Synthesis of (+)-didemniserinolipid B: Application of a 2-allyl-4-fluorophenyl auxiliary for relay ring-closing metathesis

Article abstract of DOI:10.1021/jo801666t

(Chemical Equation Presented) The synthesis of didemniserinolipid B utilizing a ketalization/ring-closing metathesis (K/RCM) strategy is described. In the course of this work, a novel 2-allyl-4-fluorophenyl auxiliary for relay ring-closing metathesis (RRC

Full text of DOI:10.1021/jo801666t

Synthesis of (+)-Didemniserinolipid B: Application of a
2-Allyl-4-fluorophenyl Auxiliary for Relay Ring-Closing Metathesis
Christopher C. Marvin, Eric A. Voight, Judy M. Suh, Christopher L. Paradise, and
Steven D. Burke*
Department of Chemistry, UniVersity of Wisconsin-Madison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706-1322
burke@chem.wisc.edu
ReceiVed July 27, 2008
The synthesis of didemniserinolipid B utilizing a ketalization/ring-closing metathesis (K/RCM) strategy
is described. In the course of this work, a novel 2-allyl-4-fluorophenyl auxiliary for relay ring-closing
metathesis (RRCM) was developed, which increased the yield of the RCM. The resulting 6,8-
dioxabicyclo[3.2.1]octene core was selectively functionalized by complimentary dihydroxylation and
epoxidation routes to install the C10 axial alcohol. This bicyclic ketal core was further functionalized by
etherification and an alkene cross metathesis with an unsaturated R-phenylselenyl ester en route to
completing the total synthesis.
Introduction
modular and efficient route to general structures of this type
could be valuable in the context of diversity-oriented synthesis.4
Ley and co-workers have recently demonstrated this concept
with their discovery of novel biologically active compounds
based on this scaffold.5
In addition to the intriguing dioxabicyclo[3.2.1]octane core,
didemniserinolipids A-C display two side chains: a relatively
short 7-carbon chain featuring an R,ꢀ-unsaturated acid (1, 3)
or ester (2), and an otherwise unfunctionalized 15-carbon chain
terminating with a serinol-derived ether. The stereochemistry
at the serinol C30 carbon could not be unambiguously assigned
Didemniserinolipids A-C (1-3, Figure 1) were isolated in
1999 by Jime´nez and co-workers from the methanol extracts
of marine tunicate Didemnum sp.1 These structurally interesting
molecules possess a central 6,8-dioxabicyclo[3.2.1]octane core
with two appended alkyl chains, one of which terminates in a
2-aminopropane 1,3-diol ether, and the other in an R,ꢀ-
unsaturated acid (or ester). Whereas the initial extract containing
these molecules was found to be potently cytotoxic (IC50 ) 0.25
µg/mL against P388, A549, and HT29 tumor cell lines), after
further purification and isolation, none of the individual didem-
niserinolipids were found to be cytotoxic in the same assays.
Despite the lack of known biological activity for the in-
dividual didemniserinolipids, many varied natural product
structures containing the 6,8-dioxabicyclo[3.2.1]octane moiety
have been reported to be biologically active.2 For example, the
closely related cyclodidemniserinol trisulfate, isolated from
Didemnum guttatum, is an inhibitor of HIV-1 integrase.3 The
large structural diversity among 6,8-dioxabicyclo[3.2.1]octane
containing natural products suggests that development of a
(2) (a) Uemura, D.; Chou, T.; Haino, T.; Nagatsu, A.; Fukuzawa, S.; Zheng,
S.-Z.; Chen, H.-S. J. Am. Chem. Soc. 1995, 117, 1155–1156. (b) McCauley,
J. A.; Nagasawa, K.; Lander, P. A.; Mischke, S. G.; Semones, M. A.; Kishi, Y.
J. Am. Chem. Soc. 1998, 120, 7647–7648. (c) Nadin, A.; Nicolaou, K. C. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1622–1656. (d) Koren-Goldshlager, G.; Klein,
P.; Rudi, A.; Benayahu, Y.; Schleyer, M.; Kashman, Y. J. Nat. Prod. 1996, 59,
262–266. (e) Araki, K.; Suenaga, K.; Sengoku, T.; Uemura, D. Tetrahedron
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2000, 2, 1605–1607.
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(5) Milroy, L.-G.; Zinzalla, G.; Prencipe, G.; Michel, P.; Ley, S. V.;
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5707.
8452 J. Org. Chem. 2008, 73, 8452–8457
10.1021/jo801666t CCC: $40.75 2008 American Chemical Society
Published on Web 09/24/2008

Synthesis of (+)-Didemniserinolipid B
the alkenes to enable their chemoselective manipulation. The
resulting rigid, facially biased dioxabicyclic templates can be
manipulated stereoselectively to install additional functional
groups. In the context of didemniserinolipid B, we felt that
construction of the bicyclic ketal core via K/RCM would enable
an efficient and modular synthesis, amenable to varying the side
chains for potential analogue preparation.
FIGURE 1. Didemniserinolipids A-C, proposed structures.
