(-)-15-Deoxyspergualin: A new and efficient enantioselective synthesis which allows the definitive assignment of the absolute configuration

Article abstract of DOI:10.1021/jo9811118

(±)-15-Deoxyspergualin (DSG) has recently been marketed in Japan for the control of corticoresistant acute renal graft rejection. A nine-step total synthesis of its eutomer ((-)-DSG) 2 has been developed starting from 7-bromoheptanenitrile 3 and N¹,N⁴-bis(benzyloxycarbonyl)spermidine. The use of a chiral α-alkylbenzyl group to protect the hydroxyl of the α- hydroxyglycine moiety allowed its chromatographic resolution and afforded a practical access to 2 with a high optical purity and a 7% overall yield. Moreover, X-ray structure analysis of the key crystalline intermediate 7b definitely confirmed the previously proposed absolute configuration of 2.

Full text of DOI:10.1021/jo9811118

J . Org. Chem. 1998, 63, 9723-9727
9723
(-)-15-Deoxysp er gu a lin : A New a n d Efficien t En a n tioselective
Syn th esis Wh ich Allow s th e Defin itive Assign m en t of th e Absolu te
Con figu r a tion
Philippe Durand,† Philippe Richard,‡ and Patrice Renaut*,†
Laboratoires Fournier S.A., 50 Route de Dijon, 21121 Daix, France, and Laboratoire de Synthe`se et
d’Electrosynthe`se Organome´tallique (UMR 5632), Faculte´ des Sciences “Gabriel”, 6 Boulevard Gabriel,
21100 Dijon, France
Received J une 10, 1998
(()-15-Deoxyspergualin (DSG) has recently been marketed in J apan for the control of corticoresistant
acute renal graft rejection. A nine-step total synthesis of its eutomer ((-)-DSG) 2 has been developed
starting from 7-bromoheptanenitrile 3 and N1,N4-bis(benzyloxycarbonyl)spermidine. The use of a
chiral R-alkylbenzyl group to protect the hydroxyl of the R-hydroxyglycine moiety allowed its
chromatographic resolution and afforded a practical access to 2 with a high optical purity and a
7% overall yield. Moreover, X-ray structure analysis of the key crystalline intermediate 7b definitely
confirmed the previously proposed absolute configuration of 2.
(-)-Spergualin 1 is an antitumor antibiotic that was
first isolated from the culture filtrates of the bacterium
strain Bacillus laterosporus BMG 162-aF2.1 This was
characterized2 as (-)-(15S)-1-amino-19-guanidino-11,15-
dihydroxy-4,9,12-triazanonadecane-10,13-dione and finely
synthesized by H. Umezawa et al. 3 in 1981. A subsequent
antitumor structure-activity relationship study4 has led
to the isolation of the nor-15-hydroxy derivative (-)-15-
Deoxyspergualin ((-)-DSG) 2. This hemisynthetic prod-
uct proved to be a very potent antitumor and immuno-
suppressor agent and represents the eutomer5 of (()-
DSG. In 1994 the racemic form received a marketing
approval in J apan for the treatment of corticoresistant
acute renal graft rejection episodes. Two syntheses of
racemic (()-DSG6a,b have been described.The enantiomer
2 was obtained by hemisynthesis from (-)-Spergualin,4
or by total synthesis via a 9-step process involving an
enzymatic resolution.7 Although the overall yield of this
last sequence was very low (0.3%), it allowed the access
to both (-)- and (+)-DSG. The (+)-isomer proved to be
far less active,4,7,8 demonstrating the crucial role of the
stereochemistry at C11. Nevertheless, determination of
the absolute configuration of the hydroxyglycine unit
present in this compound represents a real challenge due
to the difficulty in obtaining single crystals of the
hygroscopic and easily hydrolyzable DSG. However,
enzymatic resolution used for the synthesis7 of 2 suggests
that the C11 configuration could be S.
There is no general methodology available for the
synthesis of optically active hydroxyglycine derivatives.9
The described synthesis of 2 relies on an enzymatic
resolution.7 Unfortunately, this synthesis required the
use of the rather uncommon and expensive carboxypep-
tidase P. Other hydrolytic enzymes have been used to
resolve alkoxy glycine containing compounds, but they
showed strict selectivity regarding the alkoxy group and
limited examples of amino substituents have been
tested.10a-d More recently, Patel et al.10e have described
an elegant enzymatic acylative resolution of a protected
N-(7-guanidinoheptanoyl)-R-hydroxy glycine ester with
commercially available lipase. However, no synthesis of
2 has been described using this intermediate. A second
type of resolution of this amino acid unit is given by the
total synthesis of 13 and other examples of peptides
encompassing a hydroxyglycine. This moiety is intro-
duced non stereoselectively in the peptidic sequence and
the chirality brought by the other amino acids permits
* Corresponding author.
† Laboratoires Fournier S.A.
‡ Laboratoire de Synthe`se et d’Electrosynthe`se Organome´tallique.
(1) Takeuchi, T.; Iinuma, H.; Kunimoto, S.; Masada, T.; Ishizuka,
M.; Takeuchi, M.; Hamada, M.; Naganawa, H.; Kondo, S.; Umezawa,
H. J . Antibiot. 1981, 34, 1619-1621.
(2) Umezawa, H.; Kondo, S.; Iinuma, H.; Kunimoto, S.; Ikeda, Y.;
Iwazawa, H.; Ikeda, D.; Takeuchi, T. J . Antibiot. 1981, 34, 1622-1624.
(3) Kondo, S.; Iwasawa, H.; Ikeda, D.; Umeda, Y.; Ikeda, Y.; Iinuma,
H.; Umezawa, H. J . Antibiot. 1981, 34, 1625-1627.
