Synthesis of the QRSTU domain of maitotoxin and its 85- epi - And 86- epi -diastereoisomers

Article abstract of DOI:10.1021/ja103708j

A devised synthetic strategy toward the QRSTU ring system 4 of the marine-derived biotoxin maitotoxin (1) delivered, in addition to 4, its diastereoisomers 85-epi-QRSTU and 86-epi-QRSTU ring systems 5 and 6. The convergent route to these maitotoxin fragments involved coupling of UT and Q building blocks 9 (obtained from 2-deoxy-d-ribose) and 10 (obtained from d-ribose) followed by ring-closing metathesis to afford enol ether 8, whose elaboration to the targeted QRSTU ring system 4 required its conversion to hydroxy ketone 7. The latter compound (7) was transformed to the final product through a hydroxy dithioketal cyclization, followed by oxidation/methylation of the resulting O,S-mixed ketal to install the last of the five methyl groups contained within the target molecule (4). ¹³C NMR spectroscopic analysis of synthesized fragments 4, 5, and 6 and comparisons with maitotoxin provided strong support for the originally assigned structure of the QRSTU domain of the natural product.

Full text of DOI:10.1021/ja103708j

Published on Web 06/25/2010
Synthesis of the QRSTU Domain of Maitotoxin and Its 85-epi-
and 86-epi-Diastereoisomers
K. C. Nicolaou,* Christine F. Gelin, Jae Hong Seo, Zhihong Huang, and
Taiki Umezawa
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research
Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and Department of
Chemistry and Biochemistry, UniVersity of California, San Diego, 9500 Gilman DriVe,
La Jolla, California 92093
Received April 30, 2010; E-mail: kcn@scripps.edu
Abstract: A devised synthetic strategy toward the QRSTU ring system 4 of the marine-derived biotoxin
maitotoxin (1) delivered, in addition to 4, its diastereoisomers 85-epi-QRSTU and 86-epi-QRSTU ring
systems 5 and 6. The convergent route to these maitotoxin fragments involved coupling of UT and Q
building blocks 9 (obtained from 2-deoxy-D-ribose) and 10 (obtained from D-ribose) followed by ring-closing
metathesis to afford enol ether 8, whose elaboration to the targeted QRSTU ring system 4 required its
conversion to hydroxy ketone 7. The latter compound (7) was transformed to the final product through a
hydroxy dithioketal cyclization, followed by oxidation/methylation of the resulting O,S-mixed ketal to install
the last of the five methyl groups contained within the target molecule (4). 13C NMR spectroscopic analysis
of synthesized fragments 4, 5, and 6 and comparisons with maitotoxin provided strong support for the
originally assigned structure of the QRSTU domain of the natural product.
Introduction
maitotoxin, the only extended ring system of the molecule that
remained elusive until now, and its two diastereoisomers,
Maitotoxin (1, Figure 1) is the largest (MW 3422 Da) and
most toxic secondary metabolite discovered to date.1 The
Yasumoto group reported its isolation from the dinoflagellate
Gambierdiscus toxicus in 1988,1d,e and its gross structure in
1993.2 By 1996, the work of Yasumoto et al.,3 Kishi et al.4 and
Tachibana et al.5 culminated in the assignment of the complete
relative stereochemistry of this structure and its absolute
configuration. Hailed as the most powerful nonproteinoic
biotoxin, maitotoxin exerts its neurotoxicity through binding to
cell membrane ion channels, an interference that results in
harmful Ca2+ ion influx.6 We recently reported the synthesis of
the GHIJKLMNO and ABCDEFG fragments, 2 and 3, of this
natural product (Figure 1).7,8 In this article, we report the
chemical synthesis of the QRSTU ring system (4, Figure 1) of
epimeric at C85 (5, Figure 1) and C86 (6, Figure 1). We also
report the spectroscopic analysis and comparison of these
synthetic QRSTU polycyclic systems with maitotoxin, providing
further support for the originally assigned structure of the
QRSTU domain of this highly complex marine natural product.
Results and Discussion
The pentacyclic QRSTU ring framework of maitotoxin is distinct
from any other within this and other polyether marine biotoxins in
that it includes a high density of angular methyl groups, namely
five.9 This high degree of methyl substitution imparts severe steric
congestion to the structure, amounting to a special challenge to its
construction, particularly with regard to the fusion of certain rings
(1) (a) Murata, M.; Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293. (b)
Yasumoto, T.; Bagnins, R.; Randal, J. E.; Banner, A. H. Nippon Suisan
Gakkaishi 1971, 37, 724. (c) Yasumoto, T.; Bagnins, R.; Vernoux,
J. P. Nippon Suisan Gakkaishi 1976, 42, 359. (d) Yasumoto, T.;
Nakajima, I.; Bagnis, R.; Adachi, R. Nippon Suisan Gakkaishi 1977,
43, 1021. (e) Yokoyama, A.; Murata, M.; Oshima, Y.; Iwashita, T.;
Yasumoto, T. J. Biochem. 1988, 104, 184.
(6) (a) Murata, M.; Iwashita, T.; Yokoyama, A.; Sasaki, M.; Yasumoto,
T. J. Am. Chem. Soc. 1992, 114, 6594. (b) Murata, M.; Naoki, H.;
Iwashita, T.; Matsunaga, S.; Sasaki, M.; Yokoyama, A.; Yasumoto,
T. J. Am. Chem. Soc. 1993, 115, 2060. (c) Murata, M.; Naoki, H.;
Matsunaga, S.; Satake, M.; Yasumoto, T. J. Am. Chem. Soc. 1994,
116, 7098. (d) Satake, M.; Ishida, S.; Yasumoto, T. J. Am. Chem.
