Enantioselective synthesis of pachastrissamine (Jaspin B) using dirhodium(II)-catalyzed C-H amination and asymmetric dihydroxylation as key steps

Article abstract of DOI:10.1248/cpb.55.1284

Enantioselective total synthesis of anhydrophytosphingosine pachastrissamine (jaspin B) was achieved using Sharpless asymmetric dihydroxylation and dirhodium(II)-catalyzed C-H amination as key steps.

Full text of DOI:10.1248/cpb.55.1284

1284
Communications to the Editor
Chem. Pharm. Bull. 55(8) 1284—1286 (2007)
Vol. 55, No. 8
Enantioselective Synthesis of
Pachastrissamine (Jaspin B) Using
Dirhodium(II)-Catalyzed C–H
Amination and Asymmetric
Dihydroxylation as Key Steps
five-membered rings formed by the reaction with C2–H and
also with C4–Hb, selective reaction with C4–Ha forming the
cis-fused bicyclic system (2) is predicted. Although ketone
formation by the reaction of rhodium nitrenoid with C3–H is
also possible,12) the large substituent at C-2 position might
block its approach to the C3–H. Compound (3) should be
converted easily from alcohol (4). Compound (4) should be
synthesized from diol (5) via iodination of primary alcohol
and following tetrahydrofuran ring formation. The stereocen-
ters of 5 should be constructed enantioselectively using
Sharpless asymmetric dihydroxylation22) of the correspon-
ding known (E)-a,b-unsaturated ester (6).23,24)
Synthesis of the precursor of dirhodium-catalyzed C–H
amination was started from known methyl (2E)-5-p-
methoxybenzyl(PMB)oxy-2-pentanoate (6),23,24) as illustrated
in Chart 2. Asymmetric dihydroxylation of 6 was accom-
plished using AD-mix-a under usual conditions22) to give
diol (5) in 89%. Optical purity of 5 was determined to be
98.1% ee by chiral HPLC analysis (hexane/iPrOH, 90/10,
0.5 ml/min, Chiralpak AD-H; Daicel Chemical Industries,
Ltd.). Protection of diol with acetonide afforded 7, which
Takayuki YAKURA,* Seiichi SATO, and Yuya YOSHIMOTO
Graduate School of Medicine and Pharmaceutical Sciences,
University of Toyama; Sugitani, Toyama 930–0194, Japan.
Received April 25, 2007; accepted June 1, 2007;
published online June 1, 2007
Enantioselective total synthesis of anhydrophytosphingosine
pachastrissamine (jaspin B) was achieved using Sharpless asym-
metric dihydroxylation and dirhodium(II)-catalyzed C–H ami-
nation as key steps.
Key words pachastrissamine; total synthesis; C–H amination; jaspin B;
dirhodium(II); asymmetric dihydroxylation
Pachastrissamine (jaspin B, 1) was isolated from the Oki- was reduced with diisobutylaluminum hydride (DIBAL-H) at
nawan marine sponge Pachastrissa sp. by Higa and co-work- ꢁ80 °C to provide aldehyde (8). Compound (8) was homolo-
ers in 20021) and shortly after from a different sponge, Jaspis gated by Wittig reaction to give (Z)-alkene (9) in 88% yield
sp., by the Debitus group in 20032) as a naturally occurring as a single stereoisomer. The (Z)-stereochemistry of 9 was
novel anhydrophytosphingosine derivative. It exhibited cyto- determined by coupling constant (Jꢂ10.8 Hz) between vinyl
1
toxic activities against several human carcinoma cell lines. protons in its H-NMR spectrum. Both deprotection of PMB
Because of the impressive biological activity and its novel group and reduction of the C–C double bond of 9 proceeded
structural features, 1 has attracted much attention from syn- simultaneously under hydrogenation conditions to produce
thetic chemists. Recently, several total syntheses of 1 from alcohol (10) in 87% yield. Treatment of 10 with iodine and
chiral compounds such as serine, phytosphingosine, and xy- triphenylphosphine in the presence of imidazole yielded io-
lose have been reported.3—10) Dirhodium(II)-catalyzed C–H dide (11) in quantative yield. Acid deprotection of 11 and
amination of carbamates to oxazolidinone derivatives has at- following cyclization using potassium carbonate converted it
tracted much attention in recent synthetic organic chemistry into tetrahydrofuran (4) in 79% yield. According to the usual
as an important transformation11—18) because of the introduc- procedure,19—21) reaction of 4 with trichloroacetyl isocyanate
tion of nitrogen to unactivated C–H bond. Recently we re- in dichloromethane at room temperature gave the correspon-
ported applications of dirhodium(II)-catalyzed C–H amina- ding trichloroacetyl carbamate, which was treated with neu-
tion reaction to a synthesis of an immunomodulator (ꢀ)- tral alumina without purification to obtain the precursor (3)
conagenin19,20) and a facile preparation of optically active of C–H amination reaction in quantitative yield.
monoprotected 2-amino-2-methyl-1,3-propanediol.21) We re-
With the carbamate (3) in hand, we investigated C–H ami-
port here the enantioselective total synthesis of 1 using nation reaction of 3 (Table 1). Reaction of 3 with 10 mol% of
Sharpless asymmetric dihydroxylation and dirhodium(II)- dirhodium(II) tetraacetate, 4.2 equivalents of phenyliodine(III)
catalyzed C–H amination as key steps.
We planned a simple and concise enantioselective synthe-
sis of 1. Our retrosynthetic analysis is depicted in Chart 1.
Oxazolidinone (2) was selected as a temporary goal because
this intermediate can be converted to pachastrissamine using
alkali hydorolysis.4) The oxazolidinone ring of 2 should be
constructed using dirhodium(II)-catalyzed C–H amination
reaction of carbamate (3). In C–H amination reaction of 3, it
has four possible reactive C–H groups. The C2–H is the most
reactive among them because it is tertiary and a to furan
oxygen. However, as a result of the highly unfavorable ring
strain associated with the trans-ring junction between the two
Fig. 1
Chart 1
∗ To whom correspondence should be addressed. e-mail: yakura@pha.u-toyama.ac.jp
© 2007 Pharmaceutical Society of Japan