(4) Iwasawa, H.; Kondo, S.; Ikeda, D.; Takeuchi, T.; Umezawa, H.
J . Antibiot. 1982, 35, 1665-1669.
(5) An eutomer is the more potent of a pair of biologically active
enantiomers as defined in: Pedro, A.; Lehmann, F. Trends in Pharm.
Sci. 1986, 281.
(6) Umeda, Y.; Moriguchi, M.; Kuroda, H.; Nakamura, T.; Iinuma,
H.; Takeuchi, T.; Umezawa, H. J . Antibiot. 1985, 38, 886-98. (b)
Bergeron, R. J .; McManis, J . S. J . Org. Chem. 1987, 52, 1700-03.
(7) Umeda, Y.; Moriguchi, M.; Ikai, K.; Kuroda, H.; Nakaruma, T.;
Fujii, A.; Takeuchi, T.; Umezawa, H. J . Antibiot. 1987, 40, 1316-1324.
(8) Maeda, K.; Umeda, Y.; Saino, T. Ann. N.Y. Acad. Sci. 1993, 685,
123-135 and references therein.
(9) One example of chemical asymmetric synthesis of R-hydroxy-
glycine compound by asymmetric reduction of oxalic derivatives with
low stereoinduction: O’Donnell, M. J .; Chen, N.; Zhou, C.; Murray,
M.; Kubiak, C. P.; Yang, F.; Stanley, G. C. J . Org. Chem. 1997, 62,
3962-75.
(10) Chen, S.-T.; Hsiao, S.-C.; Chiori, A.-J .; Wu, S.-H.; Wang, K.-T.
J . of Chinese Chemical Society 1992, 39, 91-99. (b) Roos, E. C.;
Mooiweer, H. H.; Hiemstra, H.; Speckamp, W. N. J . Org. Chem. 1992,
57, 6769-78. (c) Kawai, M.; Hosoda, K.; Omori, Y.; Yamada, K.;
Yamamura, H.; Butsugan, Y. Peptide Chemitry 1994: M. Ohno (Ed)
32nd Symposium, Oct 1994 Fukuoka, 161-4. (d) Bogensta¨tter, M.;
Steglich, W. Tetrahedron 1997, 53, 7267-74. (e) Patel, R. N.; Banerjee,
A.; Szarka, L. J . Tetrahedron: Asymmetry, 1997, 8, 1767-1771.
10.1021/jo9811118 CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/04/1998

9724 J . Org. Chem., Vol. 63, No. 26, 1998
Durand et al.
Sch em e 1
the resolution of the hydroxyglycine motif using prepara-
tive HPLC to separate the resulting diastereomers.11
A
third approach for the resolution of the hydroxyglycine
unit consists of fractional crystallization of a mixture of
diastereomeric salts or esters obtained respectively by
reacting the racemic acid part with an optically active
amine or alcohol.10c,12,
Resu lts a n d Discu ssion
As part of a program aimed at discovering new and
more potent immunosuppressors, we needed an efficient
access to analogues of 2. We wish to report here on a new
total synthesis of 2 which also allows the definitive
assignment of the absolute stereochemistry at C11 of 2
and (-)-Spergualin.
It utilizes a new approach involving the introduction
of a chiral auxiliary directly on the hydroxyl group of the
hydroxyglycine. To our knowledge, this methodology has
never been explored.13 This site of derivatization offers
a priori two major advantages: (i) the introduced chiral-
ity is located as close as possible to the center to be
resolved which is usually a favorable situation for
separation by chromatography or crystallization, (ii) if
the chiral auxiliary introduced can play the role at the
same time of a protective group, it could alleviate the
problem of the presence of the free hydroxyl group which
makes such hemiaminal functionality rather sensitive
toward hydrolysis and renders separation and purifica-
tion uncertain. Some examples for the removal of O-
benzyl protective group on R-benzyloxy glycine deriva-
tives have already been described7,10d with retention of
configuration. We therefore decided to use an optically
active R-substituted benzylic alcohol as a mixed chiral
auxiliary-protective group as depicted in the retrosyn-
thetic analysis shown in Scheme 1. Moreover, to avoid
the use of a highly unstable free amino R-alkoxy gly-
cine,14,15 we decided to build up the N-acylated R-hydroxy
glycine unit using a properly substituted precursor
amide. To facilitate purification of intermediates, to
obtain the mildest conditions of deprotection compatible
with the poor stability of 2, and to shorten the synthesis
as much as possible, we introduced benzyloxycarbonyl
protecting groups on the guanidine moiety and on the
amine so that all O and N protecting groups could be
removed simultaneously in the final step.
glycine,16,17b R-thioalkyl glycine,16b R-acetoxy glycine,17,11f
N-chloro glycine,16a,14 or R-halogeno glycine derivatives.18
We chose the latter for its efficiency whatever the alkoxy
group is. Examples of R-chloroglycine derivatives used
as starting materials were already described in the
literature and are readily accessible in a few steps.19-22
Scheme 2 shows the pathway used to obtain 2. Com-
mercial 7-bromoheptanenitrile 3 was first hydrolyzed
with concentrated aqueous HCl into the corresponding
amide 4.23 Nucleophilic displacement of the bromide with
sodium azide in DMSO at 80 °C24 yielded 5 in which the
azido function served as a protected primary amine
needed for elaboration of the guanidine function. This
latter functionality was introduced late in the synthesis,
and in a protected form, to avoid difficulties associated
with handling such a moiety. The amide 5 was then
converted in a three-step one-pot process into the desired
intermediate 7. The first step consisted of a condensation
with methyl 2-hydroxy-2-methoxyacetate. The formed
methanol was trapped with molecular sieves.22e The so
formed R-hydroxy glycine 6 could be isolated, or treated
in situ, with thionyl chloride at 40 °C in order to form a
labile R-chloroglycine intermediate. This was then treated
with chiral benzylic alcohol in the presence of triethyl-
(17) O’Donnell, M. J .; Bennett, W. D.; Polt, R. L. Tetrahedron Lett.