Soc. 1995, 117, 7019. (e) Konoki, K.; Hashimoto, M.; Murata, M.;
Tachibana, K. Chem. Res. Toxicol. 1999, 12, 993. (f) Murata, M.;
Matsumori, N.; Konoki, K.; Oishi, T. Bull. Chem. Soc. Jpn. 2008, 81,
307.
(2) Murata, M.; Naoki, H.; Iwashita, T.; Matsunaga, S.; Sasaki, M.;
Yokoyama, A.; Yasumoto, T. J. Am. Chem. Soc. 1993, 115, 2060.
(3) (a) Murata, M.; Iwashita, T.; Yokoyama, A.; Sasaki, M.; Yasumoto,
T. J. Am. Chem. Soc. 1992, 114, 6594. (b) Murata, M.; Naoki, H.;
Matsunaga, S.; Satake, M.; Yokoyama, A.; Yasumoto, T. J. Am. Chem.
Soc. 1994, 116, 7098. (c) Satake, M.; Ishida, S.; Yasumoto, T. J. Am.
Chem. Soc. 1995, 117, 7019.
(7) (a) Nicolaou, K. C.; Cole, K. P.; Frederick, M. O.; Aversa, R. J.;
Denton, R. M. Angew. Chem., Int. Ed. 2007, 46, 8875. (b) Nicolaou,
K. C.; Frederick, M. O.; Burtoloso, A. C. B.; Denton, R. M.; Rivas,
F.; Cole, K. P.; Aversa, R. J.; Gibe, R.; Umezawa, T.; Suzuki, T.
J. Am. Chem. Soc. 2008, 130, 7466.
(4) Zheng, W.; DeMattei, J. A.; Wu, J. P.; Duan, J. J.; Cook, L. R.;
Oinuma, H.; Kishi, Y. J. Am. Chem. Soc. 1996, 118, 7946.
(5) (a) Sasaki, M.; Matsumori, N.; Muruyama, T.; Nonomura, T.; Murata,
M.; Tachibana, K.; Yasumoto, T. Angew. Chem., Int. Ed. Engl. 1996,
35, 1672. (b) Nonomura, T.; Sasaki, M.; Matsumori, N.; Murata, M.;
Tachibana, K.; Yasumoto, T. Angew. Chem., Int. Ed. Engl. 1996, 35,
1675.
(8) Nicolaou, K. C.; Aversa, R. J.; Jin, J.; Rivas, F. J. Am. Chem. Soc.
2010, 132, 6855.
(9) For selected reviews on the synthesis of fused polyether natural
products, see: (a) Nicolaou, K. C.; Frederick, M. O.; Aversa, R. J.
Angew. Chem., Int. Ed. 2008, 47, 7182. (b) Nakata, T. Chem. ReV.
2005, 105, 4314. (c) Inoue, M. Chem. ReV. 2005, 105, 4379.
9
9900 J. AM. CHEM. SOC. 2010, 132, 9900–9907
10.1021/ja103708j  2010 American Chemical Society

Synthesis of the QRSTU Domain of Maitotoxin
A R T I C L E S
Figure 1. Structures of maitotoxin (1), previously synthesized maitotoxin domains GHIJKLMNO (2) and ABCDEFG (3), targeted QRSTU domain (4), and
its diastereomeric 85-epi-QRSTU domain (5) and 86-epi-QRSTU domain (6).
and the proper spacial placement of these methyl groups around
the periphery of the target molecule.
primary alcohol 13 gave aldehyde 14, which reacted with
stabilized phosphorane Ph3PC(Me)CO2Et to afford R,ꢀ-unsatur-
ated ester 15 in 91% overall yield. DIBAL-H reduction of the
latter compound (95% yield) and Sharpless asymmetric epoxi-
dation13 of the resulting allylic alcohol (16) led to epoxide 17
in 95% yield. Transformation of epoxide 17 to R,ꢀ-unsaturated
ester epoxide 19 was achieved through SO3 ·py oxidation to
afford aldehyde 18 and reaction of the latter intermediate with
Ph3PCHCO2Me (98% overall yield for the two steps). In
anticipation of the pending ring T closure, the TBS group was
removed from 19 (TBAF, 100% yield) to furnish hydroxy
epoxide 20. Exposure of the latter intermediate to PPTS
Retrosynthetic Analysis. Aiming for optimum convergency
and flexibility for the synthetic strategy toward our defined
structure (i.e., 4), we focused on the retrosynthetic blueprint
depicted in Figure 2. It was envisioned that the oxepane ring in
4 may be forged through a hydroxy dithioketal cyclization of
7,10 followed by installation of the final angular methyl group
at C85. It was reasoned that ketone 7 might arise from enol ether
8. Disassembly of the R ring of the latter intermediate at the
indicated bonds suggested its construction from building blocks
9 and 10 through ester coupling followed by a Takai olefination/
ring-closing metathesis cascade sequence.11 Finally, the two
tetrahydropyran systems 9 and 10 could be traced back to the
enantiomerically pure, and readily available, starting materials,
2-deoxy-D-ribose (11) and D-ribose (12), respectively.
Construction of UT and Q Fragments 9 and 10. Having
defined building blocks 9 and 10 as potential precursors to the
targeted maitotoxin fragment, their synthesis was commenced
in earnest. Scheme 1 summarizes the construction of fragment
9 starting from 2-deoxy-D-ribose (11). Thus, following a
previously developed route,12 intermediate 13 was synthesized
from 11 (11 steps, 43% overall yield). Swern oxidation of
(11) Takai-Utimoto reagent: (a) Takai, K.; Kakiuchi, T.; Kataoka, Y.;
Utimoto, K. J. Org. Chem. 1994, 59, 2668. For a review summarizing
the applications of olefin metathesis in the synthesis of fused polyethers
see: (b) Clark, J. S. Chem. Commun. 2006, 3571. For earlier methods
using ring-closing metathesis to form enol ethers, see: (c) Fu, G. C.;
Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 5426. (d) Fu, G. C.;
Nguyn, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9856. (e)
Fujimura, O.; Fu, G. C.; Grubbs, R. H. J. Org. Chem. 1994, 59, 4029.
