A synthesis of the chlorosulfolipid mytilipina a via a longest linear sequence of seven steps

Article abstract of DOI:10.1002/anie.201304565

Magnificent seven: The chlorosulfolipid mytilipin A was synthesized in racemic form in seven steps and in enantioenriched form in eight steps. Key transformations include a highly diastereoselective bromoallylation of a sensitive α,β-dichloroaldehyde, a kinetic resolution of a vinyl epoxide, a convergent and highly Z-selective alkene cross-metathesis, and a chemoselective and diastereoselective dichlorination of a complex diene.

Full text of DOI:10.1002/anie.201304565

Angewandte
Chemie
DOI: 10.1002/anie.201304565
Natural Product Synthesis
A Synthesis of the Chlorosulfolipid Mytilipin A via a Longest Linear
Sequence of Seven Steps**
Won-jin Chung, Joseph S. Carlson, D. Karl Bedke, and Christopher D. Vanderwal*
Dedicated to Professor Larry Overman on the occasion of his 70th birthday
The chlorosulfolipids are a most unusual group of lipids,
known since the independent reports of chlorinated C22 lipids
isolated from the alga Ochromonas danica by the groups of
Vagelos and Haines in 1969.[1,2] These first compounds were
characterized as bis-sulfates of 1,14-docosanediol, with vary-
ing levels of chlorination up to the hexachloride, now known
as danicalipin A (1; Figure 1). In the decades since, this family
has grown to include ill-characterized C24 analogues (also
from O. danica),[3] the unusual chlorovinyl sulfate-containing
lipid malhamensilipin A (2) that was isolated from the related
alga Poterioochromonas malhamensis by Slate and Gerwick,[4]
and the mytilipins, a small group of lipids isolated in very
small quantities from toxic Adriatic mussels and reported by
Fattorusso and co-workers.[5,6] These last compounds include
the C15 lipid mytilipin A (3), which has some structural
resemblance to danicalipin A and malhamensilipin A, and
mytilipins B and C (4 and 5), two C24 lipids with an astounding
level of stereochemical complexity that includes 11 chlorine-
bearing centers. More recently, Okino and co-workers
Figure 1. Representative chlorosulfolipids.
uncovered more natural congeners in the danicalipin series
in a careful study of O. danica,[7] and Sheu and co-workers
isolated analogues of mytilipin A from an octocoral from the
Strait of Taiwan.[8] Given the diversity of sources and
structures, it is reasonable to expect that more members will
be added to the chlorosulfolipid family in the years to come.[9]
Over the past four years, several groups, including our
own, have reported syntheses of members of the chlorosulfo-
lipid family. Carreira and co-workers registered the first
synthesis when they disclosed an elegant route to racemic
mytilipin A.[10] Shortly thereafter, our group reported the
stereochemical elucidation of danicalipin A and its synthesis
in racemic form,[11] followed by the structural revision and
enantioselective synthesis of malhamensilipin A.[4b,12] These
three syntheses featured similar overall strategies with
introduction of the polar substituents by alkene oxidation
reactions.[13] The group of Yoshimitsu developed a substan-
tially different approach, featuring their method for stereo-
specific deoxydichlorination of enantioenriched epoxides,[14]
which culminated in clever asymmetric syntheses of both
mytilipin A and danicalipin A,[15] the latter of which was
[*] Dr. W.-j. Chung,[+] J. S. Carlson,[+] Dr. D. K. Bedke,
Prof. C. D. Vanderwal
Department of Chemistry, University of California, Irvine
1102 Natural Sciences II, Irvine, CA 92697-2025 (USA)
E-mail: cdv@uci.edu
Homepage: http://www.chem.uci.edu/~cdv
Dr. D. K. Bedke
contemporaneous with
a third very different, creative
approach from the Matsuda group.[16] Finally, the Carreira
group recently reported the synthesis of the proposed
structure of mytilipin B as shown in Figure 1, and came to
the conclusion that this chlorosulfolipid requires stereochem-
ical revision.[17]
Current address: Amgen, Inc., South San Francisco (USA)
[+] These authors contributed equally to this work.