1985, 26, 695-8. (b) Apitz, G.; J a¨ger, M.; J aroch, S.; Krayzel, M.;
Scha¨ffeler, L.; Steglich, W. Tetrahedron 1993, 49, 8223-32.
(18) Easton, C. J .; Pitt, M. J . Tetrahedron Lett. 1990, 31, 3471-4.
(b) Easton, C. J .; Tan, E. W.; Hay, M. P. J . Chem. Soc. Chem. Commun.
1989, 385-7.
(19) Syntheses of R-halogenoglycines from R-thioalkylglycines: see
ref 16b.
(20) Syntheses of R-halogenoglycines from R-alkoxyglycines: Kohn,
H.; Sawhney, K. N.; Le Gall, P.; Roberton, D. W.; Leander, J . D. J .
Med. Chem. 1991, 34, 2444-52.
R-Alkoxy glycine derivative syntheses have already
been described in the literature starting from R-hydroxy
(11) Young, S. D.; Tamburine, P. P. J . Am. Chem. Soc. 1989, 111,
1933-4. (b) Ping, D.; Mounier, C. E.; May, S. W. J . Biol. Chem. 1995,
270, 29250-5. (c) Ping, D.; Katopodis, A. G.; May, S. W. J . Am. Chem.
Soc. 1992, 114, 3998-4000. (d) Shiono, S.; Harada, K. Bull. Chem.
Soc. J pn 1985, 58, 1061-2. (e) Brown, A. R.; Ramage, R. Tetrahedron
Lett. 1994, 35, 789-92. (f) Gilvarg, C.; Kingsbury, W. D. U.S. Patent
4, 454, 065, J un. 12, 1984. (g) Kawahara, T.; Susuki, K.; Iwasaki, Y.;
Shimoi, H.; Akita, M.; Moro-oka, Y.; Nishikawa, Y. J . Chem. Soc. Chem.
Commun., 1992, 625-6.
(21) Syntheses of R-halogenoglycines from glycines: (a) Kober, R.;
Steglich, W. Liebigs Ann. Chem. 1983, 4, 599-609. (b) Williams, R.
M.; Sinclair, P. J .; Zhai, D.; Chen, D. J . Am. Chem. Soc. 1988, 110,
1547-57. (c) see ref 16b d) Hamon, D. P. G.; Razzino, P.; Massy-
Westropp, R. A. J . Chem. Soc. Chem. Commun. 1991, 332-3.
(22) Syntheses of R-halogenoglycines from R-hydroxyglycines: a)
Bernstein, Z.; Ben-Ishai, D. Tetrahedron 1977, 33, 881-3. (b) Bateson,
J . H.; Baxter, A. J . G.; Roberts, P. M.; Smale, T. C.; Southgate, R. J .
Chem. Soc., Perkin Trans. 1 1981, 3242-9. (c) Chiono, S.; Harada, K.
Bull. Chem. Soc. J pn. 1985, 58, 1061-2. (d) Alks, V.; Sufrin, J . R.
Synth. Commun. 1989, 19, 1479-86. (e) Daumas, M.; Vo Quang, L.;
Le Goffic, F. Synth. Commun. 1990, 20, 3395-3401. (f) Ebeling, S. C.
J . Prakt. Chem. 1994, 336, 330-332.
(12) Kawai, M.; Omori, Y.; Yamamura, H.; Butsugan, Y. Tetrahe-
dron: Asymmetry 1992, 3, 1019-20.
(13) a) We have recently patented the synthesis of (-) DSG and
analogues using this approach: Lebreton, L.; Renaut, P.; Durand, P.
PCT Int. Appl. WO 9624579, Aug. 15, 1996. (b) During preparation of
the manuscript of this publication, a patent from BMS company has
described a similar approach. Wang, X.; Thottahil, J . K. Eur. Pat. Appl.
EP 765, 866, Apr. 2, 1997.
(14) Kawai, M.; Neogi, P.; Khattri, P. S.; Butsugan, Y. Chemistry
Letter 1990, 577-80.
(23) In contrast, concentrated H2SO4 hydrolysis of the nitrile
compound afforded a mixture of 4 (32%) and the symmetrical bis(7-
bromoheptane)imide(24%).
(15) Putnam, D.; Kopecek, J . J . Bioconjugate Chem. 1995, 6, 483-
92.
(16) Kawai, M.; Hosoda, K.; Omori, Y.; Yamada, K.; Yamamura, S.;
Yamamura, H.; Butsugan, Y. Synth. Commun. 1996, 26, 1545-54. (b)
Zoller, U.; Ben-Ishai, D. Tetrahedron, 1975, 31, 863-866.
(24) For recent improvement of the procedure and references for the
synthesis of alkyl azide see: Alvarez, S. G.; Alvarez M. T. Synthesis,
1997, 4, 413-414.