(f) Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J. Am. Chem.
Soc. 1996, 118, 1565. (g) Nicolaou, K. C.; Postema, M. H. D.; Yue,
E. W.; Nadin, A. J. Am. Chem. Soc. 1996, 118, 10335. (h) Clark,
J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38, 123. (i) Clark, J. S.;
Kettle, J. G. Tetrahedron 1999, 55, 8231. For recent work using the
Takai-Utimoto reagent for the synthesis of polyethers, see: (j)
Majumder, U.; Rainier, J. D. Tetrahedron Lett. 2005, 46, 7209. (k)
Iyer, K.; Rainier, J. D. J. Am. Chem. Soc. 2007, 129, 12604.
(12) Nicolaou, K. C.; Nugiel, D. A.; Couladouros, E.; Hwang, C.-K.
Tetrahedron. 1990, 46, 4517.
(10) (a) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.; Duggan, M. E.;
Veale, C. A. J. Am. Chem. Soc. 1989, 111, 5321. (b) Nicolaou, K. C.;
Duggan, M. E.; Hwang, C.-K. J. Am. Chem. Soc. 1986, 108, 2468.
(c) Nicolaou, K. C.; Yang, Z.; Shi, G.-Q.; Gunzner, J. L.; Agrios,
K. A.; Ga¨rtner, P. Nature 1998, 392, 264.
(13) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5976.
(b) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
9
J. AM. CHEM. SOC. VOL. 132, NO. 28, 2010 9901

A R T I C L E S
Nicolaou et al.
Scheme 1. Synthesis of UT Ring System 9a
a Reagents and conditions: a) (COCl)2 (1.5 equiv), DMSO (2.0 equiv),
CH2Cl2, -78 °C, 20 min; then Et3N (4.0 equiv), 0 °C, 30 min; b)
Ph3PCMe(CO2Et) (1.3 equiv), PhMe, 70 °C, 3 h, 91% over the two steps;
c) DIBAL-H (1.0 M in CH2Cl2, 2.5 equiv), CH2Cl2, -78 °C, 1 h, 95%; d)
(-)-DET (0.26 equiv), Ti(i-PrO)4 (0.22 equiv), t-BuOOH (5.0 M in decane,
1.5 equiv), 4 Å MS, CH2Cl2, -20 °C, 10 h, 95%; e) SO3 ·py (3.0 equiv),
Et3N (5.0 equiv), CH2Cl2:DMSO (4:1), 25 °C, 1 h; f) Ph3PCH(CO2Me)
(1.3 equiv), CH2Cl2, 25 °C, 12 h, 98% over the two steps; g) TBAF (1.5
equiv), THF, 25 °C, 1 h, 100%; h) PPTS (1.0 equiv), CH2Cl2, 50 °C, 3 h,
97%; i) H2, 10% Pd/C (20% w/w), EtOAc, 25 °C, 17 h, 94%; j)
PMBOC(NH)CCl3 (1.4 equiv), La(OTf)3 (0.05 equiv), PhMe, 25 °C, 30
min, 96%; k) CSA (0.2 equiv), CH2Cl2:MeOH (2:3), 25 °C, 12 h, 90%; l)
TBSCl (3.0 equiv), imid. (5.0 equiv), DMF, 25 °C, 6 h, 99%; m) LiOH
(4.0 equiv), THF:H2O (2:1), 25 °C, 20 h, 100%. DMF ) dimethyl
formamide, imid. ) imidazole, PMB ) p-methoxybenzyl, PPTS )
pyridinium p-toluenesulfonate.
Figure 2. Retrosynthetic analysis of QRSTU pentacyclic system 4.
facilitated the intended cyclization (97% yield),14 which was
followed by hydrogenation (H2, 10% Pd/C, 94% yield) of the
resulting product to afford the desired UT ring system hydroxy
methyl ester 21. The inversion of configuration of the Me-
bearing center during the hydroxyl epoxide cyclization secured
the desired stereochemical arrangement in the growing molecule
(i.e., 21). Protection of the hydroxyl group within the latter
compound [(PMBOC(NH)CCl3, La(OTf)3 cat., 96% yield], fol-
lowed by removal of the benzylidene group (CSA, 90% yield) gave
diol 23. bis-Silylation of diol 23 (TBSCl, imid.) followed by
saponification of the resulting methyl ester bis-TBS ether derivative
yielded UT carboxylic acid fragment 9 (100% overall yield).
The construction of fragment Q (10) commenced from
D-ribose (12) and proceeded as shown in Scheme 2. Thus,
following a previously reported sequence,15 12 was converted
to hydroxy R,ꢀ-unsaturated ester 24 (three steps, 65% overall
yield). Silylation of 24 (TESOTf, 2,6-lut., 88% yield), followed
by DIBAL-H reduction (96% yield) and Sharpless asymmetric
epoxidation16 gave hydroxy epoxide 25 in 80% yield. Parikh-
Doering oxidation17 of 25 led to aldehyde 26, whose methyl-
enation (PPh3dCH2) and desilylation (TBAF) afforded diol
epoxide 28 with an 86% overall yield for the three steps.
Initially, exposure of epoxide 28 to different protic acids (i.e.,
PPTS, CSA) in either catalytic or stochiometric amounts under
various conditions did not promote the desired ring closure in
acceptable yields. Finally, it was found that, when epoxide 28
was subjected to the conditions recently reported by the Jamison
group (H2O, 70 °C, 24 h),18 the desired tetrahydropyran
compound 29 was obtained in excellent yield (83%), and with
(14) Nicolaou, K. C.; Veale, C. A.; Hwang, C.-K.; Hutchinson, J.; Prasad,
C. V. C.; Ogilvie, W. W. Angew. Chem., Int. Ed. Engl. 1991, 30,
299.
