Synthesis of the (9S, 18R)-seco acid of the leukocyte adhesion inhibitor cyclamenol A

Article abstract of DOI:10.1016/S0040-4039(99)02135-8

Cyclamenol A is a naturally occurring inhibitor of leukocyte adhesion to endothelial cells. The (9S, 18R) diastereomer of cyclamenol A seco acid was synthesized by employing Sonogashira couplings and olefination reactions as the key steps. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02135-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 625–628
Synthesis of the (9S,18R)-seco acid of the leukocyte adhesion
inhibitor cyclamenol A
Marc Nazaré and Herbert Waldmann ∗
Max-Planck-Institut für Molekulare Physiologie, Dortmund and Universität Dortmund, Fb. 3, Organische Chemie,
Otto-Hahn-Straße 11, D-44227 Dortmund, Germany
Received 28 September 1999; accepted 15 November 1999
Abstract
Cyclamenol A is a naturally occurring inhibitor of leukocyte adhesion to endothelial cells. The (9S,18R)
diastereomer of cyclamenol A seco acid was synthesized by employing Sonogashira couplings and olefination
reactions as the key steps. © 2000 Elsevier Science Ltd. All rights reserved.
Adhesion of leukocytes to endothelial cells is an important event initiated by inflammation, tissue
injury and infection.1 It facilitates the transport of leukocytes to the site of injury and subsequent
inflammation and immune responses. Over recruitment of these blood cells can be deleterious and various
diseases and disorders ranging from chronic autoimmune diseases to acute inflammation may occur.
Intervention of leukocyte recruitment by inhibiting their adhesion to endothelial cells is considered to
be a new strategy for the development of anti-inflammatory agents, and it is expected that many acute
symptoms such as reperfusion injury, stroke, asthma and arthritis may be treated with this approach. For
this purpose the development of carbohydrate based inhibitors of the selectin/sialyl Lewis X interaction
has attracted considerable interest.2 However, non-carbohydrate natural products that inhibit leukocyte
adhesion to endothelial cells have not been investigated so far.
Recently cyclamenol A 1 a macrocyclic polyene lactam with unknown absolute configuration was
isolated from Streptomyces spec. MHW 846 by chemists of the Bayer corporation (Scheme 1).3 This
compound displays leukocyte adhesion inhibiting activity in an ex vivo model and it completely inhibits
adhesion of leukocytes to arteriols in vivo (in hamsters). Given the high interest in the development of
cell adhesion inhibitors we embarked on a program directed at the synthesis of cyclamenol A and cyclic
and acyclic analogs of this polyene lactam. In this paper we report on a highly convergent synthesis of
(9S,18R)-cyclamenol A seco acid 2 from four building blocks.
Retrosynthetic considerations: In developing a synthesis plan for the construction of cyclamenol A
seco acid 2 particular attention was paid to the acid-sensitive polyene system present and the potential
danger of formation of a fully conjugated system by dehydration under acidic conditions. Further
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02135-8
tetl 16063

626
Scheme 1.
attention was focused on the fact that seco acid 2 embodies six E-double bonds and, in addition, one olefin
with Z-configuration. Therefore, in a retrosynthetic sense 2 was divided into acetylene 4 and vinyl iodide
3 to be linked by a Sonogashira coupling. The Z-configuration of the C-12–C-13 double bond should be
adjustable by Z-selective reduction of the acetylene present in the coupling product. We envisaged that
vinyl iodide 3 might be accessible from aldehyde 5 and phosphorane 6 in a Wittig reaction. From the
coupling product the desired vinyl iodide 3 should be accessible by hydrostannylation and subsequent
treatment of the vinyl stannane with iodine. Similarly, we planned to synthesize the acetylenic C-12–C-19
fragment by a Horner olefination reaction employing aldehyde 7 and phosphonate 8. This retrosynthetic
disconnection leads to a highly convergent synthesis. In particular, the two stereocenters present in the
target compound are relayed to starting materials readily accessible in both enantiomeric forms. This
strategy should give access to all four possible diastereomers of seco acid 2.
Synthesis of the C-1–C-11 fragment 3: As starting material for the fragment 3 naturally occurring
(S)-malic acid 9 was tentatively chosen. (S)-Malic acid 9 was transformed into the lactone 10 by a
known procedure.4 Protection of the hydroxy group and subsequent reduction with DIBAH afforded
lactol 11. Reaction of lactol 11 with phosphonate 125 directly yielded alkynol 13. Sequential one-
pot Swern oxidation and Wittig reaction with phosphonium salt 66 afforded, after deprotection of
the THP–acetal, alcohol 14 without any elimination of the hydroxy group. The initial Wittig reaction
proceeded only with poor stereoselectivity (E:Z=4:1). However due to the acidic deprotection conditions
an acid-catalyzed isomerization may have occurred and no (Z)-isomer in the product could be detected by
1H NMR spectroscopy. Stereoselective palladium-catalyzed hydrostannation7 and subsequent treatment
with iodine afforded vinyl iodide 3 (Scheme 2).
Synthesis of the C-12–C-19 fragment 4: As starting material for the construction of the fragment
4 commercially available (R)-hydroxyisobutyric acid methyl ester 15 was tentatively chosen. Amino
alcohol 16 was prepared from the building block according to a published procedure.8 The free amino
group was protected as a trifluoroacetamide and the alcohol was oxidized under Swern conditions to
afford amino aldehyde 7. Phosphonate 8 was efficiently obtained in a stereoselective manner starting
form E-1,4-dichloro-1-butene 18 by Arbusov reaction and subsequent Sonogashira coupling.
This sequence for the preparation of the phosphonate 8 is significantly better than previously described