Enantioselective Synthesis of (-)-15-Deoxyspergualin
J . Org. Chem., Vol. 63, No. 26, 1998 9725
Sch em e 2a
a
Reagents and reaction conditions: (a) HCl conc, 12 h, rt, 95%; (b) NaN3, DMSO, 80 °C, 3.5 h, 65%; (c) (MeO)(HO)CHCO2Me, CH2Cl2,
40 °C, 24 h, molecular sieves 4 Å; (d) SOCl2, CH2Cl2, 40 °C, 1.75 h; (e) (S)-2-NaphtCH(OH)Me, Et3N, CH2Cl2, rt, 24 h, 62% overall from
5; (f) NaOH 1 N, DME, rt, 1.5 h; (g) H2N(CH2)4N(Cbz)(CH2)3NHCbz, DCC, HOBT, CH2Cl2, rt, 48 h, 48% overall from 7; (h) flash
chromatography; (i) Ph3P, H2O, THF, 65 °C, overnight; (j) CbzNdC(SMe)NHCbz, THF, rt, 3 h, 77% overall from 8a ; (k) (1) Pd(OH)2/C
(20%), MeOH/AcOH, H2 1 atm, 76%, (2) Sephadex C-25 and Sephadex LH-20.
amine. Different benzylic alcohols have been tested.25 All
of them gave about the same yield (50-70%) and none
led to a significant induction.
or in 1 N AcOH in methanol under 1 atm of hydrogen. It
is worth mentioning that these experimental conditions
provided triacetate 2 with high purity as an hygroscopic
solid without concomitant reductive dehydroxylation as
already described for related systems.30 The compound
was transformed into the corresponding tris hydrochlo-
ride salt and further purified as described in the
literature.6b
Optical purity of 2 was measured31 and proved to be
g99.5%. This scheme is thus extremely efficient for the
synthesis in 9 steps of (+)-DSG and 2 with an overall
yield of 7.5% and an enantiomeric excess g99.5%.
Finally and despite the fact that there is no induction
with this alcohol, we chose (S)-(-)-R-methyl-2-naphtha-
lenemethanol as the most efficient auxiliary in term of
ease of separation, cost, yield, and crystallinity of the
resulting diastereomers 7 and 8. The approximately 1:1
mixture of diastereomers 7 was obtained in an overall
62% yield starting from amide 5. The synthesis of 2 was
completed as follows. Saponification of 7 gave the corre-
sponding acid, which was then coupled with the N1,N4-
bis (benzyloxycarbonyl) spermidine26 using the DCC/
HOBT methodology to afford a mixture of the diastereo-
mers 8a and 8b. Fortunately these diastereomers were
easily separated by simple flash chromatography. Con-
version of 8a to 9a was made in a one-pot two-step
process. Among the numerous methods described27 to
convert an azido group in a primary amine, we chose the
action of Ph3P/H2O28 which allows a selective conversion
in the presence of benzyloxy, and benzyloxycarbonyl
groups. The so formed primary amine was then reacted
in situ with N,N′-bis(benzyloxycarbonyl)-S-methylisothio-
urea29 to give 9a in 77% yield. Final deprotection ac-
complished in one step using Pearlman’s catalyst either
in a H2O/AcOH/THF mixture under 20 atm of hydrogen
Moreover, the intermediate diastereomers 7 were
separated by preparative HPLC. Fortunately, one of the
purified diastereomer, 7b gave single crystals suitable
for X-ray analysis.32 The ORTEP view for 7b is given in
Supporting Information. The absolute configuration of
the hetero-disubstitued carbon proved to be R. Compound
7a has been further elaborated to 2 following the same
pathway as previously described where the absolute
configuration of the chiral center is preserved.33 The
absolute sterechemistry of (-)-Deoxyspergualin can thus
be assigned definitively to the S configuration.
(29) Tian, Z.; Edward, P.; Roeske, R. W. Int. J . Pept. Protein Res.
1992, 40, 119-26.
(25) Optically active benzylic alcohols, S-(-)-1-phenyl ethanol,
S-(-)-phenyl-1-butanol, S-(-)-1-(1-naphthyl)ethanol, S-(-)-R-methyl-
2-naphthalenemethanol, S-(+)-1-indanol, R-(-)-R-tetralol are com-
mercially available. A slight induction (d.e. 30%) was observed with
the latter two compounds as determined by NMR analysis.
(26) Nishizawa, R.; Takei, Y.; Yoshida, M.; Tomiyoshi, T.; Saino, T.;
Nishikawa, K.; Nemoto, K.; Takahashi, K.; Fujii, A.; Nakamura, T.;
Takita, T.; Takeuchi, T. J . Antibiotic 1988, 41, 1629-43.
(27) Gilchrist, T. L. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991; Vol. 8; pp 381-
399.
(30) Auerbach, J .; Zamore, Mc. F.; Weinreb, S. M.J . Org. Chem.
1976, 41, 725-26.
(31) Mayo, D. J .; Tomasella, F. P.; Noroski, J . E. J . Pharm. Biochem.
Analysis 1996, 14, 457-463.
(32) The author has deposited crystallographic data for 7b with the
Cambridge Crystallographic Data Center. The data can be obtained,
on request, from the Director, Cambridge Crystallographic Data
Center, 12 Union Road, Cambridge, CB2 1EZ, U.K.
(33) We have checked that there was no epimerisation during
saponification of 7a by reesterification of the crude product with an
ethereal diazomethane solution and analysis of the crude product by
NMR. Attempts to purify and better characterize the acid intermediate
revealed its instability.
(28) Knouzi, N.; Vaultier, M.; Carrie´, R. Bull. Soc. Chim. Fr. 1985,
5, 815-9.

9726 J . Org. Chem., Vol. 63, No. 26, 1998
Durand et al.