August 2007
1285
Chart 3
Chart 4
(1), which was acetylated without purification to provide the
N,O-diacetyl derivative (15), mp 108—111 °C, [a]D25 ꢁ26.2°
(cꢂ0.30, CHCl3) {lit.5) mp 95—98 °C, [a]D22 ꢁ22.6° (cꢂ1.0,
CDCl3), lit.7) [a]D ꢁ28.4° (cꢂ1.0, CHCl3)}, in 85% yield
from 2 (Chart 4). Spectroscopic data of 1527) were identical
to those of the reported sample.
In summary, we demonstrated a simple and concise enan-
tioselective total synthesis of (ꢀ)-1 starting from a,b-unsat-
urated ester (6) using asymmetric dihydroxylation and C–H
amination reaction as key steps. Further investigation for im-
provement of the C–H amination of 3 is now underway in our
laboratory.
Chart 2
Table 1. Rh(II)-Catalyzed C–H Amination of 3a)
Yield (%)
13
No reaction
Entry
Rh(II)
Solvent
Time (h)
2
1
2
3
4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OCOCPh3)4
Rh(esp)2
CH2Cl2
13
13
13
21
Benzene
Benzene
Benzene
0
58
40
15
19
10
a) Reactions were carried out using 10 mol% of Rh(II) catalyst, 4.2 eq of PhI(OAc)2,
and 6.9 eq of MgO under reflux.
References and Notes
1) Kuroda I., Musman M., Ohtani I. I., Ichiba T., Tanaka J., Gravalos D.
G., Higa T., J. Nat. Prod., 65, 1505—1506 (2002).
2) Ledroit V., Debitus C., Lavaud C., Massiot G., Tetrahedron Lett., 44,
225—228 (2003).
3) Sudhakar N., Kumar A. R., Prabhakar A., Jagadeesh B., Rao B. V.,
Tetrahedron Lett., 46, 325—327 (2005).
4) Bhaket P., Morris K., Stauffer C. S., Datta A., Org. Lett., 7, 875—876
(2005).
5) van den Berg R. J. B. H. N., Boltje T. J., Verhagen C. P., Litjens R. E. J.
N., van der Marel G. A., Overkleeft H. S., J. Org. Chem., 71, 836—
839 (2006).
6) Du Y., Liu J., Linhardt R. J., J. Org. Chem., 71, 1251—1253 (2006).
7) Ribes C., Falomir E., Carda M., Marco J. A., Tetrahedron, 62, 5421—
5425 (2006).
8) Ramana C. V., Giri A. G., Suryawanshi S. B., Gonnade R. G., Tetrahe-
dron Lett., 48, 265—268 (2007).
9) Lee T., Lee S., Kwak Y. S., Kim D., Kim S., Org. Lett., 9, 429—432
(2007).
10) Reddy L. V. R., Reddy P. V., Shaw A. K., Tetrahedron: Asymmetry, 18,
542—546 (2007).
diacetate, and 6.9 equivalents of magnesium oxide in di-
chloromethane under reflux,19—21) however, gave no reac-
tion with recovered starting 3 (Entry 1). A similar reaction in
refluxing benzene for 13 h proceeded, unfortunately, to
afford only undesired 2-tetradecatetrahydrofuran-3-one (13)
in 58% yield with a complex mixture (Entry 2). The forma-
tion of 13 would be caused either by direct abstraction of
C3–H by rhodium nitrenoid intermediate (A) or through the
generation of four-membered ring species (14) (Chart 3).12)
This speculation spurred our use of a dirhodium(II)
catalyst having bulkier ligands. When 3 was treated with
dirhodium(II) tetra(triphenylacetate), 4.2 equivalents of
phenyliodine(III) diacetate, and 6.9 equivalents of magne-
sium oxide in benzene under reflux for 13 h, the desired 2
was obtained in 19% yield (Entry 3).25) However, ketone (13)
was still produced as a major product in 40% yield. Use of
dirhodium dirhodium(II) bis(a,a,aꢃ,aꢃ-tetramethyl-1,3-ben-
zenedipropanoate) [Rh2(esp)2]26) gave low yields of both 2
and 13 with a complex mixture (Entry 4).
11) Espino C. G., Du Bois J., Angew. Chem. Int. Ed., 40, 598—600 (2001).
12) Espino C. G., Du Bois J., “Modern Rhodium-Catalyzed Organic Reac-
tions,” ed. by Evans P. A., Wiley-VCH, Weinheim, 2005, pp. 379—
416.
13) Davies H. M. L., Long M. S., Angew. Chem. Int. Ed., 44, 3518—3520
(2005).
Finally, 2 was hydrolyzed using potassium hydroxide in
ethanol under reflux for 3 h to afford (ꢀ)-pachastrissamine
14) Trost B. M., Gunzner J. L., Dirat O., Rhee Y. H., J. Am. Chem. Soc.,
124, 10396—10415 (2002).