[**] This work was supported by the National Institutes of Health (R01
GM086483). C.D.V. is grateful for additional funding from an
AstraZeneca Excellence in Chemistry Award, an Eli Lilly Grantee
Award, and an A. P. Sloan Foundation Fellowship. J.S.C. is
supported by a National Science Foundation Graduate Research
Fellowship. D.K.B. was supported by a UC Irvine-Eli Lilly Graduate
Fellowship and a UC Irvine Physical Sciences Dissertation Fellow-
ship. We thank Materia for generous donation of metathesis catalyst
12, and Dr. Martin Schnermann, Dr. Paresma Patel, Dr. Vanessa
Marx, and Prof. Robert Grubbs for invaluable assistance with the
convergent metathesis step.
We now report a new synthesis of mytilipin Avia a longest
linear sequence of only seven steps for racemic material, and
eight for enantioenriched chlorosulfolipid, with several key
features: 1) a highly diastereoselective haloallylation of
a sensitive a,b-dichloroaldehyde, 2) a kinetic resolution of
a complex vinyl epoxide, 3) a convergent olefination via Z-
selective alkene cross-metathesis, and 4) excellent levels of
stereocontrol throughout.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304565.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Scheme 1. Synthesis of mytilipin A via a seven-step longest linear sequence. DCE=1,2-dichloroethane, DMF=N,N-dimethylformamide,
THF=tetrahydrofuran.
Crotyl alcohol was treated with molecular chlorine in the
presence of Et4NCl to afford anti-dichloride 7 (Scheme 1);
presumably this procedure generates Mioskowskiꢀs reagent[18]
(Et4NCl3) in situ. Oxidation with the Dess–Martin period-
inane followed by a careful workup afforded the sensitive and
volatile aldehyde 8 in crude form, which was immediately
converted to vinyl epoxide 9. The bromoallylaluminum
reagent shown[19] added with high diastereocontrol, consistent
with both the Felkin–Anh and Cornforth models,[20,21] and the
resulting bromohydrin was converted to the epoxide upon
treatment with aqueous base. The moderate yield in this case
might be attributed to volatility of the intermediate aldehyde
and the vinyl epoxide product; in related systems with longer
alkyl chains, yields of about 75% have been obtained.
Although strategically attractive in the context of the
chlorosulfolipids, carbonyl addition reactions to a,b-dichlor-
oaldehydes can be plagued by facile elimination reactions,
and only Yoshimitsu et al. have previously embraced this type
The success of the cross-metathesis in the face of possible
ring-closing metathesis (RCM) pathways can be attributed to:
1) the intrinsically slow reactivity of vinyl chlorides, 2) the
slow kinetics of cyclooctene formation, and 3) the high kinetic
selectivity of catalyst 12 for Z-alkenes, which presumably
prevents reaction with the E-vinyl chloride in either RCM or
cross-metathesis events. Vinyl epoxide chlorinolysis with
inversion of configuration[11,12] proceeded smoothly under
the reaction conditions shown, providing diene 14.
Uncertain about the reactivity of the isolated vinyl
chloride relative to the particularly electron-deficient allylic
chloride in 14, we were pleased to observe a completely
chemoselective, highly diastereoselective (93:7 d.r. of crude
reaction product, purified to 97:3), and efficient chlorination
using Mioskowskiꢀs reagent. The generation of hexachloride
product 15 constitutes a formal synthesis of mytilipin A, and
sulfation of the secondary alcohol according to Carreiraꢀs
conditions[10] completes the seven step (longest linear
sequence) synthesis of racemic chlorosulfolipid. This route
has enabled the preparation of over 100 mg of the target
molecule to date, with a nearly 9% yield over the entire
sequence. Although the final steps of the synthesis are related
to those previously reported by us and the Carreira group, our
rapid access to 13 takes advantage of a completely new
strategy designed for general access to several of the
chlorosulfolipids.
of C C bond-forming reaction en route to these targets.[15] In
À
our studies, we have found that a variety of allylation reagents
that presumably react via closed transition states provide
products with high levels of diastereoselectivity and without
destruction of the sensitive aldehyde substrate.
The alkene partner 11 required for the convergent step
was obtained in two steps from 8-bromo-1-octene. Formyla-
tion of the Grignard reagent derived from 10 followed by
Takai chloroolefination[22] afforded 11 on multigram scale.