1660, 2100, 3180, 3380 cm-1; 1H NMR (CDCl3) δ 1.37-1.4 (m,
4H), 1.56-1.7 (m, 4H), 2.23 (t, J ) 7.5 Hz, 2H), 3.27 (t, J ) 9
Hz, 2H), 5.6 (m, 2H); 13C (DMSO-d6) δ 24.9, 25.9, 28.1, 28.2,
35.0, 50.6, 174.3. Anal. Calcd for C7 H14 N4 O: C, 49.39; H,
8.29; N, 32.92. Found: C, 49.54; H, 8.11; N, 32.96.
Con clu sion
It is desirable to develop and market new chiral drugs
as single enantiomer, especially when only one enanti-
omer is pharmacologically active. The present synthesis
affords an easy access to (-)-Deoxyspergualin which is
the prototype of a new family of immunosuppressor
agents34 and therefore could help in the synthesis of even
more potent optically active analogues.13a Furthermore,
this work proves definitively the absolute S configuration
of (-)-Deoxyspergualin and consequently that of the C11
of (-)-Spergualin. Although nothing is known to our
knowledge about the biosynthesis of (-)-Spergualin, it
is interesting to note that the R-hydroxy glycine absolute
configuration is the same as that induced by peptidyl-
glycine R-hydroxylating monooxygenase (PHM, EC
1.14.17.3), an enzyme responsible for the hydroxylation
of the R-carbon of the carboxy terminal glycine of some
peptides.35 Finally, the approach followed here could be
useful for the synthesis of other hydroxyglycine-contain-
ing molecules.
Acetic Acid , [(7-Azid o-1-oxoh ep tyl)a m in o]h yd r oxy-,
m eth yl ester (6). A solution of 5 (3 g, 17.6 mmol) and methyl
2-hydroxy-2-methoxy acetate (1.9 mL, 19.1 mmol) in 70 mL
of CH2Cl2 was heated under reflux for 24 h in a flask connected
to a Soxhlet apparatus filled with 20 g of 4 Å molecular sieves.
The mixture was concentrated under reduced pressure and
purified by flash chromatography on silica gel (EtOAc-cyclo-
hexane, 4.5:5.5). Compound 6 was obtained as a glassy solid
(3.17 g, 70%) after recrystallization from Et2O; Rf 0,18 (EtOAc-
cyclohexane, 40:60); mp 47 °C; IR(KBr) 1445, 1545, 1655, 1750,
2096, 2861, 3331 cm-1; 1H NMR (CDCl3) δ 1.35-1.42 (m, 4H),
1.57-1.68 (m, 4H), 2.26 (t, J ) 7.2 Hz, 2H), 3.26(t, J ) 6.8
Hz, 2H), 3.85 (s, 3H), 4.28 (d, J ) 6 Hz, 1H), 5.59(dd, J ) 6
Hz, J ) 7 Hz, 1H), 6.73(d, J ) 7 Hz, 1H); 13C NMR (CDCl3) δ
24.9, 26.3, 28.53, 28.57, 36.0, 51.27, 53.2, 71.9, 169.9, 173.9;
Anal. Calcd for C10 H18 N4 O4: C, 46.51; H, 6.98; N, 21.71.
Found: C, 46.92; H, 6.75; N, 21.68.
Acetic a cid , [(7-a zid o-1-oxoh ep tyl)a m in o] [1-(2-n a p h -
th a len yl)eth oxy]-, m eth yl ester , [S-(R*,R*)] (7a ) a n d
Acetic a cid , [(7-a zid o-1-oxoh ep tyl)a m in o] [1-(2-n a p h th a -
len yl)eth oxy]-, m eth yl ester , [S-(R*,S*)] (7b). A solution
of 5 (4.4 g, 26.1 mmol) and methyl 2-hydroxy-2-methoxy
acetate (2.9 mL, 29.2 mmol) in 250 mL of CH2Cl2 was heated
under reflux for 24 h in a flask connected to a Soxhlet
apparatus filled with 30 g of 4 Å molecular sieves. After
cooling, the Soxhlet apparatus was replaced by a reflux
condenser. Thionyl chloride (2.29 mL, 31 mmol) was added,
and the resulting mixture was refluxed for 1.75 h. The reaction
mixture was concentrated under reduced pressure. The crude
chloroglycine derivative was dissolved in 50 mL of CH2Cl2,
treated dropwise with (S)-(-)-R-methyl-2-naphthalenemetha-
nol (4.5 g, 26 mmol) and triethylamine (2.29 mL, 31 mmol) in
50 mL of CH2Cl2 for 24 h at room temperature. The reaction
mixture was then washed with HCl 1 N (100 mL), brine (100
mL). The organic layer was dried (MgSO4), concentrated under
reduced pressure, and the compound was purified by flash
chromatography on silica gel (hexane/i-PrOH, 9.5:0.5) to give
6.67 g (62%) of a mixture of 7a and 7b which can be directly
used in the next step or purified by preparative HPLC to
separate 7a and 7b. From three successive injections of 1.5 g
(0.5 g/mL), elution with CH2Cl2/EtOAc, 95:5 (P, 3 bar; flux,
120 mL/min) and after evaporation of solvent, 2.05 g of pure
7a (tr ) 14 min), 1.41 g of pure 7b (tr ) 16 min) and 1.04 g of
a mixture were obtained.