Our K/RCM retrosynthesis of didemniserinolipid B is shown
in Figure 2. We foresaw installation of the C1-C6 R,ꢀ-
unsaturated side chain via an alkene cross metathesis (CM) with
an unsaturated ester such as 6, followed by chemoselective
hydrogenation of the isolated C6-C7 double bond. The C10
axial alcohol would arise from a substrate-controlled epoxidation
of the endocyclic alkene in 5,9 followed by trans-diaxial epoxide
opening with hydride.10 Williamson etherification between a
suitable serinol derivative, represented in protected form by 4,
and mesylate 5 would introduce the serinol fragment. The
requisite bicyclic ketal 5 would be directly provided by a
K/RCM sequence involving a ketone such as 7 and known C2-
symmetric diene diol 8.11 In addition to providing a rapid and
convenient route to 5, K/RCM has the benefit of desymmetrizing
8 and leaving one vinyl group unreacted and available for later
CM with 6 (or its equivalent).
We have recently disclosed a communication of our didem-
niserinolipid B synthesis using this strategy.7h In this publication
we describe the synthesis and application of a novel relay ring-
closing metathesis tail to improve the isolated yield of our key
K/RCM product and describe an alternative means to install
the C10 axial alcohol.
FIGURE 2. Revised didemniserinolipid B structure and K/RCM
retrosynthesis.
upon isolation but was elucidated for didemniserinolipid B (2)
after its first total synthesis by Ley (Figure 2).6 Ley’s pioneering
synthesis also resulted in a structural revision for didemniser-
inolipid B, as the presence of a C31 O-sulfate was identified.
The structures of didemniserinolipids A and C have yet to be
unambiguously determined.
In recent years, our laboratory has explored a novel and
efficient synthetic strategy to access bicyclic ketals and acetals
such as the 6,8-dioxabicyclo[3.2.1]octane moiety.7 Traditional
routes to such bicyclic ketals generally involve intermolecular
carbon-carbon bond formation followed by intramolecular
ketalization via dehydration of a keto diol. Our strategy exploits
a bimolecular ketalization to unite a ketone fragment with a
C2-symmetric diene diol, followed by intramolecular ring-
closing metathesis to form a carbon-carbon bond and close
the bicyclic ketal.8 This ketalization/ring-closing metathesis (K/
RCM) strategy avoids cumbersome protection/deprotection
sequences often necessary in traditional approaches to these
moieties. Used with C2-symmetric diene diols, K/RCM serves
to effectively desymmetrize the diol fragment, differentiating
Results and Discussion
From our previous experience, we were wary of the ꢀ,γ-
alkene migrating into conjugation with the ketone during acid-
catalyzed ketalization. Whereas the problem had been avoided
in previous K/RCM applications by elimination of a terminal
halide as a separate step to install the unsaturation after
ketalization,7a-e we expected that a phenyl ring substituent on
the this alkene (i.e., 12) would attenuate ꢀ,γ-alkene migration
during ketalization. Ketone 12 (Scheme 1) was thereby prepared
over 3 steps from commercially available 16-hexadecanolide
9. Macrolactone 9 was opened with lithiated dimethyl meth-
ylphosphonate to generate ꢀ-ketophosphonate 10. The crude
product 10 was used in a Horner-Wadsworth-Emmons reac-
tion with phenylacetaldehyde and K2CO3 in refluxing aqueous
methanol to provide 11, which was activated as mesylate 12
without purification. The presence of the γ-phenyl ring promoted
isomerization of the double bond from the R,ꢀ- to the ꢀ,γ-
position (5:1 ratio) during the HWE reaction, as required for
our planned RCM. The mesylate group in 12 would strategically
play two roles; it would serve as a protecting group to ensure
clean ketalization and later be a reactive leaving group for
etherification. Azeotropic removal of water successfully drove
the ketalization between keto mesylate 12 and (R,R)-diene diol
8 to completion, providing a 9:1 mixture of 13 and 14.
(6) Kiyota, H.; Dixon, D. J.; Luscombe, C. K.; Hettstedt, S.; Ley, S. V. Org.
Lett. 2002, 4, 3223–3226.
(7) (a) Burke, S. D.; Muller, N.; Beaudry, C. M. Org. Lett. 1999, 1, 1827–
1829. (b) Burke, S. D.; Voight, E. A. Org. Lett. 2001, 3, 237–240. (c) Voight,
E. A.; Rein, C.; Burke, S. D. Tetrahedron Lett. 2001, 42, 8747–8749. (d) Keller,
V. A.; Martinelli, J. R.; Strieter, E. R.; Burke, S. D. Org. Lett. 2002, 4, 467–
470. (e) Voight, E. A.; Rein, C.; Burke, S. D. J. Org. Chem. 2002, 67, 8489–
8499. (f) Voight, E. A.; Seradj, H.; Roethle, P. A.; Burke, S. D. Org. Lett. 2004,
6, 4045–4048. (g) Marvin, C. C.; Clemens, A. J. L.; Burke, S. D. Org. Lett.
