Synthesis of the naphthoquinone core of divergolides (C-D) and model studies for elaboration of the ansabridge

Article abstract of DOI:10.1016/j.tetlet.2013.03.022

Herein, we describe a facile synthesis of the naphthoquinone fragment of the aromatic core of the novel ansamycins such as hygrocins A-B and the divergolides C-D, starting from the inexpensive 2-hydroxy-3-methylbenzoic acid. We demonstrate the utility of naphthalenic synthon for further elaboration of the ansabridge via C5-C6 bond formation by employing a commercially available sterically demanding organomagnesium reagent as a model ansa chain. Facile conversion of the resulting alcohol to the naphthoquinone fragment of the targets in one pot has also been realized. These model studies set the stage for the completion of total synthesis of the biologically important novel ansamycins.

Full text of DOI:10.1016/j.tetlet.2013.03.022

Tetrahedron Letters 54 (2013) 2615–2618
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of the naphthoquinone core of divergolides (C–D) and model
studies for elaboration of the ansabridge
Sivappa Rasapalli a, , Gopalakrishna Jarugumilli a, Gangadhara Rao Yarrapothu a, James A. Golen a,
⇑
Arnold L. Rheingold b
a Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, North Dartmouth, MA 02747, United States
b Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093-0358, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, we describe a facile synthesis of the naphthoquinone fragment of the aromatic core of the novel
ansamycins such as hygrocins A–B and the divergolides C–D, starting from the inexpensive 2-hydroxy-3-
methylbenzoic acid. We demonstrate the utility of naphthalenic synthon for further elaboration of the
ansabridge via C5–C6 bond formation by employing a commercially available sterically demanding
organomagnesium reagent as a model ansa chain. Facile conversion of the resulting alcohol to the naph-
thoquinone fragment of the targets in one pot has also been realized. These model studies set the stage
for the completion of total synthesis of the biologically important novel ansamycins.
Published by Elsevier Ltd.
Received 5 February 2013
Revised 4 March 2013
Accepted 5 March 2013
Available online 14 March 2013
Keywords:
Ansamycins
Divergolides
Hygrocins
Naphthoquinone
3-Methylsalicylic acid
Ansamycins, so named because of their ‘basket-like structures’
consisting of an aromatic chromophore connected by a chain, like
the handle of a basket (ansa), at non-adjacent positions are mainly
derived from actinomycetes and are proven biologically important
macrolides.1 The structure of the aromatic moiety distinguishes
two types of ansamycins: (1) naphthalenic ansamycins (e.g., rifa-
mycins,2 naphthomycins,3 streptovaricin,4 etc.) that exhibit anti-
microbial activities (2) benzenic ansamycins (geldanamycin,5
herbimycin,6 etc.) that possess anti-cancer activities. Divergolides
C–D (1–2), recently isolated from Streptomyces sp. HKI0576—an
endophyte of the mangrove tree (Bruguiera gymnorrhiza), have
been shown to possess antibacterial and anti-cancer activities.7
They closely resemble hygrocins A–B (3–4), another family of
metabolites isolated from Streptomyces hygroscopicus, and differ
only in the unusual isobutenyl side chain at C11 instead of the
methyl group, and in the oxidation states of the aromatic cores,
while the overall topology is conserved.8 Due to the shortage of
the supply of these rare streptomyces metabolites,7,9 and lack of
synthetic routes,10 the biomedicinal potential of this unique family
has not been fully investigated and remain to be explored. Divergo-
lides A–D and hygrocins A–B have attracted the attention of syn-
thetic chemists with their interesting structures and
bioactivities.11 An enantioselective total synthesis amenable to
large scale and structural analogue production will not only enable
the undertaking SAR studies of these rare metabolites12 but also
the unambiguous stereochemical assignment of the stereocentres
(e.g., C8 of hygrocins is unassigned; numbering refers to Hert-
weck’s assignment shown in 1 of Fig. 1).7,13 We set out to develop
a synthetic route to access the analogues of these novel ansamyc-
ins as part of our ongoing quest for novel antibacterial leads.14 We
proposed two approaches, namely biomimetic and non-biomi-
metic. As shown in Scheme 1, our non-biomimetic retrosynthesis
of the targets identified two main synthons 13 and 14, that is, aro-
matic and chiral fragments, apart from the eastern segment 11,
that is, C100–C500 which is thought to be derived from 2-methyl-2-
pentenedioicacid chemistry. Depending on the disconnection of
either C4–C5 or C5–C6, one could arrive at differently functional-
ized aromatic and chiral fragments, and shown in Scheme 1 are
based on the disconnection of C5–C6.15
We initially focused our efforts on construction of the AB rings
(i.e., 13 of Scheme 1) of the tricyclic core of the target compounds
and planned to rely on the intrinsic biomimetic annulations of
N-acylated naphthoquinone for the formation of the tricyclic aro-
matic cores of divergolides C (1), D (2) and hygrocins B (4).16 3-
Methylsalicylic acid (15) with suitable functional groups required
for the A-ring was chosen as a starting material. Surprisingly, this
readily available and most obvious choice with the suitable sub-
stituents at the respective positions has not been employed thus
far in the synthesis of aromatic cores of ansa macrolides
⇑
Corresponding author. Tel.: +1 508 999 8276; fax: +1 508 999 9232.