Exp er im en ta l Section
Gen er a l. All chemicals were purchased from commercial
sources and used without further treatment excepted when
specified. THF was freshly distilled from sodium benzophenone
ketyl. Melting points were uncorrected. Proton magnetic
resonance spectra were determined either at 250 or 300 MHz
with TMS as internal standard. Carbon magnetic resonance
spectra were recorded at 62.9 or 75 MHz. The chemical shifts
are expressed in δ values relative to TMS. For spectra recorded
in D2O we used HOD (1H δ 4.80) and dioxane (13C δ 67.3) as
internal standards. IR spectra were obtained on KBr, 3M
Disposable IR card (type 61) or in solution in the specified
solvent. Rf values were measured after thin-layer chromatog-
raphy performed with precoated silica plates (Kieselgel 60 F254
,
Merck). Elemental analyses were performed with an elemental
analyzer Perkin-Elmer 2400 CHN. Preparative HPLC separa-
tion were done with laboratory-scale preparative HPLC,
Prochrom Lab. LC 50 equipped with a thermostated (29 °C)
dynamic axial column (diameter 5 cm) and using Matrex
Amicon, spheric silica Si 100 15 SP (reference 84997; pore size,
100 Å; particle size, 15 µm; quantity, 250 g).
7-Br om oh ep ta n a m id e (4). A mixture of 7-bromohep-
tanenitrile (25 g, 131 mmol) and 100 mL of concentrated HCl
was stirred for 12 h at room temperature. The mixture was
then poured into cold water (300 mL), and the white precipi-
tate was collected by filtration, washed with water, dried, and
crystallized from EtOAc-methylcyclohexane to yield 4 (26.2
g, 95%) as white crystals; Rf 0.32 (70:30, EtOAc/i-Pr2O); mp
Compound 7a crystallized after extensive drying under
vacuum. mp 32 °C; [R]25D) -50° (c 0.94, CHCl3); IR(CHCl3)
1680, 1745, 2100, 2920, 2970, 3000, 3420, 3620 cm-1; 1H NMR
(CDCl3) δ 1.35-1.39 (m, 4H), 1.48 (d, J ) 6.5 Hz, 3H), 1.54-
1.72 (m, 4H), 2.2-2.3 (m, 2H), 3.26 (t, J ) 6.8 Hz, 2H), 3.7 (s,
3H), 4.97 (q, J )6.5 Hz, 1H), 5.55 (d, J ) 9.3 Hz, 1H), 6.52 (d,
J ) 9.3 Hz, 1H), 7.44-7.54 (m, 3H), 7.81-7.87 (m, 4H); 13C
NMR (CDCl3) δ 24.02, 25.06, 26.41, 28.65, 36.44, 51.32, 52.78,
57.08, 124.50, 125.93, 126.05, 126.11, 127.65, 128.11, 128.27,
133.2, 139.60, 168.85, 173.2. Anal. Calcd for C22H28N4O4: C,
64.06; H, 6.84; N, 13.58. Found: C, 64.40; H, 6.88; N, 13.50.
Compound 7b was crystallized from Et2O/petroleum ether
84 °C; IR (KBr) 1650, 3190, 3390 cm-1 1H NMR (CDCl3) δ
;
1.34-1.52 (m, 4H), 1.66 (m, 2H), 1.87 (m, 2H), 2.24 (t, J ) 6
Hz, 2H), 3.41(t, J ) 6 Hz, 2H), 5.5 (m, 1H), 5.7 (m, 1H); 13C
NMR (DMSO-d6) δ 24.8, 27.2, 27.7, 32.0, 34.9, 35.0, 174.1.
Anal. Calcd for C7H14BrNO: C, 40.40; H, 6.78; N, 6.73.
Found: C, 40.60; H, 6.55; N, 6.54.
7-Azid oh ep ta n a m id e (5). A mixture of 4 (26.2 g, 126
mmol) and sodium azide (16.4 g, 250 mmol) in DMSO (150
mL) was stirred at 80 °C for 3.5 h. The cooled mixture was
poured into water and extracted with EtOAc. The organic layer
was washed with brine, dried (MgSO4), and concentrated to
yield a crude product which was purified by crystallization
from EtOAc/i-Pr2O. 5 was obtained as white needles (14 g,
65%); Rf 0.38 (70:30, EtOAc: i-Pr2O); mp 62 °C; IR(KBr) 1630,
at 20 °C and submitted to X-ray analysis. mp 52 °C; [R]25
)
D
-92° (c 0.96, CHCl3); IR(CHCl3) 1680, 1750, 2090, 2920, 2970,
3000, 3420, 3620 cm-1; 1H NMR (CDCl3) δ 1.05-1.18 (m, 4H),
1.23-1.31 (m, 2H), 1.39-1.44 (m, 2H), 1.58 (d, J ) 6.4 Hz,
3H), 1.69-1.79 (ABX, 1H), 1.87-1.94 (ABX, 1H), 3.16 (t, J )
7 Hz, 2H), 3.8 (s, 3H), 4.95 (q, J ) 6.5 Hz, 1H), 5.86 (d, J ) 9
Hz, 1H), 6.17 (d, J ) 9 Hz, 1H), 7.42-7.5 (m, 3H), 7.71 (s,1H),
7.79-7.82 (m, 3H);13C NMR (CDCl3) δ 29.6, 24.5, 26.23, 28.45,
28.52, 36.0, 51.29, 52.86, 76.42, 77.95, 124.63, 124.11, 125.86,
126.16, 127.64, 127.91, 128.14, 132.91, 133.17, 140.96, 168.67,
172.72. Anal. Calcd for C22H28N4O4: C, 64.06; H, 6.84; N, 13.58.
Found: C, 64.21; H, 6.87; N, 13.59.
(34) See ref 8. (b) See ref 13a. (c) Renaut, P.; Lebreton, L.; Dutartre,
P.; Derrepas, P.; Samreth, S. Eur. Pat. Appl. EP 600762, J un 8, 1994.
(d) Lebreton, L.; Renaut, P.; Dumas C. Eur. Pat. Appl. EP 743300,
Nov. 20, 1996.