2007, 9, 5353–5356. (h) Marvin, C. C.; Voight, E. A.; Burke, S. D. Org. Lett.
2007, 9, 5357–5359.
(8) (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4490–4527. (b) Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140. (c)
Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199–2238. (d) Connon, S. J.;
Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900–1923. (e) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29. (f) Fu¨rstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012–3043.
Ketal 13 underwent RCM upon exposure to 10.5 mol% of
Grubbs’ first generation metathesis catalyst (G1) to afford the
(9) (a) Azzari, E.; Faggi, C.; Gelsomini, N.; Taddei, M. Tetrahedron Lett.
1989, 30, 6067–6070. (b) Tchilibon, S.; Mechoulam, R. Org. Lett. 2000, 2, 3301–
3303. (c) Hanus, L. O.; Tchilibon, S.; Ponde, D. E.; Breuer, A.; Fride, E.;
Mechoulam, R. Org. Biomol. Chem. 2005, 3, 1116–1123.
(10) Fu¨rst, A.; Plattner, P. A. HelV. Chim. Acta 1949, 32, 275–283.
(11) (a) Burke, S. D.; Sametz, G. M. Org. Lett. 1999, 1, 71–74. (b) Yadav,
J. S.; Mysorekar, S. V.; Pawar, S. M.; Gurjar, M. K. J. Carbohydr. Chem. 1990,
9, 307–316.
J. Org. Chem. Vol. 73, No. 21, 2008 8453

Marvin et al.
SCHEME 1. Synthesis of Bicyclic Ketal 5
FIGURE 3. Potential metathesis pathways.
Relay-ring closing metathesis (RRCM) has found increasing
application in cases where RCM fails to compete with CM
dimerization pathways wherein one of two alkenes reacts slowly
due to electronic or steric reasons.12 We were intrigued by the
prospect of appending an ortho-allyl substituent to the phenyl
ring of 13, to provide a novel group for RRCM that would direct
the course of the metathesis to bicyclic ketal 5. In addition to
directing the initiation site for the ruthenium alkylidene and
controlling the path of our RCM, this relay tail would release
an indene ring upon RCM, which was expected to slow down
competing CM pathways by being less reactive than styrene.
Scheme 2 details the straightforward synthesis of ketone 21
possessing the requisite relay group from commercially available
aryl fluoro bromide 16. Following palladium-mediated cross-
coupling of 16 with allyl indium to provide 17,13 DIBALH
reduction of the nitrile and hydrolytic workup gave aldehyde
18. The starting material 16 was chosen as it strategically
positioned a fluorine atom para- to the acetaldehyde group in
18. The electron-withdrawing nature of this group contributed
to the use of ꢀ-keto phosphonate 10 for a Horner-Wadsworth-
Emmons reaction by facilitating isomerization of the newly
produced alkene into conjugation with the aryl ring. Without
the p-fluoro substituent, little isomerization was observed.
Mesylation of 19 occurred in nearly quantitative yield to provide
20. Ketalization with diene diol 8 as described previously gave
21 and 22 as an inseparable mixture in a 4:1 ratio. The decreased
yield for this ketalization is due in part to isomerization of the
ortho-allyl group.14
SCHEME 2. Synthesis of the Relay-RCM Group
desired bicyclic ketal 5 (53% isolated yield, 81% yield based
on recovered starting material). This reaction was stopped early,
as prolonged reaction times led to decreased isolated yields due
to formation of significant amounts of 15. While the phenyl
ring had served a convenient role in minimizing alkene
migration, its presence proved detrimental during metathesis.
The stoichiometric styrene released during RCM underwent CM
with 5, providing 15 as its concentration increased during the
progression of this reaction.
Although stopping the RCM of 13 at approximately 50%
conversion was a practical solution to minimize the formation
of 15, we sought a more elegant solution to this problem. In
addition to the obvious factor of the competing CM with styrene
leading to the decreased yield of 5, we suspected that the
initiation site of the RCM was problematic. Pseudo-C2-sym-
metric ketal 13 contains three distinct alkenes that can interact
with the Grubbs’ catalyst. As reaction at the phenyl-substituted
alkene is expected to be slow, initiation of metathesis is
anticipated to occur at one of two diastereotopic vinyl groups.
The diastereotopic relationship between these vinyl groups
dictates that the ruthenium catalyst has essentially equal
opportunity to initiate at a productive site leading to RCM, or
at an unproductive site leading to cross metathesis or dimer-
ization (Figure 3).
To our delight, bicyclic ketal 5 was isolated in 82% yield
upon treatment of this mixture with the first generation Grubbs’
catalyst G1 at room temperature (Scheme 3). Presumably, the
catalyst initiates at the unhindered allyl group on the aryl ring
to provide ruthenium alkylidene 23. Subsequent ring-closure
releases 6-fluoroindene and produces ruthenium alkylidene 24
followed by RCM to produce bicyclic ketal 5.
(12) Review: (a) Debra, J. W. Angew. Chem., Int. Ed. 2005, 44, 1912–1915.
