Construction of the A ring of halichomycin via a RCM strategy

Article abstract of DOI:10.1016/j.tetlet.2013.06.027

Attempts to the synthesis of the A ring of halichomycin via ring-closing metathesis (RCM) reaction were investigated. When triene 5 was used as the precursor of cyclization, only unexpected byproduct aldehyde 17 was obtained. When diene 6 was used as the precursor of cyclization, the desired product 20 was obtained in reasonable yield. This work demonstrated that both modification of the substrate and the RCM reaction conditions are important for obtaining the desired 11-membered macrocycle in reasonable yield.

Full text of DOI:10.1016/j.tetlet.2013.06.027

Tetrahedron Letters 54 (2013) 4343–4345
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Construction of the A ring of halichomycin via a RCM strategy
⇑
Shiyong Mao, Yanxing Jia
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Attempts to the synthesis of the A ring of halichomycin via ring-closing metathesis (RCM) reaction were
investigated. When triene 5 was used as the precursor of cyclization, only unexpected byproduct alde-
hyde 17 was obtained. When diene 6 was used as the precursor of cyclization, the desired product 20
was obtained in reasonable yield. This work demonstrated that both modification of the substrate and
the RCM reaction conditions are important for obtaining the desired 11-membered macrocycle in reason-
able yield.
Received 17 April 2013
Revised 28 May 2013
Accepted 9 June 2013
Available online 14 June 2013
Keywords:
Halichomycin
Ó 2013 Elsevier Ltd. All rights reserved.
Total synthesis
Natural product
Ring-closing metathesis (RCM)
O
Halichomycin is produced by a strain of Streptomyces hygroscop-
icus, which was isolated from the gastrointestinal tract of the mar-
ine fish Halichoeres bleekeri (Fig. 1).1 It exhibits potent cytotoxicity
Me
Me
17
10
OMe
O
Me
C
OMe
NH
24
(ED50 0.13 lg/mL) against a murine P388 lymphocytic leukemia
22
A
Me
Me
A
O
Me
AcO
cell line, and has potential use as an anticancer drug. Halichomycin
contains a structurally unique tricyclic macrolactam, which in-
cludes an 11/13-membered bicyclic hemimacrolactam (AB ring)
and a fully functionalized 11-membered ether ring (C ring). It also
has 10 stereocenters including six contiguous stereocenters, and
five double bonds.
O
8
16
15
O
25
B
1
OTBDPS
O
Me
2
Me
Me Me Me
halichomycin (1)
Figure 1. Structures of halichomycin and A ring of halichomycin.
The total synthesis of halichomycin is highly challenging be-
cause of the overall complexity of the molecule. There are only a
few groups that have reported its synthetic studies.2 Our group
has been actively studying the synthesis of halichomycin and re-
ported an efficient and convergent synthesis of the C5–C18 frag-
ment of halichomycin.2c However, our attempts to construct its A
ring (2) via macrolactonization failed. The main problem was that
the oxidation of alcohol 3 could not provide the desired macrocyc-
lization precursor acid 4 (Scheme 1).3 Considering no report on the
construction of any single ring of this molecule has been published
so far, we decided to explore an alternative strategy for the con-
struction of the A ring of halichomycin.
OMe
OMe
CO2H
OH
[O]
OTBS
OTBS
Me
AcO
Me
AcO
OTBDPS
OTBDPS
Me Me
Me Me
3
4
Scheme 1. Our failed macrocyclization approach.
Ring-closing metathesis (RCM) has become a ubiquitous tool for
the synthesis of carbon- and heterocylic ring systems, and it is par-
ticularly well-suited for the efficient synthesis of macrocycles as an
alternative to the classic macrolactonization approach.4 However,
applications of RCM to construct 11-membered macrocycles re-
main scarce and sometimes with rather low yield.5 Moreover, the
selectivity is dependent upon many factors, such as ring size and
position of the olefin.5a–c,e–g Herein, we report the construction of
the A ring of halichomycin via a RCM strategy.
Retrosynthetic analysis of the A ring system (2) is shown in
Scheme 2. In view of the existing conjugated dienes in compound
2, we envisioned that the conjugated diene could be formed by 1,3-
diene-ene RCM from compound 5 with simultaneous formation of
the macrocycle. Although there are a few reports on the construc-
tion of macrocycles via 1,3-diene-ene RCM strategy, no such for-
mation of 11-membered macrocycle is reported in the literature.6
Given that RCM of the conjugated diene might lead to four differ-
⇑
Corresponding author. Tel.: +86 10 8280 5166; fax: +86 10 8280 2724.