(35) Kawahara, T.; Susuki, K.; Iwasaki, Y.; Shimoi, H.; Akita, M.;
Moro-oka, Y.; Nishikawa, Y. J . Chem. Soc., Chem. Commun. 1992,
625-626.
2,6,11,14-Tetr a a za h en eicosa n oic a cid , 21-a zid o-13-[1-
(2-n a p h th a len yl)eth oxy]-12,15-d ioxo-6[(p h en ylm eth oxy)-

Enantioselective Synthesis of (-)-15-Deoxyspergualin
J . Org. Chem., Vol. 63, No. 26, 1998 9727
ca r bon yl]-, p h en ylm eth yl ester , [S-(R*,R*)] (8a ) a n d
2,6,11,14-Tetr a a za h en eicosa n oic a cid , 21-a zid o-13-[1-(2-
n a p h t h a len yl)et h oxy]-12,15-d ioxo-6[(p h en ylm et h oxy)-
ca r bon yl]-, p h en ylm eth yl ester , [S-(R*,S*)] (8b). A mix-
ture of 1 N NaOH (1.45 mL, 1.45 mmol) and 7 (0.5 g, 1.21
mmol) in 10 mL of DME was stirred for 1.5 h at room
temperature then diluted with water (20 mL) and acidified
with HCl 1N to pH 2. The aqueous phase was extracted with
EtOAc and the organic phases were dried (Na2SO4) and
concentrated to yield 0.47 g (98%) of the crude diastereomeric
mixture of acids. This mixture was dissolved in 10 mL of CH2-
Cl2 and hydroxybenzotriazole (0.16 g, 1.18 mmol) followed by
DCC (0.27 g, 1.3 mmol) were added. After stirring at room
temperature for 30 min N1,N4-bis (benzyloxycarbonyl) sper-
midine26 (0.52 g, 1.26 mmol) was added, the mixture was
stirred at room temperature for 48 h, washed with saturated
aqueous NaHCO3, brine, and the organic layer was dried
(MgSO4). Concentration of the organic phases gave the mixture
of epimers which were separated by flash chromatography on
silica gel (EtOAc/i-Pr2O, 8.5:1.5). 8a (0.45 g, 48%) was obtained
(4s, 8H), 5.2 (d, J ) 9 Hz, 1H), 5.7-5.9 (2m, 1H), 6.9-7.4 (m,
22H), 7.44-7.54 (m, 3H), 7.81-7.9 (m,4H), 8.26 (br t, 1H), 11.7-
(s, 1H); 13C NMR (CD3CN) δ 24.24, 26.09, 27.16, 28.98, 29.39,
29.53, 36.66, 39.22, 41.67, 45.28, 66.74, 67.45, 67.72, 68.90,
76.39, 76.95, 125.44, 126.91, 127.06, 127.31, 128.57, 128.66,
128.72, 128.82, 128.86, 129.08, 129.32, 129.35, 129.43, 129.47,
129.58, 129.66, 134.14, 134.20, 138.34, 138.41, 141.24, 154.57,
157.09, 164.84, 168.77, 174.75. Anal. Calcd for C61H71N7O11
:
C, 67.94; H, 6.64; N, 9.09. Found: C, 67.68; H, 6.65; N, 9.06.
7-[(Am in oim in om eth yl)a m in o]-N-[(1S)-2-[[4-[(3-a m in o-
p r op yl)a m in o]b u t yl]a m in o]-1-h yd r oxy-2-oxoet h yl]h ep -
ta n a m id e (2). A flask containing a solution of 9a (0.1 g, 0.093
mmol) in 1 N AcOH in methanol (10 mL) was purged with
nitrogen. To this solution was added 50 mg (50 wt %) of
palladium hydroxide (Pearlman’s catalyst, 20% on carbon/50%
H2O). The mixture was stirred 8 h under 1 atm of hydrogen
at room temperature. The mixture was purged with N2 and
filtered. The filtrate was purged with N2, 50 mg (50 wt %) of
Pearlman’s catalyst was added again and the mixture was
treated as above overnight. The mixture was purged with N2,
filtered and water was added. The solution was concentrated
under reduced pressure and extracted three times with CH2-
Cl2. The aqueous phase was lyophilized. The resulting powder
was dissolved in H2O (10 mL) and lyophilized again to give
the triacetate 2 as an hygroscopic white powder. The chemical
purity was determined to be >98% by HPLC analysis (as
described below). The product was then further purified and
transformed to the tris(hydrochloride) following the literature
protocol6b on CM Sephadex C-25 and Sephadex LH-20 col-
umns. The freeze-dried product was obtained as an hygroscopic
powder (30 mg, 68%); Rf 0.6 (R. P.18, 3:6.5:0.5, CH3CN/H2O/
TFA); [R]22D ) -14.5° (c 1, H2O) [lit.7 [R]21D ) -14.3 (c 1, H2O)];
1H NMR (D2O) δ 1.3-1.45 (m, 4H), 1.5-1.8 (m, 8H), 2-2.2
(m, 2H), 2.3 (t, J ) 4.5 Hz, 2H), 3.05-3.25 (m, 8H), 3.27-3.3
(m, 2H), 5.45 (s, 1H); 13C NMR (D2O) δ 23.64, 24.46, 25.57,