(16) Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Redd, L. A.; Sharpless,
K. B.; Walker, F. J. Tetrahedron 1990, 46, 245.
(15) (a) Kane, P. D.; Mann, J. J. Chem. Soc., Chem. Commun. 1983, 224.
(b) Kane, P. D.; Mann, J. J. Chem. Soc., Perkin Trans. I 1984, 657.
(17) Parikh, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89, 5505.
9
9902 J. AM. CHEM. SOC. VOL. 132, NO. 28, 2010

Synthesis of the QRSTU Domain of Maitotoxin
A R T I C L E S
Scheme 2. Synthesis of Q Ring Building Block 10a
stereocenter. With the Q ring cast, a four-step functionalization
sequence of the growing molecule [(i) tosylation (TsCl, Et3N,
97% yield) of the primary alcohol; (ii) benzylation (BnBr, NaOt-
Bu, 100% yield) of the secondary alcohol; (iii) acetonide
cleavage (CSA, 85% yield); and (iv) benzylidene formation
(PhCH(OMe)2, CSA, 75% yield)] gave fully protected inter-
mediate 30. Regioselective hydroboration/oxidation (9-BBN, aq
H2O2/NaOH, 95% yield) of the vinyl group of 30, followed by
protection of the resultant primary alcohol (BnBr, NaOt-Bu, 86%
yield) and regioselective opening of the benzylidene with
DIBAL-H yielded alcohol 31. Exposure of the latter compound
(31) to KCN in DMSO at 80 °C, followed by silylation of the
free alcohol (TBSOTf, 2,6-lut.), furnished nitrile 32 in 81% yield
over the three steps. Reduction of nitrile 32 with DIBAL-H set
the stage for installation of the substituted methylene unit, which
was carried out with CH3CH2PPh3Br and NaHMDS (81% yield
over the two steps)19 to afford the corresponding olefin, whose
desilylation with TBAF provided hydroxy pyran 34. Finally,
transformation of 34 to the desired tertiary alcohol Q fragment
10 was readily accomplished through oxidation with DMP (to
afford ketone 35, 95% yield for the two steps) followed by the
addition of MeMgCl (98% yield). The exquisite stereocontrol
observed in the last reaction was expected on steric grounds as
revealed through manual molecular modeling.
Coupling of UT and Q Fragments 9 and 10. Union of the
two key building blocks 9 and 10 was achieved as shown in
Scheme 3. Our initial attempts to accomplish this task employing
the Yamaguchi esterification and other standard coupling conditions
failed to yield the desired product.20 It was soon discovered,
however, that by preforming the acid chloride of acid 9 using
(COCl)2 and catalytic amounts of DMF and adding to it the anion
of tertiary alcohol 10 (formed with KHMDS), the desired ester 37
was formed in 65% yield (100% based on 10).21 At this point it
was necessary to swap the two TBS groups for a cyclic silane [Si(t-
Bu)2] in order to augment the robustness of the growing substrate.
Thus, desilylation of 37 with TBAF, followed by reprotection of
the resultant diol 38 using t-Bu2Si(OTf)2 and 2,6-lutidine, afforded
cyclic silane ester 39 in 94% yield over the two steps. The stage
was now set for formation of the intended R ring enol ether. To
that end, 39 was subjected to the Takai-Utimoto reaction to
achieve both the olefination and ring-closing metathesis in one pot,
furnishing enol ether 40 in 93% yield.11j,k Regioselective hydrobo-
ration of 40 and DMP oxidation of the resultant alcohol led to
diastereomeric ketones 41 and 42 (90% combined yield). As
anticipated from the diastereoselectivity of the hydroboration step,
the undesired 86-epi-QRSTU ketone 41 was the major product
(41:42 ∼3:1 dr), due to shielding of the R-face of the enol ether
substrate by the R-angular methyl group at C82. Epimerization of
the 86-epi-QRTSU ketone 41 to the desired diastereoisomer 42
was more problematic than expected. Thus, it was after considerable
experimentation that we found conditions to accomplish this goal
a Reagents and conditions: a) TESOTf (1.2 equiv), 2,6-lut. (1.5 equiv),
CH2Cl2, 0 °C, 14 h, 88%; b) DIBAL-H (1.0 M in CH2Cl2, 2.2 equiv),
CH2Cl2, -78 °C, 30 min, 96%; c) (-)-DET (0.39 equiv), Ti(i-PrO)4 (0.30
equiv), t-BuOOH (5.0 M in decane, 2.2 equiv), 4 Å MS, CH2Cl2, -20 °C,
48 h, 80%; d) SO3 ·py (3.0 equiv), Et3N (4.0 equiv), CH2Cl2/DMSO (5:1),
25 °C, 3 h; e) CH3PPh3Br (1.5 equiv), NaHMDS (1.0 M in THF, 1.4 equiv),