E-mail address: yxjia@bjmu.edu.cn (Y. Jia).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.027

4344
RCM
S. Mao, Y. Jia / Tetrahedron Letters 54 (2013) 4343–4345
1. (CF3CH2O)2P(O)CHMeCO2Et,
OMe
O
Br
OMe
O
TBSO
KHMDS, THF, -78 °C, 80%
CHO
2. DIBAL-H, Et2O, -78 °C, 90%
3. Ph3P, NBS, THF, 0 °C, 80%
Me
O
Me
O
Me
AcO
8
esterification
9
OTBDPS
OTBDPS
alkylation
Me Me
Me
2
OAc
Me
OMe
O
O
Ph2Se2, Zn, AlCl3, CH3CN, reflux
50%
6
OH
MeO
PhSe
O
10
PivCl, NEt3, THF
11
OMe
OMe
O
O
O
PhSe
O
OTBDPS
O
Me
O
O
esterification
12
OTBDPS
alkylation
TBSO
Me
Me
Me Me
7
5
O
O
LiBH4
LHMDS
THF/MeOH
OTBDPS
O
OTBDPS
then 9
O
Scheme 2. Retrosynthetic analysis.
THF, -78 °C
70%
0 °C
90%
Me
Me
Me
7
Me
13
ent products (9- vs 11-membered ring and cis/trans isomers) and
the conformation of the open-chain precursor could affect the
RCM reaction, the masked conjugated diene 6 could be used as a
cyclization precursor. Elimination of the hydroxyl group could gen-
erate a double bond after the RCM. Both compounds 5 and 6 could
be prepared from the known compound 72c by sequential alkyl-
ation, reduction, selective mono-protection, and esterification.
Our first attempt to construct the A ring used triene 5 as the
starting material since this route is short and can provide addi-
tional insights into the preparation of the 11-membered macrocy-
cle containing conjugated diene. Our synthesis commenced with
the preparation of dienylic bromide 9 and acid 11 as illustrated
in Scheme 3. The dienylic bromide 9 was synthesized by a se-
quence of Still–Gennari’s olefination,7 reduction with DIBAL-H,
and bromination. The acid 11 was prepared from the known lac-
TBSCl
DMAP
OTBDPS
OTBDPS
OH
OH
Me
HO
Me
TBSO
CH2Cl2, rt
96%
Me
14
Me
15
Me
Me
SePh
OMe
NaIO4, THF, rt
80%
12, DMAP, THF
O
O
Me
TBSO
60%
OTBDPS
Me Me
16
tone 10, which is prepared from D-malic acid as reported in the lit-
O
erature.8 Treatment of lactone 10 with (PhSe)2 in the presence of
Zn/AlCl3 gave the corresponding acid 11 in 50% yield.9
OMe
OMe
Grubbs II
CH2Cl2
O
O
Me
TBSO
With three key fragments in hand, we investigated the synthe-
sis of compound 5. a-Alkylation of lactone 7 with dienylic bromide
O
O
Me
TBSO
reflux
20%
OTBDPS
OTBDPS
9 smoothly afforded the desired coupling product 13. Reduction of
lactone 13 with lithium borohydride followed by selective protec-
tion of primary alcohol using TBSCl gave secondary alcohol 15. Di-
rect esterification of alcohol 15 and acid 11 under standard
coupling conditions gave the desired ester 16 in low yield. To im-
prove the yield, we investigated the DMAP-catalyzed method for
mixed-anhydride acylation of alcohols recently developed by Ishi-
hara.10 Thus, acid 11 reacting with pivaloyl chloride in the pres-
ence of Et3N provided the desired anhydride 12, which was
directly coupled with alcohol 15 under DMAP-catalyzed conditions
to afford the desired ester 16 in 60% yield. The oxidative elimina-
tion of phenyl selenide in 16 with H2O2 provided the target triene
5 in only 30% yield.11 Gratefully, when NaIO4 was used as the oxi-
dant, compound 5 could be obtained in 80% yield.12
Me
Me
Me Me
5
17
Scheme 3. Synthesis of trienes 5 and failed RCM.
1. LHMDS, THF, HMPA
then 18, -78 °C
TBSO
O
2. LiBH4, THF, 0 °C
OTBDPS
O
OTBDPS
OH
Me
AcO
3. Ac2O, DMAP
CH2Cl2, rt
Me
Me
51% (3 steps)
Me Me
19
7
OMe
TBSO
1. 12, DMAP, THF
Grubbs II (1 equiv)
CH2Cl2
50%
Having succeeded in the synthesis of the cyclization precursor
triene 5, the stage was set for the RCM reaction. Compound 5
was treated with the second generation Grubbs catalyst
(20% mol) in CH2Cl2 at reflux for 24 h. Interestingly, no desired
cyclization product was observed; instead, the aldehyde 16 was
isolated in 20% yield along with 20% of starting material. Literature
search showed aldehyde as a byproduct of RCM reaction has al-
ready been reported.13 A variety of RCM reaction conditions was
further screened, including catalysts, solvents, and additives. How-
ever, no desired cyclization product was obtained.