Also see: (b) Sato, D.; Fujiwara, K.; Kawai, H.; Suzuki, T. Tetrahedron Lett.
2008, 49, 1514–1517. (c) Roethle, P. A.; Chen, I. T.; Trauner, D. J. Am. Chem.
Soc. 2007, 129, 8960–8961. (d) Hansen, E. P.; Lee, D. Org. Lett. 2004, 6, 2035–
2038. (e) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H.
J. Am. Chem. Soc. 2004, 126, 10210–10211. (f) Wang, X.; Bowman, E. J.;
Bowman, B. J.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2004, 43, 3601–3605.
(g) Robinson, J.; Piscopio, A. D.; Zhu, L. Abstracts of Papers; 226th National
Meeting of the American Chemical Society, New York; American Chemical
Society: Washington, DC; ORGN-118.
(13) (a) Lee, P. H.; Sung, S.-Y.; Lee, K. Org. Lett. 2001, 3, 3201–3204. (b)
Lee, K.; Lee, J.; Lee, P. H. J. Org. Chem. 2002, 67, 8265–8268.
(14) This reaction was not optimized to the extent of the ketalization of 12
and 8.
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Synthesis of (+)-Didemniserinolipid B
SCHEME 3. Relay-RCM Sequence
SCHEME 5. Epoxidation Route to Install the C10 Alcohol
at a much slower rate in a similar system.7a,e To remove the
unnecessary C11 hydroxyl, cyclic sulfate 28 was prepared in
79% yield using 1,1′-sulfonyldiimidazole and sodium hydride
in DMF. Reductive opening of cyclic sulfate 28 with sodium
borohydride (5 equiv.) in dimethylacetamide, followed by
hydrolysis of the resultant sulfate in aqueous sulfuric acid in
THF provided axial alcohol 29 in 53% yield (2 steps). The azido
group was subsequently reduced and protected in one-pot via
Staudinger reduction18 and reaction with N-(9-fluorenylmethox-
ycarbonyloxy)succinimide to give Fmoc-protected amine 30 in
excellent yield.
SCHEME 4. Installation of the C10 Alcohol via
Dihydroxylation/Cyclic Sulfate Opening
Due to the relatively low overall yield and the multistep nature
of the sequence to install the C10 alcohol (32% over 4 steps),
we became interested in an alternative strategy to install this
functional group (Scheme 5). Concurrent with this modification
to our route, we reconsidered the protecting strategy for the
serinol fragment. By using known serinol derivative 31,19 we
would not need to reduce the azide and would thereby further
shorten our synthesis by making it more convergent. Further-
more, replacement of the benzyl ether in 25 with an acid-labile
group would provide for a more straightforward endgame. After
some optimization, Williamson etherification of 5 with the
sodium alkoxide of 31 proceeded cleanly to afford 32 with only
trace amounts (∼3%) of the elimination byproduct. The more
electron-rich endocyclic olefin of bicyclic diene 32 underwent
chemo- and stereoselective epoxidation with 1 equiv of m-CPBA
at 4 °C.9 This protocol gave 60% yield of epoxide 33 after one
recycle of recovered starting material 32. The isolated yield of
33 suffers from competitive epoxidation of the vinyl group (the
other possible epoxides are produced in 15% combined yield).
Reductive trans-diaxial opening of epoxide 33 was accom-
plished by treatment with LAH in THF to give C10 alcohol 34
in 86% yield. This epoxidation/LAH reduction provided a more
practical protocol for the installation of the C10 alcohol (52%
from 32).
With reliable and high-yielding routes to bicyclic mesylate
5 in hand, an appropriately protected serinol derivative was
needed. Azido alcohol 25 (Scheme 4) appeared to be a suitable
choice,15 and after deprotonation with sodium hydride, the
alkoxide reacted with mesylate 5 to give azido ether 26 in 89%
yield.16 To install the C10 axial alcohol, the more electron-rich
endocyclic double bond was first selectively dihydroxylated
using Sharpless’s asymmetric dihydroxylation conditions.7b,e,17
While the stereochemistry of the resulting diol was controlled
by the bridged bicyclic ketal, AD-mix R proved to be the
matched chiral reagent, since AD-mix ꢀ gave the same product
Completion of didemniserinolipid B required elaboration of
the C6-C7 alkene to the C1-C7 enoate-containing side chain.
Whereas we originally pursued the cross metathesis of 34 with
known diene 6,20 attempts to selectively hydrogenate the C6-C7
alkene were stymied by either over-reduction of the R,ꢀ-
unsaturated ester or no reaction.21 Successful installation of the
remaining C1-C7 side chain is shown in Scheme 6. Cross
metathesis of 34 and known racemic selenide 3522 in refluxing
dichloromethane with Grubbs’ second generation catalyst G2
(15) He, L.; Wanunu, M.; Byun, H.-S.; Bittman, R. J. Org. Chem. 1999, 64,
6049–6055.