THF, 0 °C, 40 min; then 26 (1.0 equiv), THF, 0 f 25 °C, 3 h, 86% over
the two steps; f) TBAF (2.5 equiv), THF, 25 °C, 1 h, 100%; g) 0.1 M in
H2O, 70 °C, 16 h, 83%; h) TsCl (1.5 equiv), Et3N (1.9 equiv), CH2Cl2, 50
°C, 12 h, 97%; i) BnBr (2.0 equiv), NaOt-Bu (2.5 equiv), THF, 25 °C, 4 h,
100%; j) CSA (0.05 equiv), MeOH/CH2Cl2 (4:1), 25 °C, 48 h, 85%; k)
PhCH(OMe)2 (3.0 equiv), CSA (0.05 equiv), CH2Cl2, 25 °C, 24 h, 75%; l)
9-BBN (3.0 equiv), THF, 80 °C, 2 h; then H2O2 (35% aq, 15 equiv), NaOH
(3.0 M aq, 15 equiv), 25 °C, 3 h, 95%; m) BnBr (2.5 equiv), NaOt-Bu (3.0
equiv), THF, 25 °C, 2 h, 86%; n) DIBAL-H (1.0 M in CH2Cl2, 3.0 equiv),
CH2Cl2, 0 °C, 30 min; o) KCN (2.0 equiv), DMSO, 80 °C, 14 h; p) TBSOTf
(1.5 equiv), 2,6-lut. (2.0 equiv), CH2Cl2, 0 °C, 45 min, 81% over the three
steps; q) DIBAL-H (1.0 M in CH2Cl2, 3.0 equiv), Et2O, 0 °C, 30 min; r)
CH3CH2PPh3Br (3.2 equiv), NaHMDS (1.0 M in THF, 3.0 equiv), THF, 0
°C, 5 min; then 33 (1.0 equiv), THF, 0 °C, 15 min, 81% over the two
steps; s) TBAF (2.0 equiv), THF, 25 °C, 1 h; t) DMP (2.0 equiv), CH2Cl2,
25 °C, 30 min, 95% over the two steps; u) MeMgCl (4.0 equiv), Et2O, 0
°C, 20 min, 98%. 9-BBN ) 9-borabicyclo[3.3.1]nonane, Bn ) benzyl, CSA
) (()-camphor-10-sulfonic acid, DET ) diethyl tartrate, DIBAL-H )
diisobutylaluminum hydride, DMP ) Dess-Martin periodinane, DMSO
) dimethyl sulfoxide, lut. ) lutidine, NaHMDS ) sodium bis(trimethyl-
silyl)amide, py ) pyridine, TBAF ) tetra-n-butylammonium fluoride, TBS
) tert-butyldimethylsilyl, TES ) triethylsilyl, THF ) tetrahydrofuran, Ts
) p-toluenesulfonyl.
(18) (a) Vilotijevic, I.; Jamison, T. F. Science 2007, 317, 1189. For a
mechanistic study on the water-promoted cyclization of epoxy alcohols,
see: (b) Byers, J. A.; Jamison, T. F. J. Am. Chem. Soc. 2009, 131,
6383. For an application of water-promoted epoxide-opening cascades
toward total synthesis, see: (c) Van Dyke, A. R.; Jamison, T. F. Angew.
Chem., Int. Ed. 2009, 48, 4430. For a review on epoxide-opening
cascades in water, see: (d) Morten, C. J.; Byers, J. A.; Van Dyke,
A. R.; Vilotijevic, I.; Jamison, T. F. Chem. Soc. ReV. 2009, 38, 3175.
(19) Johnson, H. W. B.; Majumder, U.; Rainier, J. D. Chem.sEur. J. 2006,
12, 1747.
(20) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989. (b) Shiina, I.; Kubota, M.; Oshiumi,
H.; Hashizume, M. J. Org. Chem. 2004, 69, 1822.
the desired stereochemical arrangement by virture of the
accompanying inversion of configuration at the Me-bearing
(21) Wilmouth, S.; Pellissier, H.; Santelli, M. Tetrahedron 1998, 54, 10079.
9
J. AM. CHEM. SOC. VOL. 132, NO. 28, 2010 9903

A R T I C L E S
Nicolaou et al.
Scheme 4. Synthesis of 86-epi-QRSTU Ring System 6a
Scheme 3. Coupling of Fragments 9 and 10 and Synthesis of
86-epi-QRSTU Ketone 41 and QRSTU Ketone 42a
a Reagents and conditions: a) acid 9 (1.4 equiv), (COCl)2 (2.1 equiv),
DMF (0.1 mol %), PhH, 25 °C, 2 h; b) alcohol 10 (1.0 equiv), KHMDS
(1.4 equiv), THF, 0 °C, 15 min; then 36 (1.5 equiv), THF, 0 °C, 30 min,
65% (100% based on 10); c) TBAF (3.0 equiv), THF, 25 °C, 1.5 h; d)
t-Bu2Si(OTf)2 (1.5 equiv), 2,6-lut. (3.0 equiv), THF, 25 °C, 1 h, 94% over
the two steps; e) TiCl4 (33 equiv), TMEDA (190 equiv), THF (228 equiv),
Zn (71 equiv), PbCl2 (3.9 equiv), CH2Cl2, 25 °C, 20 min; then 39 (1.0
equiv), CH3CHBr2 (32 equiv), CH2Cl2, 60 °C, 1 h, 93%; f) BH3 ·THF (1.0
M in THF, 10 equiv), THF, 0 °C, 14 h; then H2O2 (35% aq, 15 equiv),
NaOH (3.0 M aq, 15 equiv), 25 °C, 5 h; g) DMP (2.0 equiv), NaHCO3 (4.0
equiv), CH2Cl2, 25 °C, 30 min, 90% over the two steps (∼3:1 dr 41:42); h)
K2CO3 (2.0 equiv), EtOH, 25 °C, 3 h, 89%. KHMDS ) potassium
bis(trimethylsilyl)amide, TMEDA ) N,N,N′,N′-tetramethyl-ethane-1,2-diamine.
a Reagents and conditions: a) DDQ (2.0 equiv), CH2Cl2:H2O (20:1), 0
°C, 3 h, 83%; b) Zn(OTf)2 (2.0 equiv), EtSH (48 equiv), CH2Cl2, 25 °C,
3 h, 77%; c) m-CPBA (5.0 equiv), CH2Cl2, 0 °C, 20 min; then Me3Al (2.0
M in heptanes, 10 equiv), 0 °C, 30 min, 93%; d) TBAF (5.0 equiv), THF,
25 °C, 19 h, 98%; e) H2, 20% Pd(OH)2/C (50% w/w), THF, 25 °C, 17 h,
100%. DDQ ) 2,3-dichloro-5,6-dicyanobenzoquinone, m-CPBA ) m-
chloroperbenzoic acid.