26.22 (2C), 28.42, 28.47, 36.20, 37.28, 39.22, 41.81, 45.16,
48.08, 72.63, 157.39, 171.97, 178.08. HRMS found 388.3036
(C18 H38 N7 O3 (M+H) calcd 388.30361). The chemical purity
was determined to be >98% by HPLC analysis (Inertsil OSD
2, Gl Sciences Inc.; Solvent A, water with 0.05% TFA; Solvent
B, CH3CN with 0.05% TFA: 2% Solvent B, 5 min, 2-80%
Solvent B in 15 min, 1 mL/min, 30 °C). The enantiomeric
purity of the product was determined to be g99.5% by HPLC
column analysis (Chiralcel OD, Daicel Chemical Industries,
Ltd.) following the literature protocol.31
as an oil; Rf: 0.63 (EtOAc/i-Pr2O, 8:2); [R]22 ) -40.7° (c 5.4,
D
1
CHCl3); IR (CHCl3) 1680, 2100 cm-1; H NMR (DMSO-d6) δ
1.1-1.6 (m, 17H), 2-2.2 (m, 2H), 2.85-3.17 (m, 8H), 3.3 (t, J
) 6.7 Hz, 2H), 4.79 (q, J ) 6 Hz, 1H), 5 (s, 2H), 5.04 (s, 2H),
5.17 (d, J ) 9 Hz, 1H), 7.1-7.37 (m, 11H), 7.45-7.57 (m, 3H),
7.8 (s, 1H), 7.81-7.9 (m, 3H), 7.95-8.05 (m, 1H), 8.65, (d, J )
9 Hz, 1H); 13C NMR (DMSO-d6) δ 24.12, 25.07, 26.04, 26.42,
28.23, 28.32, 35.21, 38.2, 38.4, 50.75, 65.36, 66.18, 74.72, 76.15,
124.65, 125.47, 126.32, 127.50, 127.72, 127.92, 128.18, 128.53,
128.58, 132.79, 132.90, 137.26, 137.40, 140.61, 155.42, 156.2,
167.15, 173.48. Anal. Calcd for C44H55N7O7: C, 66.56; H, 6.98;
N, 12.35. Found: C, 66.51; H, 7.00; N, 12.29.
8b (0.33 g, 35%) was obtained as an oil; [R]22 ) -19.4° (c
D
1.1, CHCl3); IR (CHCl3) 1680, 2100 cm-1; 1H NMR (DMSO-d6)
δ 1.1-1.5 (m, 15H), 1.6-1.7 (m, 2H), 1.9-2.1 (m, 2H), 2.9-3
(m, 2H), 3.1-3.23 (m, 8H), 4.79 (q, J ) 6.2 Hz, 1H), 4.99 (s,
2H), 5.05 (s, 2H), 5.56 (d, J ) 9 Hz, 1H), 7.29-7.35 (m, 11H),
7.46-7.51 (m, 3H), 7.78 (s, 1H), 7.78-7.9 (m, 3H), 8.1-8.2 (m,
1H), 8.51 (d, J ) 9 Hz, 1H); 13C NMR (DMSO-d6) δ 22.56,
24.54, 25.67, 26.18, 27.87, 27.9, 30.31, 34.74, 37.9, 38.19, 50.41,
65.07, 65.89, 74.76, 46.45, 124.11, 124.546, 125.549, 125.87,
127.21, 127.34, 127.43, 127.63, 128.23, 128.28, 132.23, 132.60,
136.99, 137.12, 141.1, 155.15, 155.98, 167.35, 172.88. Anal.
Calcd for C44H55N7O7: C, 66.56; H, 6.98; N, 12.35. Found: C,
66.62; H, 7.07; N, 12.01.
2,4,12,15,20,24-Hexa a za p en ta cos-2-en ed ioic a cid , 13-[1-
(2-n aph th alen yl)eth oxy]-11,14-dioxo-20[(ph en ylm eth oxy)-
ca r b on yl]-3-[[(p h en ylm et h oxy)ca r b on yl]a m in o]-, b is-
(ph en ylm eth yl) ester , [S-(R*,R*)] (9a). A mixture of triphenyl
phosphine (0.149 g, 0.567 mmol), 8a (0.450 g, 0.567 mmol) and
0.68 mL of water in THF (30 mL) was heated at reflux
overnight. After cooling at room temperature, N,N′-bis(ben-
zyloxycarbonyl)-S-methylisothiourea (0.223 g, 0.623 mmol) was
added and the mixture was stirred for 3 h at room tempera-
ture. Concentration of the mixture gave a crude product which
was purified by chromatography on silica gel (EtOAc/i-Pr2O,
5:5). 9a (0.47 g, 77%) was obtained as a white solid by
crystallization from Et2O; mp 98 °C; Rf 0.59 (EtOAc/i-Pr2O,
Ack n ow led gm en t. We are grateful to Prochrom
S.A. for the loan of the preparative HPLC apparatus
and especially to J . de Tournemire for technical and
scientific assistance and to A. Dhennequin and Dr. V.
Lucas for the analytical studies. We thank Dr. D. Qasmi,
Dr. B. Badet, Dr. P. Padovani and P. Peralba for their
helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: Synthesis and char-
acterization data of bis(7-bromoheptane)imide from 7-bromo-
heptanenitrile, ORTEP drawing, and X-ray structure data for
the intermediate 7b (8 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
8:2), Rf 0.25 (hexane/i-PrOH, 9:1); [R]25 ) -33.1° (c 1.0,
D
CHCl3); IR(KBr) 1640, 1690, 1710, 1730, 2830, 3020, 3060,
3300 cm-1; 1H NMR (CD3CN) δ 1.29-1.57 (m,14H), 1.48 (d, J
) 7.5 Hz, 3H), 2.17 (t, J ) 7 Hz, 2H), 2.95-3 (m, 2H), 3.04-
3.2 (m, 6H), 3.32 (m, 2H), 4.86 (q, J ) 6 Hz, 1H), 5.01-5.17
J O9811118