(16) Wrodnigg, T. M.; Gaderbauer, W.; Greimel, P.; Ha¨usler, H.; Sprenger,
F. K.; Stu¨tz, A. E.; Virgona, C.; Withers, S. G. J. Carbohydr. Chem. 2000, 19,
975–990.
(17) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483–2547. (b) Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem.
Soc. 1992, 114, 7570–7571.
(18) Dong, L.; Roosenberg, J. M.; Miller, M. J. J. Am. Chem. Soc. 2002,
124, 15001–15005.
(19) (a) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361–2364. (b)
Dondoni, A.; Marra, A.; Merino, P. J. Am. Chem. Soc. 1994, 116, 3324–3336.
(20) Marshall, J. A.; Sabatini, J. J. Org. Lett. 2005, 7, 4819–4822.
J. Org. Chem. Vol. 73, No. 21, 2008 8455

Marvin et al.
SCHEME 6. Completion of Didemniserinolipid B
reaction mixture with DMF and addition of piperidine to provide
(+)-didemniserinolipid B (2).26 Synthetic 2 thus obtained was
identical to the natural product by comparison to published 1H
and 13C NMR, MS, IR, and optical rotation data.27
In summary, didemniserinolipid B has been prepared in 2.6%
overall yield via a concise route with a longest linear sequence
(LLS) of 12 steps from ketone 12 and diene diol 8 (15 step
LLS from commercially available materials). In addition to the
use of a K/RCM sequence to establish the bicyclic ketal core,
an alternative route using a relay-ring closing metathesis has
been developed which improves the efficiency of the RCM
process. This novel RRCM group avoids unproductive dimer-
ization and cross metathesis pathways via the extrusion of an
indene ring that does not participate in alkene metathesis with
either the substrate or the desired product under these conditions.
The resulting bicyclic ketal template enabled a chemo- and
stereoselective epoxidation sequence to install the C10 axial
alcohol, and facilitated modular appendage of both the serinol
and C1-C7 side chains. This versatile route could potentially
be applied to the synthesis of the remaining didemniserinolipids
or to the HIV-1 integrase inhibitor cyclodidemniserinol
trisulfate.1,8 Production of (+)-didemniserinolipid B further
showcases the merits of the K/RCM strategy in the rapid
construction of bicyclic ketals and their conversion to complex
natural products.
Experimental Section28
Relay Ring-Closing Metathesis Preparation of 5. Ketal 21
(30.5 mg, 0.050 mmol) was dissolved in 9 mL CH2Cl2. This reaction
was gently refluxed and Grubbs’ catalyst G1 (4 mg, 0.005 mmol)
was added as a solution in 1 mL of CH2Cl2 over 2 h. The reac-
tion was refluxed for an additional hour after the addition of Grubbs’
catalyst was complete. It was then cooled and stirred open to air
overnight. The resulting brown solution was concentrated in Vacuo.
Flash column chromatography (20-40% ether:hexanes) provided
bicyclic ketal 5 as a white solid (18 mg, 0.0407 mmol, 82% yield).
1H NMR (CDCl3) δ 6.08 (1H, app ddt, J ) 9.5, 4.5, 2 Hz), 5.86
(1H, ddd, J ) 17, 10, 7.5 Hz), 5.74 (1H, ddd, J ) 10, 4, 3 Hz),
5.23 (1H, ddd, J ) 17, 1.5, 1 Hz), 5.12 (1H, ddd, J ) 10, 1.5, 1
Hz), 4.46 (1H, br d, J ) 7.5 Hz), 4.37 (1H, d, J ) 4.5 Hz), 4.22
(2H, t, J ) 6.5 Hz), 3.00 (3H, s), 2.44 (1H, ap dt, J ) 18, 2.5 Hz),
2.12 (1H, ddd, J ) 18, 4, 2 Hz), 1.9-1.6 (4H, m), 1.6-1.2 (24H,
m); 13C NMR (CDCl3) δ 138.1 (CH), 128.4 (CH), 125.5 (CH),
116.3 (CH2), 108.6 (C), 85.9 (CH), 76.5 (CH), 70.1 (CH2), 38.1
(CH2), 37.3 (CH3), 36.9 (CH2), 29.8-28.9 (CH2 × 11), 25.3 (CH2),
23.3 (CH2); IR (thin film) 3041, 2919, 2849 cm-1; HRMS (ESI)
gave exclusively the E isomer of 35 in 74% as an inconsequen-
tial 1:1 mixture of diastereomers. Whereas the selective reduc-
tion of the ∆6,7 alkene in 36 was unsuccessful with Pd/C and 1
atm of hydrogen, use of diimide reduction conditions success-
fully provided 37 in near quantitative yield.23 Oxidation of the
phenylselenide with m-CPBA established the necessary R,ꢀ-
unsaturated ester in 38 via selenoxide elimination.24
Unsaturated ester 38 was converted to didemniserinolipid B
in four steps. The acetonide and Boc protecting groups were
removed by heating 38 in a 5:1 mixture of ethanol and 1 N
HCl at 50 °C. The bicyclic ketal and ethyl ester both survive
these conditions, with the amino alcohol obtained in 75% yield.