E-mail address: srasapalli@umassd.edu (S. Rasapalli).
0040-4039/$ - see front matter Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.03.022

2616
S. Rasapalli et al. / Tetrahedron Letters 54 (2013) 2615–2618
O
O
O
OH
B
H
H
N
O
O
N
O
H
C
O
A
HO
NH
HO
HO
6
O
O
OH
O
HO
OH
O
HO
O
O
8
O
O
OH
Hygrocin A 3
( )
Divergolide D 2
( )
(anti-cancer)
Divergolide C (1)
(anti-bacterial)
(weak anti-bacterial)
O
H
N
O
O
H
N
O
O
HN
HO
O
H
O
H3CO
O
O
HO
HO
O
O
O
OH
O
O
O
O
OH
O
O
N
O
O
N
H
OH
Hygrocin B (4)
R1
O
R2
Ansalactam (5)
Rubradirins (6)
(weak anti-bacterial)
Figure 1. Structures of ansamycins.
O
H
OH
B
O
H
N
C
O
N
O
O
H
A
O
HO
NH
HO
HO
6
O
O
O
OH
O
O
O
HO
O
OH
O
O
O
OR
11
HO
O
1
O
O
OH
HO
2
Eastern Segment (
)
9
NHBoc
+
O
O
O
HO
NHBoc
O
H
N
H
N
H
N
O
O
O
O
1"
O
H
4
HO
C-C
Aromatic Fragment (13)
HO
HO
formation
5
HO
O
6
O
O
O
O
5"
O
O
O
O
O
Oxidation
HO OH
O
O
R2O
OR1
M
R
OR2
HO
OH
HO
R1O
R
C6-C12 Chiral fragment (14)
12
Western Segment (
)
10
Scheme 1. Retrosynthesis of divergolides C (1) and D (2).
7
8
presumably due to the lack of methods/reports for selective ring
annulations and further manipulations. We decided to undertake
this approach with the hope of developing methods to annulate
the B-ring via electrophilic aromatic substitution chemistry. If suc-
cessful, this work would not only develop the facile chemistry for
the large scale access to the aromatic cores of the proposed targets,
that is, divergolides C–D (1–2) and hygrocins A–B (3–4), but also
provides the access to the aromatic cores of other important ans-
amycins such as ansalactam 5, rubradirin 6, salinisporomycins,3
chaxamycins17 and rifamycins2 through slight modifications.