The key convergent bond formation—Z-selective alkene
cross-metathesis[23] using the Grubbs cycloadamantyl catalyst
12[24]—generated Z-vinyl epoxide 13 with complete control of
alkene geometry. We attribute the relatively low yield in this
particular case to catalyst deactivation by the chlorinated
vinyl epoxide; however, this step compares favorably overall
with previous syntheses of this type of epoxyalkene via poorly
selective Wittig reactions that require several extra steps.[10–12]
Unfortunately, we were unable to achieve effectively more
than a single turnover with 12;[25] however, this reaction is
notable for the ability to directly introduce the vinyl chloride,
which eliminates at least three post-convergence steps.[10,15a]
The convergent Z-selective alkene cross-metathesis to
form 13 is noteworthy for its complete diastereoselectivity if
not for its efficiency. To see if the extremely high selectivity
we observed was general for vinyl epoxides, as well as to
investigate the low catalytic activity of 12 with respect to the
specific case in Scheme 1, we tested the reactivity of cis-3,4-
epoxy-1-undecene (18) with 1-decene [Eq. (1)]. With
2
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
10 mol% of catalyst 12, complete conversion to Z-vinyl
epoxide 19 was observed (83% yield, > 20:1 Z/E). With
1 mol% catalyst, the product was isolated in 43% yield
(incomplete conversion), with equal selectivity. Therefore, it
appears that vinyl epoxides are subject to highly Z-selective
cross-metathesis with catalyst 12, and that the poor efficiency
observed in the convergent step to form 13 is likely specific to
chlorinated substrates of type 9.
In principle, adaptation of our route to the enantioselec-
tive preparation of mytilipin A simply requires access to
enantioenriched dichloroalcohol 7. However, methods for the
asymmetric dichlorination of alkenes, including the allylic
alcohol substrates pertinent to our synthesis, are not yet at
a level of sophistication appropriate for the first step in
complex molecule synthesis.[26] We contemplated accessing
enantioenriched dichloroalcohols using either the stereospe-
cific deoxydichlorination of an optically active epoxyalcohol
derivative according to the method of Yoshimitsu,[14] or by
resolution. Because it would add only one step to the
sequence, we opted to investigate resolution strategies.
Unfortunately, attempts at kinetic resolution of dichloroalco-
hol 7 (and dichloroaldehyde 8) using a variety of approaches
were unsuccessful; however, racemic vinyl epoxide 9 could be
resolved by adapting the meso-epoxide desymmetrizing
chlorinolysis of Denmark and co-workers (Scheme 2).[27]
can be assembled in a relatively straightforward fashion. The
synthesis of racemic mytilipin A that we report requires only
seven linear steps from commercially available starting
materials and features only productive chemical transforma-
tions. Using kinetic resolution of a vinyl epoxide, enantioen-
riched chlorosulfolipid can be obtained with only one addi-
tional operation. Furthermore, our synthesis demonstrates
that a,b-dichloroaldehydes can participate in efficient and
highly stereoselective carbonyl addition reactions, and that Z-
selective alkene cross-metathesis is a powerful method for
convergent olefination en route to the chlorosulfolipids. The
successful application of these catalysts in this context further
documents the ever-expanding reach of metathesis processes
for stereocontrolled natural product synthesis.
Received: May 27, 2013
Published online: && &&, &&&&
Keywords: kinetic resolution · lipids · metathesis ·
.
natural products · total synthesis
[1] J. Elovson, P. R. Vagelos, Proc. Natl. Acad. Sci. USA 1969, 62,
957 – 963.
[2] T. H. Haines, M. Pousada, B. Stern, G. L. Mayers, Biochem. J.
1969, 113, 565 – 566.
[3] T. H. Haines, Prog. Chem. Fats Other Lipids 1971, 11, 297 – 345.
[4] a) J. L. Chen, P. J. Proteau, M. A. Roberts, W. H. Gerwick, D. L.
Slate, R. H. Lee, J. Nat. Prod. 1994, 57, 524 – 527; b) A. R.
Pereira, T. Byrum, G. M. Shibuya, C. D. Vanderwal, W. H.
Gerwick, J. Nat. Prod. 2010, 73, 279 – 283.
[5] a) P. Ciminiello, E. Fattorusso, M. Forino, S. Magno, M. Di Rosa,
A. Ianaro, R. Poletti, J. Org. Chem. 2001, 66, 578 – 582; b) P.
Ciminiello, C. DellꢀAversano, E. Fattorusso, M. Forino, M.
Di Rosa, A. Ianaro, R. Poletti, J. Am. Chem. Soc. 2002, 124,
13114 – 13120; c) P. Ciminiello, C. DellꢀAversano, E. Fattorusso,
M. Forino, S. Magno, P. Di Meglio, A. Ianaro, R. Poletti,
Tetrahedron 2004, 60, 7093 – 7098.