Use of FmocOSu resulted in quantitative conversion of 39 to
Fmoc-protected amine 40. The final two steps follow the
sequence described in Ley’s didemniserinolipid B synthesis.6
The monosulfate was prepared by treatment of 40 with 1 equiv
of SO3•Py at 110 °C for 1 h using microwave irradiation.25 The
Fmoc-protecting group was then removed upon dilution of the
calcd for C24H42O5SNa (M+Na+) 465.2651, found 465.2672; [R]24
D
+27 (c 1.0, CHCl3); mp 47-49 °C.
Serinol Ether 32. Known serinol acetonide 31 (691.3 mg, 2.99
mmol) was dissolved in dry DMSO (3 mL). Sodium hydride (124.3
mg, 60% dispersion in mineral oil, 3.1 mmol) and mesylate 5 (666.7
mg, 1.50 mmol) were added sequentially. The reaction immediately
changed color from nearly colorless to deep red. The reaction was
stirred at room temperature for 16 h, and was then quenched by
addition of saturated aqueous NH4Cl (20 mL) and diluted with
CH2Cl2 (20 mL). These layers were separated and the aqueous layer
extracted with CH2Cl2 (5 × 15 mL). The combined ether layers
were dried (MgSO4) and concentrated in Vacuo. Purification by flash
(21) Hydrogenation using H2 (1 atm), 10% Pd/C, in THF or diimide
conditions (NaOAc, TsNHNH2, DME, reflux) gave over reduction to the
completely saturated derivative. Poisoning 10% Pd/C with Et3N under 1 atm H2
or using Lindlar’s catalyst gave only recovered starting material. Marvin, C. C.
Ph.D. Thesis, University of Wisconsin-Madison, 2008.
(22) Krauss, I. J.; Mandal, M.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2007, 46, 5576–5579.
(23) (a) Pastro, D. J.; Taylor, R. T. Org. React. 1991, 40, 91–155. (b) Wiberg,
N.; Fischer, G.; Bachhuber, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 385–
386.
(24) (a) Reich, H. J.; Wollowitz, S. Org. React. 1993, 44, 1–296. (b) Reich,
H. J. Acc. Chem. Res. 1979, 12, 22–30. (c) Reich, H. J.; Reich, I. L.; Renga,
J. M. J. Am. Chem. Soc. 1973, 95, 5813–5815. (d) Sharpless, K. B.; Lauer, R. F.;
Teranishi, A. Y. J. Am. Chem. Soc. 1973, 95, 6137–6139.
(25) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001,
57, 9225–9283.
(26) Ley and co-workers obtained a 49% yield for this sequence, see ref 6.
In addition to didemniserinolipid B, we observed amino alcohol 39, which
suggests the sulfonation step is not going to completion.
(27) See the Supporting Information.
(28) For general procedures and syntheses of 10-21, 26-30, 33, 34, 39, 40
and 2, see the Supporting Information.
8456 J. Org. Chem. Vol. 73, No. 21, 2008

Synthesis of (+)-Didemniserinolipid B
column chromatography (20%-40% ether:hexanes) yielded serinol
ether 32 (0.75 g, 1.29 mmol, 86% yield) as a colorless oil. Rf )
0.40 (20% EtOAc:hexanes); 1H NMR (CDCl3) δ 6.08 (1H, ddt, J
) 10, 5, 2 Hz), 5.87 (1H, ddd, J ) 17, 10, 7 Hz), 5.74 (1H, ddd,
J ) 10, 4, 3 Hz), 5.24 (1H, ddd, J ) 17, 1.5, 1.3 Hz), 5.13 (1H,
ddd, J ) 10, 1.5, 1.3 Hz), 4.47 (1H, d, J ) 8 Hz), 4.37 (1H, d, J
) 5 Hz), 4.1-4.05 (1H, m), 4.05-3.9 (2H, m), 3.61-3.26 (4H,
m), 2.45 (1H, dt, J ) 18, 2.5 Hz), 2.13 (1H, ddd, J ) 18, 4, 2 Hz),
1.82-1.77 (2H, m), 1.57-1.44 (17H, m), 1.40-1.26 (24H, m);
13C NMR (CDCl3) δ 151.7 (C), 138.2 (CH), 128.5 (CH), 125.6
(CH), 116.4 (CH2), 108.7 (C), 93.7 (C) rotamer A, 93.2 (C)
rotamer B, 85.9 (CH), 79.7 (C) rotamer, 76.6 (CH), 71.4 (CH2),
70.0 (CH2) rotamer A, 69.3 (CH2) rotamer B, 65.7 (CH2) rotamer
A, 65.4 (CH2) rotamer B, 56.5 (CH) rotamer A, 56.4 (CH)
rotamer B, 38.1 (CH2), 37.0 (CH2), 29.9-29.3 (CH2 × 12), 28.4
(CH3 × 3), 27.5 (CH3) rotamer A, 26.7 (CH3) rotamer B, 26.1
(CH2), 24.4 (CH3) rotamer A, 23.4 (CH2), 23.1 (CH3) rotamer
B; IR (thin film) 2975, 2937, 2857, 1702 cm-1; HRMS (ESI)
calcd for C34H59NO6Na (M+Na+) 600.4240, found 600.4232;
column chromatography (60-80% ether/hexanes) provided alkyl
selenide 37 (466.5 mg, 0.529 mmol, 96% yield) as a colorless oil.