Our synthesis thus commenced from 3-methylsalicylic methyl
ester 16, synthesized from commercially available 3-methylsalicy-
clic acid 15 using the known literature procedure, as shown in
Scheme 2.18 Formylation of ester 16 under Duff’s conditions
provided formylated phenol which was converted into its methyl
ether 17 before subjecting it to Wittig olefination.19 The required
phosphorane 18 was prepared following the literature protocol.20
The Wittig olefination of aldehyde 17 was carried out in DMSO
at moderate temperatures to obtain acid 19 in good yield after
acid–base extraction.21 The unoptimized intramolecular acylation
under NaOAc/Ac2O refluxing conditions provided the desired
naphthalenic compound 20 along with the undesired regioisomer
in 2:1 ratio, whose separation was effected quite easily at the phe-
nol stage after the deprotection of the acetate functionality that is
formed concomitantly.22 The connectivity of the required isomer
was confirmed through X-ray structure determination. We rea-
soned that conversion of the bis-ester 20 to a tricyclic naphthalene
core with lactone moiety may enable us to differentiate the ester

S. Rasapalli et al. / Tetrahedron Letters 54 (2013) 2615–2618
2617
COOMe
OH
PPh3
1) HMTA, TFA
O
HOOC
K2CO3, Me2SO4
80 oC, 12 h, 71%
COOMe
HO
O
O
18
DMSO, 40 oC, 24 h
1) NaOAc, Ac2O,
reflux, 2 h
HO
2) K2CO3, MeI
DMF, rt, 85%
O
Bu4NBr (cat)
CH2Cl2-H2O,
rt, 4 h, 86%
O
OMe
O
OMe
O
OMe
O
OH
2) NaOMe, MeOH
rt, 1 h,
(55% over 3 steps)
(2:1 mixture)
15
16
17
19
COOMe
COOMe
COOMe
COOMe
MeSO3H, DCE
120 oC, 2 h
1) NaBH4, diglyme, 1 h
PCC, DCM
6 h, rt, 82%
O
O
O
O
O
2) Me2SO4, K2CO3
acetone, 40 oC, 12 h
75% (over 2 steps)
O
80%
OH
O
HO
O
O
OMe
O
21
22
20
23
1) LiOH, THF/ H2O
2) DPPA, Et3N, t-BuOH
reflux, 3 h
85% over2 steps
Solid state structures of 21 and 20 with thermal elipsoids at 50% probability
O
NHBoc
NHBoc
NHBoc
BrMg
THF, -78 oC
1 h, 55%
NHBoc
25
O
O
DMP, CH2Cl2, Py
rt, 5 min, 70%
O
O
5
O
OMe
OH
6
O
O
O
O
O
24
27
28
26
DMP, CH2Cl2, Py
rt, 5 h, 68%
Scheme 2. Synthesis of naphthoquinone core of divergolides C (1) and D (2), and model studies of C5–C6 bond formation.
carbonyls for further manipulations. Thus the lactone 21 was pre-
pared in a facile way starting from the ester through the lactoniza-
tion of naphthol ester 20 with methanesulfonic acid in refluxing
dichloroethane conditions, whose structure was confirmed
through X-ray crystallography. The lactone 21 was selectively
manipulated and converted into N-Boc-carbamate derivative 24
through a series of functional group interconversions as shown in
Scheme 2. Briefly, the carboxylic acid precursor for Curtius rear-
rangement was made through the sequence of selective reduction
of lactone 21 to alcohol, methylation of the resulting phenol 22,
oxidation of the primary alcohol to aldehyde 23 and hydrolysis
of the ester.23 Facile Curtius rearrangement of the acid under mod-
ified conditions24 in t-BuOH allowed the introduction of the carba-
mate group on to the B-ring. Limited attempts to introduce the
missing oxygen on to the B-ring of carbamate 24 at this stage of
the synthesis were unproductive.25 We reasoned that proceeding
with monooxygenated B-ring might prove useful for annulation
of the C-ring later on in the synthesis efforts via aromatic Claisen
rearrangement. Hence, we decided to establish the efficacy of the
C5–C6 bond formation through the Grignard reaction of the alde-
hyde 24 as we were aware of the problems due to the steric
encumbrance at C5.26 We were delighted with the clean outcome
of the reaction of aldehyde 24 with Grignard reagent 25 to afford
the alcohol 26. Probably, it is the electrophilicity of our aromatic
partner that helped us in doing away with the perils associated
with this coupling with organomagenisum reagent 24.27 It was fur-
ther gratifying to observe the concomitant oxidation of the alcohol
to the naphthoquinone ketone 28 with DMP/pyridine conditions in
an opened flask at ambient temperatures.28 It is pertinent to men-
tion that this transform has not been optimized further and we are
currently studying the scope and the limitations of DMP mediated
oxidation of such amino compounds to naphthoquinones.