(K2CO3, EtOH, 25 °C, strictly anaerobic).22 Pleasantly, this protocol
channeled the undesired epimer (41) to the thermodynamically
favored QRSTU ketone 42 in 89% yield.
Synthesis of 86-epi-QRSTU, QRSTU, and 85-epi-QRSTU
Ring Systems of Maitotoxin. With ample quantities of the QRSTU
ketones 41 and 42 readily available, the drive toward the synthesis
of the QRSTU ring system 4 of maitotoxin was undertaken. As it
turned out, the developed route to QRSTU system 4 also delivered
its diastereoisomers, 85-epi-QRSTU and 86-epi-QRSTU ring
systems 5 and 6. Our first foray en route to the desired goal was
directed toward the 86-epi-QRSTU ring system 6, starting from
the initially obtained 86-epi-QRSTU ketone 41 in order to scout
the road ahead since it was readily available. In addition to the
preparation for the final drive toward the QRSTU ring system 4,
the construction of the 86-epi-QRSTU system would also allow
for its NMR spectroscopic comparisons with the primary target of
our investigation (i.e., QRSTU ring system 4) and maitotoxin,
thereby providing further support (or lack thereof) of the originally
assigned structure of that region of the natural product.
Scheme 4 depicts the synthesis of the targeted 86-epi-QRSTU
ring system 6 from 86-epi-QRSTU ketone 41. Thus, exposure
of 41 to DDQ furnished hydroxy ketone 43 (83% yield), whose
treatment with EtSH in the presence of Zn(OTf)2 induced
(22) For an example of a similar isomerization, see: (a) Crimmins, M. T.;
McDougall, P. J.; Ellis, J. M. Org. Lett. 2006, 8, 4079.
9
9904 J. AM. CHEM. SOC. VOL. 132, NO. 28, 2010

Synthesis of the QRSTU Domain of Maitotoxin
A R T I C L E S
Scheme 5. Completion of the Synthesis of Maitotoxin QRSTU Ring System 4 and 85-epi-QRSTU Ring System 5a
a Reagents and conditions: a) DDQ (2.0 equiv), CH2Cl2:H2O (20:1), 0 °C, 3 h, 87%; b) Zn(OTf)2 (2.0 equiv), EtSH (48 equiv), CH2Cl2, 25 °C, 3 h, 83%;
or c) TMSOTf (2.0 equiv), TMSSEt (3.0 equiv), CH2Cl2, -78 °C, 3 h, 95%; d) AgClO4 (3.0 equiv), NaHCO3 (3.0 equiv), SiO2, 4 Å MS, MeNO2, 25 °C,
1.5 h, 72%, 3:1 dr 49b:49a; e) m-CPBA (4.0 equiv), CH2Cl2, 0 °C, 2 h; then Me3Al (2.0 M in hexanes, 8.0 equiv), -78 °C, 12 h, then 0 °C, 1 h, 95%, ∼1:0.8
dr 52a:52b from mixture of ∼3:1 dr 49b:49a; 92% 52a (only) from 49a; 94%, ∼1.5:1 dr 52b:52a from 49b; f) TBAF (5.0 equiv), THF, 25 °C, 14 h, 87%
from 52a, 92% from 52b; g) H2, 20% Pd(OH)2/C (50% w/w), THF, 25 °C, 12 h, 4: 100%, 5: 87%.
the desired ring closure,23 forming mixed O,S-ketal 44 as a
single diastereoisomer in 77% yield. The indicated configura-
tions at the RS ring junction were based on the observed nOes
(see structure 44, Scheme 4). The required C85-Me group was
then introduced into the growing molecule through a one-pot, two-
step procedure involving oxidation of 44 to the corresponding
sulfone with m-CPBA, followed by addition of Me3Al to oxonium
intermediate 45 from the less sterically hindered convex face to
afford methylated polycyclic system 46 in 93% overall yield.10a
The indicated stereochemical arrangement around the C85-C86 ring
junction within 46 was confirmed through the observed nOes (see
structure 46, Scheme 4). With all five angular methyl groups
installed in their intended positions around the targeted maitotoxin
framework, intermediate 46 was then converted to the desired 86-
epi-QRSTU ring system 6 by global deprotection, achieved through
sequential desilylation (TBAF, 98% yield) and debenzylation [H2,
Pd(OH)2, 100% yield].
With the accomplishment of the synthesis of 86-epi-QRSTU
ring system 6 came intelligence and confidence for the final
drive toward the QRSTU ring framework (i.e., 4) of maitotoxin.
Scheme 5 summarizes the rather adventurous chemistry that led
not only to this targeted fragment (4), but also to its diastere-
(23) (a) Nicolaou, K. C.; Veale, C. A.; Hwang, C.-K.; Hutchinson, J.;
Prasad, C. V. C.; Ogilvie, W. W. Angew. Chem., Int. Ed. Engl. 1991,
130, 304. (b) Fuwa, H.; Sasaki, M.; Tachibana, K. Tetrahedron 2001,
57, 3019.
9
J. AM. CHEM. SOC. VOL. 132, NO. 28, 2010 9905

A R T I C L E S
Nicolaou et al.