627
Scheme 2. Reagents and conditions. (a) DHP, PPTS, CH2Cl2; (b) DIBAH, CH2Cl2, −78°C, 83% for two steps; (c) K2CO3,
8, MeOH, 80%; (d) (COCl)2, DMSO, NEt3, CH2Cl2, then 10, 80%; (e) PPTS, MeOH, 45°C, 90%; (f) Bu3SnH, (Ph3P)4Pd,
CH2Cl2, then I2, −20°C, 68%
procedures.9 The crude aldehyde 7 was condensed with the phosphonate 8 to give the coupling product as
a mixture of stereoisomers (E:Z=3:1). Although the construction did not proceed in a highly stereoselec-
tive manner, pure E-olefin could be obtained by treatment of the isomeric mixture with catalytic amounts
of iodine and in daylight. The remaining Z-isomer could be easily separated from the equilibrated mixture
(E:Z=10:1) by column-chromatography on silica gel. Finally, deprotection of the acetylenic terminus
furnished C-12–C-19 fragment 4 (Scheme 3).
Scheme 3. Reagents and conditions. (a) TFAA, NEt3, CH2Cl2, 90%; (b) (COCl)2, DMSO, NEt3; (c) P(OMe)3, 110°C, 83%; (d)
TMS–acetylene, piperidine, (PhCN)2PdCl2, CuI, THF, 70%; (e) LDA, THF, −78°C, 14, 65% for two steps; (f) I2(cat.) CH2Cl2,
80%; (g) AgNO3, KCN, 90%
Final coupling and (Z)-selective reduction: Vinyl iodide 3 was stereoselectively coupled with alkyne
4 by means of a Sonogashira reaction10 to yield the entire C-backbone of cyclamenol A 1. Fortunately,
this compound was quite stable and thus the stereoselective reduction of the acetylene was attempted.
Upon treatment of the alkyne with activated zinc11 the protected cyclamenol seco acid 212 was obtained
smoothly and with complete stereoselectivity (Scheme 4).
Scheme 4. Reagents and conditions. (a) Piperidine, (PhCN)2PdCl2, CuI, PhH, 87%; (b) Zn(Ag/Cu), MeOH, 55%

628
In conclusion, we have developed a highly convergent synthesis of the (9S,18R) diastereomer of
cyclamenol A seco acid. This route makes the target compound accessible in multigram amounts (up
to 2 g were prepared). By means of this modular building block strategy various cyclamenol A analogs
should be readily accessible.13
Acknowledgements
This research was supported by the BAYER AG and the Fonds der Chemischen Industrie.
References
1. T. A. Springer, Cell 1994, 76, 301–314.
2. Reviews: (a) Sears, P.; Wong, C.-H. Angew. Chem. 1999, 111, 2446–2471; Angew. Chem., Int. Ed. 1999, 38, 2300–2324; (b)
Giannis, A. Angew. Chem. 1994, 106, 188–191; Angew. Chem., Int. Ed. Engl. 1994, 33, 178–181.
3. Müller, H.; Bischoff, E.; Fiedler, V. B.; Weber, K.; Fugmann, B.; Rosen, B. Patent BAYER AG, DE 4231289 A1 940324.
4. Collum, D. B.; McDonald, J. H.; Still, W. C. J. Am. Chem. Soc. 1980, 102, 2118–2120.
5. Mueller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521–522.
6. Durrant, G.; Green, R.; Lambeth, P.; Lester, M. G.; Taylor, N. R. J. Chem. Soc., Perkin. Trans. 1 1983, 2211–2214.
7. Zhang, H. Z.; Guibé, F.; Balavoine, G. J. Org. Chem. 1990, 55, 1857–1867.
8. Barrow, R.; Henscheidt, T.; Kieng, J.; Paik, S.; Moore, R. E.; Tius, M. A. J. Am. Chem. Soc. 1995, 117, 2479–2490.
9. Nicolaou, K. C.; Veale, C. A.; Webber, S. E.; Katerinopoulos, H. J. Am. Chem. Soc. 1985, 107, 7515–7518.
10. Sonagashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467–4470.
11. Boland, W.; Schroer, N.; Sieler, C. Helv. Chim. Acta 1987, 70, 1025–1040.
12. Compound 2: 1H NMR (500 MHz, CDCl3): δ=7.28 (dd, J=15 Hz, 10 Hz, 1H, H-3), 6.77 (dd, J=15 Hz, 10 Hz, 1H, H-5),
6.62 (m, 2H, NH, H-4), 6.50 (dd, J=15 Hz, 10 Hz, 1H, H-2), 6.27 (d, J=14.5 Hz, 1H, H-15), 6.23 (d, J=14.5, 1H, H-16),
6.13 (dd, J=15 Hz, 10 Hz, 1H, H-14), 6.07 (dd, J=11 Hz, 10 Hz, 1H, H-12), 5.92 (dd, J=11 Hz, 10 Hz, 1H, H-13), 5.78 (d,
J=14.5 Hz, 1H, H-6), 5.68 (dd, J=14.5 Hz, 10 Hz, 1H, H-7), 5.62 (m, 1H, H-11), 5.45 (dd, J=15 Hz, 7 Hz, 1H, H-17), 5.20
(dd, J=15 Hz, 7 Hz, 1H, H-10), 4.20 (m, 1H, H-9), 3.82 (s, 1H, OCH3), 3.05 (m, 1H, H0-19), 2.85 (m, 1H, H0-19), 2.40 (m,
2H, H-8), 2.20 (m, 1H, H-18), 1.02 (d, J=7.5 Hz, 3H, H-20).
13. Synthesis of (9S,18R)-cyclamenol A via a vanadium-mediated pinacol coupling as the key step: Nazaré, M.; Waldmann, H.
Angew. Chem. 2000, 112, in press.