereochemistry as (R,R).