Table 1. Chemical Shifts (δ, ppm) of C79 to C96 and C150 to C154
for Maitotoxin (MTX, 1) and QRSTU Ring Systems 4, 5, and 6 and
Differences Between Each of the Latter Three Compounds and
MTX (1) (∆δ, ppm)a
oisomer, 85-epi-QRSTU ring system 5. Thus, treatment of
QRSTU ketone 42 with DDQ liberated hydroxy ketone 47 (87%
yield), which upon reaction with EtSH in the presence of
Zn(OTf)2 furnished hydroxy dithioketal 48 in 83% yield. An
improved yield (95%) of 48 was obtained with TMSSEt in the
presence of TMSOTf.24 Exposure of the latter compound to our
previously developed cyclization conditions (AgClO4, NaHCO3,
MeNO2)10 led to a mixture of C85 diastereomeric closed O,S-
mixed ketals 49b and 49a (∼3:1 dr) in 72% combined yield.
Chromatographic separation of 49a and 49b allowed for their
configurational assignments as shown based on NMR spectro-
scopic analysis (see nOes, Scheme 5).
δ for MTX δ for 4 difference δ for 5 difference δ for 6 difference
carbon (1) (ppm)
(ppm) (∆δ, ppm) (ppm) (∆δ, ppm) (ppm) (∆δ, ppm)
150
79
80
81
151
82
83
84
152
85
86
87
88
153
89
90
91
154
92
93
94
19.8
75.4
81.4
74.8
15.2
76.4
64.7
41.0
16.5
78.4
74.1
25.9
38.6
19.5
79.5
72.1
43.2
16.0
75.0
71.9
32.0
80.2
71.4
19.4
79.8
72.5
76.2
14.5
75.9
64.1
41.3
16.4
78.0
74.1
26.1
38.9
19.7
79.4
71.8
43.2
15.7
74.0
71.2
34.9
67.3
76.5
0.4
-4.4
8.9
-1.4
0.7
0.5
0.6
-0.3
0.1
0.4
0.0
-0.2
-0.3
-0.2
0.1
0.3
0.0
0.3
1.0
19.3
79.7
72.4
76.7
13.7
75.6
62.5
41.1
28.8
77.4
74.2
24.6
36.3
16.1
80.0
74.5
43.5
16.3
74.1
71.3
35.1
67.4
76.5
0.5
-4.3
9.0
-1.9
1.5
0.8
2.2
-0.1
-12.3
1.0
-0.1
1.3
2.3
3.4
-0.5
-2.4
-0.3
-0.3
0.9
19.5
79.9
72.3
76.0
19.1
75.6
64.1
35.6
24.9
77.8
83.8
32.1
43.2
16.4
78.3
71.9
43.0
15.6
74.0
71.3
35.0
67.3
76.5
0.3
-4.5
9.1
-1.2
-3.9
0.8
0.6
5.4
-8.4
0.6
-9.7
-6.2
-4.6
3.1
1.2
0.2
0.2
0.4
1.0
0.6
Since we expected (on the basis of steric grounds) the
diastereoselectivity in the next step (i.e., oxidation to the
corresponding sulfone and subsequent reaction with Me3Al) to
proceed through an oxonium species, thereby erasing the C85
stereocenter and delivering the desired methylated product, we
moved forward with a mixture of epimers 49b and 49a (∼3:1
dr). Thus, oxidation of this mixture with m-CPBA, followed
by addition of Me3Al to the resulting reaction mixture fur-
nished,25 to our surprise, a diastereomeric mixture of pentacycles
52a (ꢀ-85-Me) and 52b (R-85-Me) as a ∼1:0.8 dr mixture (95%
combined yield), with desired product 52a as the major isomer.
Various changes in reaction temperature, solvent, and stoichi-
ometry of Me3Al did not improve the diastereoselectivity of
this reaction. Chromatographic separation of 52a and 52b led to
their configurational assignments through NMR spectroscopic
analysis (see nOes, Scheme 5). The fact that the diastereomeric
ratio of the obtained products did not reflect the diastereomeric
ratio of the starting mixture was intriguing. Faced with this
unexpected result, we proceeded to subject each diastereoisomer
(i.e., 49a and 49b) to the methylation conditions (m-CPBA; then
Me3Al) individually in order to shed light on the diastereoselectivity
of this methylation process. While the reactions of both 49a and
49b proceeded in equally high yield as with the mixture, their
selectivities were surprising. Thus, whereas thioketal 49b (major)
led to a mixture of methylated products 52b:52a (∼1.5:1 dr),
diastereoisomer 49a (minor) gave exclusively the desired methy-
lated diastereoisomer 52a.26 These results suggest that the methy-
lation reaction of the corresponding sulfones (i.e., 50a and 50b)
proceeds through a more complex mechanism than assumed (i.e.,
through nucleophilic attack by a methyl anion on a common
oxonium intermediate). On the basis of the inspection of manual
molecular models of 49a,b-51a,b we propose the following
speculative mechanism to explain these observations. Thus, sulfone
50a is exclusively and rapidly converted to oxonium species 51a,
which is also rapidly and exclusively converted to methylated
product 52a (TLC analysis). In contrast, sulfone 50b is sluggishly
converted to oxonium species 51b (TLC analysis as compared to
50a), whose strained nature forces it to undergo a ring flip into the
more comfortable oxonium 51a (thermodynamically more stable)
at a rate comparable to that of its methylation to give 52b. The
surmised rate differences of formation of oxonium species 51a and
51b from the two diastereomeric sulfones may be explained by
the alignment of the lone pair of electrons from the oxygen atom
0.7
0.6
-2.9
12.9
-5.1
-3.1
12.8
-5.1
-3.0
12.9
-5.1
95
96
a 150 MHz, 1:1 methanol-d4/pyridine-d5.
in relation to the σ* orbital of the C-S bond in 50a (antiparallel)
and 50b (nonantiparallel). The reaction of sulfone 50b leading to
both 52b and 52a (∼1.5:1 dr) is, therefore, a consequence of
leakage of oxonium species 51b to 51a, whereas the reverse
conversion of 51a to 51b does not occur due to the thermodynamic
stability of the former species. Whereas the methylation rates of
oxonium species 51a and 51b may or may not be a factor in the
observed diastereospecificity (or lack thereof) of these reactions,
the rates of formation of these oxonium species from the corre-
sponding sulfones are unlikely to influence the diastereoselectivities
of their methylation.