Conclusions
In summary, we have developed facile chemistry to convert
inexpensive 3-methylsalicylic acid into the naphthoquinone core
of ansamycins, specifically suitable for divergolides C–D and hyg-
rocins A–B, and established the efficacy of the difficult C5–C6 bond
formation using a model substrate for aliphatic (C6–C12) fragment
which is currently being synthesized through the chiron approach
in our lab. The inexpensive, readily available starting materials and
the sequence of simple operations lend this route amenable to ac-
cess the naphthalenic intermediates in large scales required for
further elaboration to complex ansamycins. The lactone 21 is also
poised for coupling studies for C5–C6 bond formation, provided if
we can introduce a non-electrophilic group in the place of carbeth-
oxy group and we are currently exploring the Wittig olefination
with modified phosphoranes to introduce the nitro or carbamate
directly on to the B-ring of 21. Optimization of the synthesis of
20 using the Knochel’s regioselective acylation conditions29 to
improvise the overall synthetic efficiency along with the applica-
tion of the model studies described herein to complete the total
synthesis of the targets is underway in our laboratory and will be
reported in near future.
Acknowledgments
This work was supported through the Startup and Healey Foun-
dation funds of UMass Dartmouth, and partly from Microbiotix,

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S. Rasapalli et al. / Tetrahedron Letters 54 (2013) 2615–2618
9. (a) Keller-Schierlein, W.; Meyer, M.; Cellai, L.; Cerrini, S.; Lamba, D.; Segre, A.;
Fedeli, W.; Brufani, M. J. J. Antibiot. 1984, 37, 1357; (b) Lu, C.; Shen, Y. J. Antibiot.
2007, 60, 649; (c) Wilson, M. C.; Nam, S.-J.; Gulder, T. A. M.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W.; Moore, B. S. J. Am. Chem. Soc. 2011, 133, 1971; (d)
Whitfield, G. B.; Olson, E. C.; Herr, R. R.; Fox, J. A.; Bergy, M. E.; Boyack, G. A. Am.
Rev. Tuberc. Pulm. Dis. 1957, 75, 584; (e) DeBoer, C.; Meulman, P. A.; Wnuk, R. J.;
Peterson, D. H. J. Antibiot. 1970, 23, 442; (f) Sasaki, K.; Rinehart, K. L., Jr. J. Am.
Chem. Soc. 1970, 92, 7591; (g) Omura, S.; Iwai, Y.; Takahashi, Y.; Sadakane, N.;
Nakagawa, A. J. Antibiot. 1979, 32, 255; (h) Omura, S.; Nakagawa, A.; Sadakane,
N. Tetrahedron Lett. 1979, 20, 4323.
10. Yun, H.; Chou, T.; Dong, H.; Tian, Y.; Li, Y.; Danishefsky, S. J. J. Org. Chem. 2005,
70, 10375.
11. (a) Kuttruff, C. A.; Geiger, S.; Cakmak, M.; Mayer, P.; Trauner, D. Org. Lett. 2012,
14, 1070; (b) Zhao, G.; Wu, J.; Dai, W.-M. Synlett 2012, 2845; (c) Pennington, L.
L.; Moody, C. J. Abstracts of Papers, 238th ACS National Meeting, Washington,
DC, United States, 2009
Inc, Worcester. We thank Dr. Venkataraman Dandapani for his help
with acquiring some NMR spectra of advanced intermediates in
this study.
Supplementary data
Supplementary data (crystallographic data excluding structure
factors) for the structures 20 and 21 in this paper have been depos-
ited with the Cambridge Crystallographic Data Centre as supple-
mentary publication Nos. CCDC 922930 and CCDC 922929,
respectively. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
(fax: +44 (0)1223-336033 or e-mail: deposit@ccdc.cam.ac.Uk)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2013.03.022.
12. (a) Fenical, W.; Jensen, P. R. Nat. Chem. Biol. 2006, 2, 666; (b) Koehn, F. E.;
Carter, G. T. Nat. Rev. Drug Disc. 2005, 4, 206.