O
O
Me
AcO
reflux, 16 h
60%
2. NaIO4, THF, rt
80%
OTBDPS
Me Me
6
OMe
TBSO
OTBS
O
O
Me
I
AcO
Me
18
OTBDPS
Me Me
20
We reasoned that the conformation of the backbone must have
a profound influence on the outcomes of the RCM reaction. There-
fore, we turned our attention to use compound 6 as the starting
Scheme 4. Synthesis of A ring of halichomycin.

S. Mao, Y. Jia / Tetrahedron Letters 54 (2013) 4343–4345
4345
material of RCM, in which the (Z)-olefin was masked as a hydroxy
group.
References and notes
1. Takahashi, C.; Takada, T.; Yamada, T.; Minoura, K.; Uchida, K.; Matsumura, E.;
Numata, A. Tetrahedron Lett. 1994, 35, 5013–5014.
2. (a) McCann, E. E.; Janes, G.; Ortsey, C.; Wood, J. L. Tetrahedron Lett. 1997, 38,
303–304; (b) Hale, K. J.; Dimopoulos, P.; Cheung, M. L. F.; Frigerio, M.; Steed, J.
W.; Levett, P. C. Org. Lett. 2002, 4, 897–900; (c) Li, Q.; Mao, S.; Jia, Y. J. Org. Chem.
2012, 77, 4111–4116.
To prepare compound 6, the iodide fragment 18 was needed,
which was prepared following the protocol of Parthasarathi.14
The chirally pure 18 was used as the starting material to decrease
the number of diastereoisomers after a-alkylation, thus facilitating
the synthesis. Compound 6 was quickly obtained following the
same synthetic route as described for 5 (Scheme 4). However,
two issues should be addressed: (1) the addition of HMPA was
3. Li, Q. Ph.D. Thesis, Peking University, 2012.
4. For reviews, see: (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–4450;
(b) Fürstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043; (c) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29; (d) Deiters, A.; Martin, S. F. Chem.
Rev. 2004, 104, 2199–2238; (e) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.
Chem., Int. Ed. 2005, 44, 4490–4527; (f) Gradillas, A.; Pérez-Castells, J. Angew.
Chem., Int. Ed. 2006, 45, 6086–6101; (g) Schrock, R. R.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2003, 42, 4592–4633; (h) Grubbs, R. H. In Handbook of Metathesis;
Wiley-VCH: Weinheim, 2003; Vols 1–3,; (i) Monfette, S; Fogg, D. E. Chem. Rev.
2009, 109, 3783–3816; (j) Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev. 2010,
110, 1746–1787; (k) Yu, M.; Wang, C.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.;
Schock, R. R.; Hoveyda, A. H. Nature 2011, 479, 88–93.
5. For syntheses of 11-membered rings by RCM, see (a) Winkler, J. D.; Holland, J.
M.; Kasparec, J.; Axelsen, P. H. Tetrahedron 1999, 55, 8199–8214; (b) Fürstner,
A.; Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann, C. W.; Mynott, R. J. Am.
Chem. Soc. 2002, 124, 7061–7069; (c) Wipf, P.; Stephenson, C. R. J.; Walczak, M.
A. A. Org. Lett. 2004, 6, 3009–3012; (d) Nicolaou, K. C.; Montagnon, T.;
Vassilikogiannakis, G.; Mathison, C. J. N. J. Am. Chem. Soc. 2005, 127, 8872–
8888; (e) Fürstner, A.; Müller, C. Chem. Commun. 2005, 5583–5585; (f)
Matsumura, T.; Akiba, M.; Arai, S.; Nakawa, M.; Nishida, A. Tetrahedron Lett.
2007, 48, 1265–1268; (g) Vassilikogiannakis, G.; Margaros, I.; Tofi, M. Org. Lett.
2004, 6, 205–208; (h) Cai, Z.; Nattawut, Y.; Harmata, M. Org. Lett. 2012, 14,
1661–1663.
6. For selected examples of 1,3-diene-ene RCM in the synthesis of macrocycles,
see: (a) Barluenga, S.; Lopez, P.; Moulin, E.; Winssinger, N. Angew. Chem., Int. Ed.