All that remained to reach the targeted QRSTU maitotoxin
segment 4 was removal of the protecting groups from interme-
diate 52a. This task was easily accomplished through removal
of the silyl groups (TBAF, 87% yield) and hydrogenolysis of
the benzyl ethers [H2, Pd(OH)2 cat., 100% yield] of the latter
intermediate, furnishing the much sought after QRSTU ring
system 4. The epimeric 85-epi-QRSTU ring system 5 was
similarly generated from epimeric intermediate 52b (TBAF,
92% yield; H2, Pd(OH)2 cat., 87% yield).
Comparison of the 13C NMR Chemical Shifts of QRSTU
Ring Systems 4, 5, and 6 with Those Corresponding to the
Same Region of Maitotoxin. Having obtained maitotoxin dia-
stereomeric fragments QRSTU (4), 85-epi-QRSTU (5) and 86-
epi-QRSTU (6) through synthesis, we welcomed the opportunity
to compare their 13C NMR spectral data with those of the
QRSTU domain of the natural product, as a means of securing
further support for the originally assigned structure of the natural
product.27,28 Table 1 lists the 13C NMR chemical shifts (δ, ppm)
for these three QRSTU ring systems (i.e., 4, 5 and 6) together
with those of the corresponding domain of natural maitotoxin
[MTX (1)] and their differences (∆δ, ppm).3c Figure 3 graphi-
(24) Noyori, R.; Murata, S.; Suzuki, M. Tetrahedron 1981, 37, 3899.
(25) Fuwa, H.; Ebine, M.; Bourdelais, A. J.; Baden, D. G.; Sasaki, M. J. Am.
Chem. Soc. 2006, 128, 16989.
(26) For the use of AgClO4-promoted cyclization of dithioketals to form
O,S-ketal oxepanes followed by an oxidation/methylation procedure
that gives similar diastereoselectivities, see: (a) Torikai, K.; Yari, H.;
Murata, M.; Oishi, T. Heterocycles 2006, 70, 161. (b) Torikai, K.;
Yari, H.; Mori, M.; Ujihara, S.; Matsumori, M.; Murata, M.; Oishi,
T. Bioorg. Med. Chem. Lett. 2006, 16, 6355.
(27) Gallimore, A. R.; Spencer, J. B. Angew. Chem., Int. Ed. 2006, 45,
4406.
(28) Nicolaou, K. C.; Frederick, M. O. Angew. Chem., Int. Ed. 2007, 46,
5278.
9
9906 J. AM. CHEM. SOC. VOL. 132, NO. 28, 2010

Synthesis of the QRSTU Domain of Maitotoxin
A R T I C L E S
Figure 3. Graphically depicted 13C chemical shift differences (∆δ, ppm) for each carbon between C79 to C96 and C150 to C154 for maitotoxin (1) and QRSTU
ring systems (4, top), 85-epi-QRSTU (5, middle), and 86-epi-QRSTU (6, bottom).
cally presents these differences for each diastereomeric structure
(4, 5 and 6) with maitotoxin (1) (carbons C79 to C96 and C150 to
C154). As seen from these graphs, the structure resembling
maitotoxin the most is that of 4, with the average difference
(∆δ) for carbons C81 to C94 and C150 to C154 being 0.54 ppm,
and a maximum difference (∆δ) for a given carbon being 2.9
ppm (C94). The carbons at the two edges of the molecule (i.e.,
C79, C80, C95, C96) were excluded from the comparisons due to
the rather drastic structural differences between their neighboring
groups from those surrounding the same structural domain (i.e.,
QRSTU) of the natural product. In contrast, diastereoisomers 5
and 6 demonstrated significant variations from maitotoxin, with
an average difference (∆δ) of 1.9 ppm and 2.7 ppm, respec-
tively, and maximum difference (∆δ) for a given carbon of 12.3
ppm (C152) and 9.7 ppm (C86), respectively. Interestingly, the
carbons exhibiting the maximum differences from the natural
product are those residing either on (C86) or adjacent (C152) to
the RS ring junction of these diastereoisomers. These findings
provide compelling support for the correctness of the originally
assigned structure of the QRSTU domain of maitotoxin as
represented by QRSTU ring system 4 (Figure 3, top).
and chemical investigations. The unique synthetic challenge
posed by this pentamethylated pentacycle was successfully met
through a convergent strategy that relied on our previously
developed hydroxy dithioketal cyclization methodology10 to
forge the oxepane ring of the molecule and install the final
methyl group. Comparison of the 13C NMR spectroscopic data
of the synthesized QRSTU ring systems with those of maitotoxin
led to further support for the originally assigned Yasumoto-
Kishi-Tachibana structure of this most complex secondary
metabolite.2-6 Significantly, QRSTU ring system 4 and its
precursors are appropriately functionalized at their two ends for
further elaboration and coupling with suitably activated neigh-
boring ring systems of maitotoxin for the purposes of construct-
ing larger domains of the natural product.
Acknowledgment. We thank Drs. D.-H. Huang and G. Siuzdak
for spectroscopic and mass spectrometric assistance, respectively.
Financial support for this work was provided by the National Institutes
of Health (U.S.A.), The Skaggs Institute for Chemical Biology, and
the National Science Foundation (predoctoral fellowship to C.F.G).
Supporting Information Available: Experimental procedures
and characterization data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
Conclusion
The described chemistry provided access to the QRSTU
fragment 4 of maitotoxin (1) and its diastereoisomers 85-epi-
QRSTU (5) and 86-epi-QRSTU (6) fragments for biological
JA103708J
9
J. AM. CHEM. SOC. VOL. 132, NO. 28, 2010 9907