13. Stereochemistry of the C8 (as per the numbering of the divergolides of
Hertweck) has not been assigned unequivocally: Cai, P.; Kong, F. M.; Ruppen,
M. E.; Glasier, G.; Carter, G. T. J. Nat. Prod. 2005, 68, 1736.
14. (a) Shah, A.; Sivappa, R.; Mello, C.; Singh, B. R.; Cai, S. J. Med. Plants Res. 2012, 6,
234–242; (b) Rasapalli, S.; Saibu, A. A. 38th ACS Northeast Regional Meeting,
Rochester, NY, USA, Sept 30–Oct 3, 2012.; (c) Rasapalli, S.; Dhawane, A. 242nd
ACS National Meeting, Philadelphia, USA, Aug 19–23, 2012
15. The alternative disconnection has also been under communication.
16. (a) Ding, L.; Maier, A.; Fiebig, H.-H.; Goerls, H.; Lin, W.-H.; Peschel, G.;
Hertweck, C. Angew. Chem., Int. Ed. 2011, 50, 1630; (b) Cai, P.; Kong, F. M.;
Ruppen, M. E.; Glasier, G.; Carter, G. T. J. Nat. Prod. 2005, 68, 1736.
17. Rateb, M. E.; Houssen, W. E.; Arnold, M.; Abdelrahman, M. H.; Deng, H.;
Harrison, W. T. A.; Okoro, C. K.; Asenjo, J. A.; Andrews, B. A.; Ferguson, G.; Bull,
A. T.; Goodfellow, M.; Ebel, R.; Jaspars, M. J. Nat. Prod. 2011, 74, 1491–1499.
18. Deng, B. L.; Hartman, T. L.; Buckheit, R. W., Jr.; Pannecouque, C.; De Clercq, E.;
Fanwick, P. E.; Cushman, M. J. Med. Chem. 2005, 48, 6140.
19. Caulfield, T. J.; J. Clemens, R. S.; Francis, B. S.; Freed, S.; John, T.-B.; Le, B.;
Pedgrift, A. D.; Ramos, G.; Rosse, M.; Smrcina, D. S.; Thorpe, W.; Wire, J. Z. PCT
Int. Appl. WO 2008151211, 2008.; (b) Duff, J. C. J. Chem. Soc. 1947, 547.
20. (a) Hoveyda, H.; Brantis, C. E.; Dutheuil, G.; Zoute, L.; Schils, D.; Fraser, G. PCT
Int. Appl. WO 2011076732, 2011.; (b) Caulfield, T. J.; J. Clemens, R. S.; Francis, B.
S.; Freed, S.; John, T.-B.; Le, B.; Pedgrift, A. D.; Ramos, G.; Rosse, M.; Smrcina, D.
S.; Thorpe, W.; Wire, J. Zhao. PCT Int. Appl. WO 2008151211, 2008.; (c)
McKenna, J.; Papa, P. W.; Sakata, S. T.; Erdman, P. E.; Packard, G. K. PCT Int.
Appl. 2007084560.; (d) Hoveyda, H.; Brantis, C. E.; Dutheuil, G.; Zoute, L.;
Schils, D.; Bernard, J. PCT Int. Appl. 2010066682.
References and notes
1. For recent reviews on ansamycin natural products, see: (a) Wrona, I. E.;
Agouridas, V.; Panek, J. S. C. R. Acad. Sci. (Paris) 2008, 11, 1483; (b) Floss, H. G.;
Yu, T. W. Chem. Rev. 2005, 105, 621; (c) Kang, Q.; Shen, Y.; Bai, L. Nat. Prod. Rep.
2012, 29, 243; (d) Funayama, S.; Cordell, G. A. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science: Amsterdam, 2000; Vol. 23, p
51.; (e) Bryskier, A. In Antimicrobial Agents; Bryskier, A., Ed.; ASM Press:
Washington, DC, 2005; p 906.
2. (a) Calvori, C.; Frontali, L.; Leoni, L.; Tecce, G. Nature 1965, 207, 417–418; (b)
Sensi, P.; Margalith, P.; Timbal, M. Farmaco Ed. Sci. 1959, 14, 146; (c) Xu, W.;
Neckers, L. Clin. Cancer Res. 2007, 13, 1625; (d) Miyata, Y. Curr. Pharm. Des.
2005, 11, 1131.
3. (a) Bhuyan, B. K.; Owen, S. P.; Dietz, A. Antimicrob. Agents Chemother. 1965, 10,
91; (b) Williams, T. H. J. Antibiot. 1975, 28, 85; (c) Lu, C. H.; Shen, Y. M. J.