Rf ) 0.62 (100% ether); H NMR (CDCl3) δ 7.61-7.58 (2H, m),
1
7.36-7.26 (3H, m), 4.17-3.85 (7H, m), 3.61 (1H, br s), 3.59 (1H,
dd, J ) 9, 6.5 Hz), 3.52-3.27 (4H, m), 2.29 (1H, t, J ) 7.5 Hz),
2.04-1.23 (60H, m), 1.17 (3H, t, J ) 7 Hz); 13C NMR (CDCl3) δ
173.0 (C), 135.5 (CH × 2), 128.9 (CH × 2), 128.3 (CH), 128.1
(C), 109.5 (C), 82.3 (CH), 80.2 (C) rotamer A, 79.7 (C) rotamer
B, 77.8 (CH), 71.4 (CH2), 70.0 (CH2) rotamer A, 69.2 (CH2) rotamer
B, 66.3 (CH), 65.7 (CH2) rotamer A, 65.4 (CH2) rotamer B, 60.8
(CH2), 60.1 (CH2) rotamer A (2nd rotamer did not resolve from
noise), 56.4 (br CH), 43.6 (CH), 37.5 (CH2), 35.1 (CH2) diastere-
omer A, 35.1 (CH2), 34.3 (CH2) diastereomer B, 31.7 (CH2), 30.1
(CH2), 29.8-29.4 (CH2 × 8), 29.0 (CH2) diastereomers A and B,
28.9 (CH2), 28.4 (CH3 × 3), 28.0 (CH2), 27.5 (CH3) rotamer A,
26.7 (CH3) rotamer B, 26.1 (CH2), 25.3 (CH2) diastereomer A, 25.2
(CH2), 25.0 (CH2), 24.8 (CH2) diastereomer B, 24.4 (CH3) rotamer
A, 23.0 (CH3) rotamer B, 22.9 (CH2), 14.0 (CH3); IR (CHCl3 soln)
3010, 2929, 2856, 1721, 1691 cm-1; HRMS (ESI) calcd for
C47H79NO9SeNa (M + Na+) 898.4872 (monoisotopic), found
[r]25 +57.1 (c 1.195 CHCl3).
D
898.4863; [R]25 +32.6 (c 1.18, CHCl3).
Alkenyl Selinide 36. Axial alcohol 34 (610 mg, 1.02 mmol)
and alkene 3528 (4.45 g, 14.3 mmol) were dissolved in CH2Cl2 (30
mL). Grubbs’ second generation catalyst G2 was added in one
portion, the reaction was heated to 45 °C and stirred for 16 h. NMO
(120.6 mg) was added and the solvent was removed in Vacuo.
Purification by flash column chromatography (40-80% ether/
hexanes) provided recovered alcohol 33 (69.1 mg, 0.12 mmol, 11%
recovered yield), and alkenyl selenide 36 (664 mg, 0.755 mmol,
D
r,ꢀ-Unsaturated Ester 38. Alkyl selenide 37 (62.7 mg, 0.0712
mmol) was dissolved in CH2Cl2 (5 mL) and cooled to -78 °C. A
CH2Cl2 (5 mL) solution of m-CPBA (21.1 mg, <77% purity, 0.094
mmol) was added dropwise via cannula. After 2 h, Hu¨nig’s base
(0.05 mL) was added and the cold bath was removed. After an
additional 2 h at rt, the reaction was concentrated in Vacuo. Flash
column chromatography (60-80% ether/hexanes, then 100% ether)
provided R,ꢀ-unsaturated ester 38 (46 mg, 0.064 mmol, 89% yield)
1
74% yield) as a yellow oil. Rf ) 0.25 (40% EtOAc:hexanes); H
1
NMR (CDCl3) δ 7.61-7.58 (2H, m), 7.34-7.26 (3H, m), 5.63 (1H,
dt, J ) 15, 6 Hz), 5.45 (1H, dd, J ) 15, 7 Hz), 4.28 (1H, d, J )
8 Hz), 4.09 (2H, q, J ) 7 Hz), 4.20-3.90 (4H, m), 3.68 (1H, br s),
3.59 (1H, dd, J ) 8.5, 6.5 Hz), 3.6-3.25 (4H, m), 2.47 (1H, br s),
2.09-1.22 (24H, m), 1.16 (3H, t, J ) 7 Hz); 13C NMR (CDCl3) δ
172.8 (C), 135.6 (CH) diastereomer A, 135.5 (CH) diastereomer
B, 133.0 (CH) diastereomer A, 132.6 (CH) diastereomer B, 130.2
(CH) diastereomer A, 130.2 (CH), 130.0 (CH) diastereomer B,
128.9 (CH), 128.5 (CH), 128.4 (CH), 128.0 (C), 109.9 (C), 93.7
(C) rotamer A, 93.2 (C) rotamer B, 83.3 (CH), 79.6 (C) rotamer
A, 78.9 (CH) diastereomer A, 78.8 (CH) diastereomer B, 78.6 (CH)
rotamer B, 71.3 (CH2), 70.0 (CH2) rotamer A, 69.3 (CH2) rotamer