[6] The mytilipins initially went unnamed, and then were given the
descriptive names hexachlorosulfolipid (for 3) and undecachlor-
osulfolipids A and B (for 4 and 5, respectively). Recently, the
mytilipin name has been adopted in light of the origin of these
compounds from the mussel Mytilus galloprovincialis.
[7] T. Kawahara, Y. Kumaki, T. Kamada, T. Ishii, T. Okino, J. Org.
Chem. 2009, 74, 6016 – 6024.
[8] C.-H. Chao, H.-C. Huang, G.-H. Wang, Z.-H. Wen, W.-H. Wang,
I.-M. Chen, J.-H. Sheu, Chem. Pharm. Bull. 2010, 58, 944 – 946.
[9] For reviews on the chlorosulfolipids, see: a) D. K. Bedke, C. D.
Vanderwal, Nat. Prod. Rep. 2011, 28, 15 – 25; b) C. Nilewski,
E. M. Carreira, Eur. J. Org. Chem. 2012, 1685 – 1698.
[10] C. Nilewski, R. W. Geisser, E. M. Carreira, Nature 2009, 457,
573 – 576.
Scheme 2. Kinetic resolution affords enantioenriched vinyl epoxide
(+)-9.
The strong preference for ring opening of the vinyl epoxide
at the allylic position (as opposed to the position proximal to
the electron-withdrawing chloride residues) is presumably
key to success. A selectivity factor of 13 was realized, allowing
for material of 93.5:6.5 e.r. to be obtained at 57% conversion
(by NMR analysis) and in 43% isolated yield.[28] On the basis
of this result, we have defined an eight-step enantioselective
synthesis of mytilipin A.[29,30] More details about this inter-
esting resolution will be forthcoming in a full account.
[11] D. K. Bedke, G. M. Shibuya, A. Pereira, W. H. Gerwick, T. H.
Haines, C. D. Vanderwal, J. Am. Chem. Soc. 2009, 131, 7570 –
7572.
[12] D. K. Bedke, G. M. Shibuya, A. R. Pereira, W. H. Gerwick, C. D.
Vanderwal, J. Am. Chem. Soc. 2010, 132, 2542 – 2543.
[13] G. M. Shibuya, J. S. Kanady, C. D. Vanderwal, J. Am. Chem. Soc.
2008, 130, 12514 – 12518.
[14] T. Yoshimitsu, N. Fujumoto, T. Tanaka, J. Org. Chem. 2009, 74,
696 – 702.
A few short years ago, the highly chlorinated lipids shown
in Figure 1 might have appeared to be intractable problems
for chemical synthesis, because of the dearth of previous work
on stereochemically complex polychlorinated compounds.
Now, with the recent advances made by several groups,[10–16]
and with the design and execution of our new direct synthesis
described here, it has become clear that the chlorosulfolipids
[15] a) T. Yoshimitsu, N. Fujumoto, R. Nakatani, N. Kojima, T.
Tanaka, J. Org. Chem. 2010, 75, 5425 – 5437; b) T. Yoshimitsu, R.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
Nakatani, A. Kobayashi, T. Tanaka, Org. Lett. 2011, 13, 908 –
911.
[16] T. Umezawa, M. Shibata, K. Kaneko, T. Okino, F. Matsuda, Org.
Lett. 2011, 13, 904 – 907.
[17] C. Nilewski, N. R. Deprez, T. C. Fessard, D. B. Li, R. W. Geisser,
E. M. Carreira, Angew. Chem. 2011, 123, 8087 – 8091; Angew.
Chem. Int. Ed. 2011, 50, 7940 – 7943.
[18] T. Schlama, K. Gabriel, V. Gouverneur, C. Mioskowski, Angew.
Chem. 1997, 109, 2440 – 2442; Angew. Chem. Int. Ed. Engl. 1997,
36, 2342 – 2344.
[19] The corresponding chloroallylaluminum reagents have been
previously reported: A. Hosomi, S. Kohra, Y. Tominaga, M.
Ando, H. Sakurai, Chem. Pharm. Bull. 1987, 35, 3058 – 3061.
[20] The addition of organometallic nucleophiles to a-chloroalde-
hydes generally proceeds to afford the anti product, consistent
with the polar Felkin – Anh model (hyperconjugative stabiliza-
tion of the transition state/steric control), though the Cornforth
model (dipole minimization/steric control) also accounts for the
stereochemistry of the products. For an excellent discussion and
lead reference, see: V. J. Cee, C. J. Cramer, D. A. Evans, J. Am.