2004, 43, 3467–3470; (b) Lu, K.; Huang, M.; Xiang, Z.; Liu, Y.; Chen, J.; Yang, Z.
Org. Lett. 2006, 8, 1193–1196; (c) Hayashi, Y.; Shoji, M.; Ishikawa, H.;
Yamaguchi, J.; Tamura, T.; Imai, H.; Nishigaya, Y.; Takabe, K.; Kakeya, H.;
Osada, H. Angew. Chem., Int. Ed. 2008, 47, 6657–6660; (d) Sun, L.; Feng, G.;
Guan, Y.; Liu, Y.; Wu, J.; Dai, W. Synlett 2009, 2361–2365; (e) Gallenkamp, D.;
Fürstner, A. J. Am. Chem. Soc. 2011, 133, 9232–9235.
7. (a) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408; (b) Bates, R.
H.; Shotwell, J. B.; Roush, W. R. Org. Lett. 2008, 10, 4343–4346.
8. For the synthesis of compound 10, see: (a) Green, D. L. C.; Kiddle, J. J.;
Thompson, C. M. Tetrahedron 1995, 51, 2865–2874; (b) White, J. D.; Hrnciar, P. J.
Org. Chem. 2000, 65, 9129–9142; (c) Mulzer, J.; Mantoulidis, A.; Ohler, E. J. Org.
Chem. 2000, 65, 7456–7467; (d) Marina, T.; Yang, Q.; Courtney, C.; Babak, B. E. J.
Org. Chem 2009, 4242–4253.
needed for the
a-alkylation of lactone 7 with iodide 18, which
could dramatically increase the yield; (2) the primary alcohol
was protected with the acetyl group in order to facilitate the later
transformation of the hydroxy group.
Treatment of 6 with 20% mol of Grubbs’ second-generation cat-
alyst in CH2Cl2 at reflux successfully provided the expected (E)-20
as an exclusive isomer, but in 10% yield. In fact, it is a certain chal-
lenge to carry out RCM reaction with such a highly functionalized
substrate. After several trials, we found that the addition of
25% mol Grubbs’ second-generation catalyst to the reaction every
4 h (repeated 3 times) afforded the desired product 20 in 60% yield.
It is of particular note that no (Z)-product and dimer product was
detected.
In summary, synthesis of the A ring of halichomycin via ring-
closing metathesis (RCM) reaction was investigated. When triene
5 was used as the precursor of cyclization, only unexpected
byproduct aldehyde 17 was obtained. When diene 6 was used as
the precursor of cyclization, the desired product 20 was obtained
in reasonable yield. This work demonstrated that both modifica-
tion of the substrate and the RCM reaction conditions are impor-
tant for obtaining the desired 11-membered macrocycle in
reasonable yield. Further efforts toward the total synthesis of hal-
ichomycin are currently underway in our laboratory and the result
will be reported in due course.
Acknowledgments
9. Nazari, M.; Movassagh, B. Tetrahedron Lett. 2009, 50, 438–441.
10. (a) Sakakura, A.; Kawajiri, K.; Ohkubo, T.; Kosugi, Y.; Ishihara, K. J. Am. Chem.
Soc. 2007, 129, 14775–14779; (b) Zhang, F.; Jia, Y. Tetrahedron 2009, 65, 6840–
6843.
11. Barton, Derek H. R.; Crich, D.; Hervé, Y.; Potier, P.; Thierry, J. Tetrahedron 1985,
41, 4347–4357.
We are grateful for the generous financial support by the Na-
tional Natural Science Foundation of China (Nos. 21290180,
20972007), the National Basic Research Program of China (973 Pro-
gram, No. 2010CB833200), and the Ph.D. Programs Foundation of
Ministry of Education of China (No. 20120001110100)
12. Xiao, Y.; Kent, L.; Liu, P. Org. Lett. 2008, 10, 5521–5524.
13. (a) Grubbs, R. H. In Handbook of Metathesis; Wiley-VCH: Weinheim, 2003; Vol.
1, pp 120–127; (b) Pump, E.; Fischer, R. C.; Slugovc, C. Organometallics 2012, 31,
6972–6979; (c) Toumi, M.; Couty, F.; Evano, G. J. Org. Chem. 2008, 73, 1270–
1281.
Supplementary data
14. (a) Narasimhulu, C. P.; Das, P. Synthesis 2009, 474–482; (b) Narasimhulu, C. P.;
Das, P. Tetrahedron Lett. 2008, 49, 3185–3188.
Supplementary data (experimental procedures and data for all
new compounds) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2013.06.027.