Antibiot. 2007, 60, 649; (d) Meyer, M.; Keller-Schierlein, W.; Megahed, S.;
Zahner, H.; Segre, A. Helv. Chim. Acta 1986, 69, 1356; (e) Mukhopadhyay, T.;
Franco, C. M.; Reddy, G. C.; Ganguli, B. N.; Fehlhaber, H. W. J. Antibiot. 1985, 38,
948; (f) Yang, Y. H.; Fu, X. L.; Li, L. Q.; Zeng, Y.; Li, C. Y.; He, Y. N.; Zhao, P. J. J. Nat.
Prod. 2012, 75, 1409; (g) Chen, M.; Roush, W. R. J. Org. Chem. 2013, 78, 3.
4. (a) Rinehart, K. L.; Shield, L. S. Prog. Chem. Org. Nat. Prod. 1976, 33, 231; (b)
Rinehart, K. L., Jr.; Antosz, F. J.; Deshmukh, P. V.; Kakinuma, K.; Martin, P. K.;
Milavetz, B. I.; Sasaki, K.; Witty, T. R.; Li, L. H.; Ruesser, F. J. Antibiot. 1976, 29,
201; (c) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990, 112,
6348; (d) Roush, W. R.; Coffey, D. S.; Madar, D. J. J. Am. Chem. Soc. 1997, 119,
11331.
5. (a) Fukuyo, Y.; Hunt, C. R.; Horikoshi, N. Cancer Lett. 2010, 290, 24; (b) DeBoer,
C.; Meulman, P. A.; Wnuk, R. J.; Peterson, D. H. J. Antibiot. (Tokyo) 1970, 23, 442;
(c) Sasaki, K.; Rinehart, K. L., Jr.; Slomp, G.; Grostic, M. F.; Olson, E. C. J. Am.
Chem. Soc. 1970, 92, 7591; (d) Johnson, R. D.; Haber, A.; Rinehart, K. L., Jr. J. Am.
Chem. Soc. 1974, 96, 3316; (e) BeBoer, C.; Dietz, A. J. Antibiot. 1976, 29, 1182; (f)
Porter, J. R.; Ge, J.; Lee, J.; Normant, E.; West, K. Curr. Top. Med. Chem. 2009, 9,
1386; Li, T.; Ni, S.; Jia, C.; Wang, H.; Sun, G.; Wu, L.; Gan, M.; Shan, G.; He, W.;
Lin, L.; Zhou, H.; Wang, Y. J. Nat. Prod. 2012, 75, 1480.
21. (a) Nishiyama, T.; Miyazawa, M. J. Oleo Sci. 2003, 52, 331.
22. (a) Rizzacasa, M. A.; Sargent, M. V. Aust. J. Chem. 1987, 40, 1737; (b) Borsche, W.
Justus Liebigs Ann. Chem. 1936, 526, 1; (c) Tietze, L. F.; Liu, D. ARKIVOC 2008, 8,
193; (d) Nishiyama, T.; Miyazawa, M. J. Oleo Sci. 2003, 52, 331; (e) Vela, M. A.;
Fronczek, F. R.; Horn, G. W.; McLaughlin, M. L. J. Org. Chem. 1990, 55, 2913; (f)
Boger, D. L.; Turnbull, P. J. Org. Chem. 1998, 63, 8004; (g) Comber, M. F.; Sargent,
M. V. J. Chem. Soc., Perkin Trans. 1 1991, 2783; (h) Hughes, A. B.; Sargent, M. V. J.
Chem. Soc., Perkin Trans. 1 1989, 449; (i) Cason, J. J. Am. Chem. Soc. 1941, 63, 828;
(j) El-Abbady, A. M.; Doss, S. H.; Moussa, H. H.; Nosseir, M. J. Org. Chem. 1961,
26, 4871; (k) House, H. O.; Larson, J. K. J. Org. Chem. 1968, 33, 448.
23. (a) Packer, R. J.; Smith, D. C. C. J. Chem. Soc. 1967, 2194; (b) Cammidge, A. N.;
Ozturk, O. J. Org. Chem. 2002, 67, 7457.
6. (a) Rascher, A.; Hu, Z.; Buchanan, G. O.; Reid, R.; Hutchinson, C. R. Appl. Environ.