Chem. Soc. 2006, 128, 2920 – 2930.
314; d) L. E. Rosebrugh, M. B. Herbert, V. M. Marx, B. K. Keitz,
R. H. Grubbs, J. Am. Chem. Soc. 2013, 135, 1276 – 1279.
[25] Under otherwise identical reaction conditions, we obtained 10%
yield of 13 with 10 mol% 12, 34% of 13 with 50 mol% 12, and
only 39% of 13 with 100 mol% 12. However, we note that we
have seen examples where more than one turnover is observed,
and do not believe that there is a mechanistic explanation for the
limitation in terms of turnover. Rather, catalyst decomposition
appears to be competitive with the desired transformation.
[26] For the most advanced system to date for catalytic asymmetric
dichlorination of allylic alcohols, and an excellent lead reference,
see: K. C. Nicolaou, N. L. Simmons, Y. Ying, P. M. Heretsch, J. S.
Chen, J. Am. Chem. Soc. 2011, 133, 8134 – 8137. For a stoichio-
metric reagent system that enabled enantioselective dichlorina-
tion in the context of a complex natural product synthesis, see:
S. A. Snyder, Z.-Y. Tang, R. Gupta, J. Am. Chem. Soc. 2009, 131,
5744 – 5745.
[27] a) S. E. Denmark, P. A. Barsanti, K.-T. Wong, R. A. Stavenger, J.
Org. Chem. 1998, 63, 2428 – 2429; b) S. E. Denmark, P. A.
Barsanti, G. L. Beutner, T. W. Wilson, Adv. Synth. Catal. 2007,
349, 567 – 582.
[21] Carbonyl additions to simple a-chloroaldehydes are often highly
diastereoselective. See: R. Britton, B. Kang, Nat. Prod. Rep.
2013, 30, 227 – 236.
[22] K. Takai, K. Nitta, K. Utimoto, J. Am. Chem. Soc. 1986, 108,
7408 – 7410.
[28] Surprisingly, the monomeric catalyst described in Ref. [27a] was
less selective than 16. This result contrasts with the report in
Ref. [27b] wherein dimeric catalysts of type 16 were less
effective at meso-epoxide desymmetrizations than the corre-
sponding monomeric catalysts.
[23] For the first application of Z-selective alkene cross-metathesis in
natural product synthesis, see: S. J. Meek, R. V. OꢀBrien, J.
Llaveria, R. R. Schrock, A. H. Hoveyda, Nature 2011, 471, 461 –
466.
[24] a) K. Endo, R. H. Grubbs, J. Am. Chem. Soc. 2011, 133, 8525 –
8527; b) B. K. Keitz, K. Endo, P. R. Patel, M. B. Herbert, R. H.
Grubbs, J. Am. Chem. Soc. 2012, 134, 693 – 699; c) M. B.
Herbert, V. M. Marx, R. L. Pederson, R. H. Grubbs, Angew.
Chem. 2013, 125, 328 – 332; Angew. Chem. Int. Ed. 2013, 52, 310 –
[29] The stereochemical outcome of the resolution of vinyl epoxide
(Æ)-9 was opposite to what we expected on the basis of
Denmarkꢀs epoxide desymmetrization. Ultimately, this unanti-
cipated outcome resulted in the synthesis of the unnatural
enantiomer of mytilipin A.
[30] The Carreira group used a Sharpless epoxidation of racemic anti-
4,5-dichloro-2-buten-1-ol followed by diastereomer separation
to render their synthesis of mytilipin A enantioselective: R. W.
Geisser, D. Sc. Dissertation, ETH Zꢁrich, 2010.
4
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Natural Product Synthesis
W.-j. Chung, J. S. Carlson, D. K. Bedke,
C. D. Vanderwal*
&&&& — &&&&
A Synthesis of the Chlorosulfolipid
Mytilipin A via a Longest Linear Sequence
of Seven Steps
Magnificent seven: The chlorosulfolipid
mytilipin A was synthesized in racemic
form in seven steps and in enantioen-
riched form in eight steps. Key trans-
formations include a highly diastereose-
lective bromoallylation of a sensitive a,b-
dichloroaldehyde, a kinetic resolution of
a vinyl epoxide, a convergent and highly
Z-selective alkene cross-metathesis, and
a chemoselective and diastereoselective
dichlorination of a complex diene.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!