B, 66.0 (CH), 65.7 (CH2) rotamer A, 65.4 (CH2) rotamer B, 60.9
(CH2), 60.2 (CH2), 56.4 (CH) rotamer A, 56.3 (CH) rotamer B,
43.4 (CH), 37.7 (CH2), 34.1 (CH2) diastereomer A, 31.6 (CH2)
diastereomer B, 31.4 (CH2), 31.3 (CH2), 30.9 (CH2) diastereomer
A, 30.3 (CH2) diastereomer B, 29.8-29.4 (CH2 × 9), 28.4 (CH3
× 3), 27.5 (CH3) rotamer A, 27.4 (CH2) diastereomer A, 26.7 (CH3)
rotamer B, 26.1 (CH2), 24.9 (CH2), 24.4 (br CH3) rotamers A, 23.2
(CH2), 23.2 (CH3) rotamer B, 14.2 (CH3) diastereomer A, 14.0
(CH3) diastereomer B; IR (thin film) 3480 (br), 2926, 2854, 1729,
1700 cm-1; HRMS (ESI) calcd for C47H77NO9SeNa (M + Na+)
as a colorless oil. Rf ) 0.52 (100% ether); H NMR (CDCl3) δ
6.94 (1H, dt, J ) 15.5, 7 Hz), 5.81 (1H, d, J ) 15.5 Hz), 4.18 (2H,
q, J ) 7 Hz), 4.05 (1H, br s), 4.00-3.86 (4H, m), 3.65-3.25 (5H,
m), 2.44 (1H, br d, J ) 9 Hz), 2.21 (2H, q, J ) 6.5 Hz),
1.96 (1H, m), 1.84-1.26 (55H, m); 13C NMR (CDCl3) δ 166.6
(C), 148.8 (CH), 121.5 (CH), 109.6 (C), 93.8 (C) rotamer A, 93.7
(C) rotamer B, 82.4 (CH), 80.2 (C) rotamer A, 79.7 (C) rotamer
B, 77.7 (CH), 71.3 (CH2), 70.0 (CH2) rotamer A, 69.3 (CH2) rotamer
B, 66.2 (CH), 65.7 (CH2) rotamer A, 65.4 (CH2) rotamer B, 60.1
(CH2), 56.5 (CH) rotamer A, 56.4 (CH) rotamer B, 37.5 (CH2),
35.0 (CH2), 32.0 (CH2), 30.1 (CH2), 29.7-29.4 (CH2 × 13), 28.4
(CH3 × 3), 27.8 (CH2), 27.5 (CH3) rotamer A, 26.7 (CH3) rotamer
B, 26.1 (CH2), 25.1 (CH2), 24.4 (CH3) rotamer A, 23.1 (CH3)
rotamer B, 23.0 (CH2), 14.3 (CH3); IR (CHCl3 soln) 3010, 2929,
2856, 1693 (br) cm-1; HRMS (ESI) calcd for C41H73NO9 (M +
Na+) 746.5178, found 746.5159; [R]25 +37.6 (c 0.98, CHCl3).
D
Acknowledgment. Financial support for this work from the
NIH (GM069352 and CA108488) and NIH CBI training grant
T32 GM008505 (C.C.M. and E.A.V.) is gratefully acknowl-
edged, as is support of departmental NMR facilities by grants
from the NIH (1 S10 RR0 8389-01) and NSF (CHE-9208463).
We would also like to thank Matt Dodge (University of
896.4721 (monoisotopic), found 896.4758; [R]25 +33.5 (c 1.08,
D
CHCl3).
1
Wisconsin-Madison) for obtaining the high field H and 13C
Alkyl Selenide 37. Alkenyl selenide 36 (482 mg, 0.548 mmol)
was dissolved in 1,2-dimethoxyethane (40 mL). p-Toluenesulfonyl
hydrazide (4.95 g, 26.6 mmol) was added, and this solution was
heated to reflux (oil bath temperature 85 °C). A solution of NaOAc
(2.24 g, 27.3 mmol) in H2O (40 mL) was added via syringe pump
over 3 h. The reaction was stirred for an additional 2 h, and then
cooled to rt. The reaction mixture was extracted exhaustively with
CH2Cl2 (75 mL portions). The combined organic layers were dried
(MgSO4), filtered, and concentrated in Vacuo. Purification by flash
NMR data for synthetic 2.
Supporting Information Available: Experimental proce-
dures and 1H and 13C NMR spectra for all new compounds and
a comparison of 2 with literature data are provided. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO801666T
J. Org. Chem. Vol. 73, No. 21, 2008 8457