Microbiol. 2005, 71, 4862–4871; (b) Omura, S. Y.; Iwai, Y.; Takahashi, N.;
Sadakane, A.; Nakagawa, H.; Oiwa, Y.; Hasegawa; Ikai, T. J. Antibiot. 1979, 32,
255; (c) Canova, S.; Bellosta, V.; Bigot, A.; Mailliet, P.; Mignani, S.; Cossy, J. Org.
Lett. 2007, 9, 145; (d) Omura, S.; Iwai, Y.; Sakadane, N.; Nakagawa, A.; Oiwa, H.;
Hasegawa, Y.; Ikai, T. J. Antibiot. 1979, 32, 255; (e) Omura, S.; Nakagawa, A.;
Sadakane, N. Tetrahedron Lett. 1979, 44, 4323; (f) Furusaki, A.; Matsumoto, T.;
Nakagawa, A.; Omura, S. J. Antibiot. 1980, 33, 781; (g) Shibata, K.;
Satsumabayashi, S.; Sano, H.; Komiyama, K.; Nakagawa, A.; Omura, S. J.
Antibiot. 1986, 39, 415; (h) Lin, L.-Z.; Blasko, G.; Cordell, G. A. J. Nat. Prod. 1988,
51, 1161; (i) Yamaki, H.; Iguchi-Ariga, S. M. M.; Ariga, H. J. Antibiot. 1989, 42,
604; (j) Yamashita, T.; Sakai, M.; Kawai, Y.; Aono, M.; Takahashi, K. J. Antibiot.
1989, 42, 1015; (k) Suzukake-Tsuchiya, K.; Moriya, Y.; Hori, M.; Uehara, Y.;
Takeuchi, T. J. Antibiot. 1989, 42, 1831; (l) Nagaishi, K.; Adachi, R.; Matsui, S.;
Yamaguchi, T.; Kasahara, T.; Suzuki, K. J. J. Cell. Phys. 1999, 180, 345; (m)
Sakagami, M.; Morrison, P.; Welch, W. J. Cell Stress Chaperones 1999, 4, 19; (n)
Janin, Y. L. J. Med. Chem. 2005, 48, 7503.
24. (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94, 6203; (b)
Lebel, H.; Leogane, O. Org. Lett. 2006, 8, 5717; (c) Ninomiya, K.; Shioiri, T.;
Yamada, S. Tetrahedron 1974, 30, 2151; (d) Murato, K.; Shioiri, T.; Yamada, S.
Chem. Pharm. Bull. 1975, 23, 1738; (e) Capson, T. L.; Poulter, C. D. Tetrahedron
Lett. 1984, 25, 3515; (f) Wolff, O.; Waldvogel, S. R. Synthesis 2004, 1303; (g)
Sawada, D.; Sasayama, S.; Takahashi, H.; Ikegami, S. Tetrahedron Lett. 2006, 47,
7219.
25. (a) Ueda, S.; Nagasawa, H. Angew. Chem., Int. Ed. 2008, 47, 6411; (b) Ueda, S.;
Nagasawa, H. J. Org. Chem. 2009, 74, 4272.
26. Kuttruff, C. A.; Geiger, S.; Cakmak, M.; Mayer, P.; Trauner, D. Org. Lett. 2012, 14,
1070.
27. We are currently evalauting the addition of long chain RLis which is not as
straightforward.
28. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155; (b) Dess, D. B.; Martin, J.
C. J. Am. Chem. Soc. 1991, 113, 7277; (c) Luo, H. B.; Xie, Y. Y. Chin. Chem. Lett.
2003, 14, 555; (d) Magdziak, D.; Rodriguez, A. A.; Van De Water, R. W.; Pettus,
T. R. R. Org. Lett. 2002, 4, 285. and references there in.
29. (a) Wunderlich, S. H.; Bresser, T.; Dunst, C.; Monzon, G.; Knochel, P. Synthesis
2010, 15, 2670; (b) Wunderlich, S. H.; Knochel, P. Angew. Chem., Int. Ed. 2007,
46, 7685.
7. Ding, L.; Maier, A.; Fiebig, H.-H.; Goerls, H.; Lin, W.-H.; Peschel, G.; Hertweck, C.
Angew. Chem., Int. Ed. 2011, 50, 1630.
8. Cai, P.; Kong, F. M.; Ruppen, M. E.; Glasier, G.; Carter, G. T. J. Nat. Prod. 2005, 68,
1736.