1286
Vol. 55, No. 8
15) Hinman A., Du Bois J., J. Am. Chem. Soc., 125, 11510—11511
(2003).
0.49 mmol), MgO (32 mg, 0.80 mmol), and Rh2(OCOCPh3)4 (16 mg,
0.012 mmol) in benzene (2.5 ml) was refluxed for 13 h. After the mix-
ture was cooled to room temperature, it was passed through a short
Celite pad and the filtrate was concentrated. The residue was chro-
matographed on silica gel (Et2O) to give 2 (7 mg, 19%) and 13 (13 mg,
40%). Spectroscopic data of 2 were identical to those of the reported
sample.4)
16) Huang H., Panek J. S., Org. Lett., 5, 1991—1993 (2003).
17) Parker K. A., Chang W., Org. Lett., 5, 3891—3893 (2003).
18) Parker K. A., Chang W., Org. Lett., 7, 1785—1788 (2005).
19) Yakura T., Yoshimoto Y., Ishida C., Mabuchi S., Synlett, 2006, 930—
932 (2006).
20) Yakura T., Yoshimoto Y., Ishida C., Mabuchi S., Tetrahedron, 63,
4429—4438 (2007).
21) Yakura T., Yoshimoto Y., Ishida C., Chem. Pharm. Bull., 55, in press
(2007).
26) Espino C. G., Fiori K. W., Kim M., Du Bois J., J. Am. Chem. Soc., 126,
15378—15379 (2004).
27) Compound 15: mp 108—111 °C. [a]D25 ꢁ26.2° (cꢂ0.30, CHCl3). IR
1
(KBr) cmꢁ1: 3215, 1740, 1647. H-NMR (270 MHz, CDCl3) d: 0.88
22) Sharpless K. B., Amberg W., Bennani Y. L., Crispino G. A., Hartung
J., Jeong K.-S., Kwong H.-L., Morikawa K., Wang Z.-M., Xu D.,
Zhang X.-L., J. Org. Chem., 57, 2768—2771 (1992).
23) Oka T., Murai A., Tetrahedron, 54, 1—20 (1998).
24) Cordero F. M., Gensini M., Goti A., Brandi A., Org. Lett., 2, 2475—
2477 (2000).
(3H, t, Jꢂ6.6 Hz), 1.16—1.36 (24H, br m), 1.40—1.56 (2H, m), 1.97
(3H, s), 2.17 (3H, s), 3.60 (1H, t, Jꢂ8.1 Hz), 3.86—3.95 (1H, m), 4.08
(1H, t, Jꢂ8.5 Hz), 4.82 (1H, qd, Jꢂ8.1, 5.4 Hz), 5.38 (1H, dd, Jꢂ5.4,
3.5 Hz), 5.58 (1H, br d, Jꢂ7.8 Hz). 13C-NMR (67.5 MHz, CDCl3) d:
14.1, 20.7, 22.7, 23.2, 26.0, 29.29, 29.34, 29.46, 29.53, 29.57, 29.61,
29.64, 29.7, 31.9, 51.3, 70.0, 73.6, 81.2, 169.9 (2). HR-MS m/z:
383.30290 (Calcd for C22H41NO4 (Mꢀ): 383.30356).
25)
A suspension of 3 (38 mg, 0.116 mmol), PhI(OAc)2 (157 mg,