The first total synthesis of (S)-clavulazine from d-mannitol

Article abstract of DOI:10.1016/j.tetlet.2006.08.006

The first total synthesis of the marine natural product, (S)-clavulazine has been accomplished. d-Mannitol was used as a chiral starting material. Enantioselective zinc-mediated allylation, and ring-closing metathesis are the key steps in the synthesis. S

Full text of DOI:10.1016/j.tetlet.2006.08.006

Tetrahedron Letters 47 (2006) 7149–7151
The first total synthesis of (S)-clavulazine from D-mannitolI
S. Praveen Kumar,a K. Nagaiaha,* and Mukund S. Chorghadeb
aOrganic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
bChorghade Enterprises, 14, Carlson Circle, Nature, MA 01760, USA
Received 30 May 2006; revised 27 July 2006; accepted 2 August 2006
Available online 22 August 2006
Abstract—The first total synthesis of the marine natural product (S)-clavulazine has been accomplished. D-Mannitol was used as a
chiral starting material; enantioselective zinc-mediated allylation, and ring-closing metathesis are the key steps in the synthesis. Sub-
sequent condensation followed by dehydrogenation yielded the natural product, (S)-clavulazine.
Ó 2006 Elsevier Ltd. All rights reserved.
Several families of natural alkaloids that display impor-
tant biological properties have been reported from mar-
ine sponges. Yoshimasa and co-workers reported the
isolation of palythazine, isopalythazine, and similar
alkaloids from Palythoa tuberculosa,1a all of which
incorporate a pyrazine skeleton. The absolute stereo-
chemistry of palythazine was conclusively established
after the first total synthesis.1b Clavulazine (1) (Fig. 1)
isolated from the Okinawan soft coral Clavularia viri-
dis,2 possesses a unique pyrano fused pyrazine ring sys-
tem with a single asymmetric center. Recently Ya-Ching
Shen and co-workers isolated clavulazole A, clavulazole
B, and clavulazine (1).3 These compounds, structurally
related to furazano[3,4-b]pyrazine derivatives show a
biological activity in the field of antimicrobials,4a herbi-
cides, plant growth regulators4b and Gram-positive bac-
teria.4c Tetrahydropyrido[3,4-b]pyrazine derivatives are
effective medicines for skin disease caused by the prolif-
eration of keratinocytes4d leading to much current inter-
est in fused pyrazine compounds for medicine and
agriculture. We herein report the synthesis of dihydro-
pyrano[3,4-b]pyrazine (clavulazine 1).
Our synthetic plan for the total synthesis of clavulazine
utilized commercial D-mannitol. Enantioselective zinc-
mediated allylation to control the stereogenic center, a
ring-closing metathesis (RCM) to the pyran ring and
diamine condensation with glyoxal followed by aromati-
zation with DDQ are the key steps. The retrosynthesis is
summarized in Scheme 1.
N
N
H2N
H2N
O
O
N
N
N
O
O
O
OH
OH
OMOM
OMOM
HO
OH
HO
O
N
14
1
4
palythazine
Isopalythazine
O
OH
O
N
O
N
N
N
N
OH
O
OH
OH
O
O
N
8c
OH
clavulazole A
clavulazole B
clavulazine (1)
O
Figure 1.
D-Mannitol
H
O
O
Keywords: Clavulazine; Glyoxal; Grubbs’ catalyst; Zinc allylation.
q IICT Communication No. 060627.
2
*
Corresponding author. Tel.: +91 40 27160387; fax: +91 40 27160512/
387; e-mail: nagaiah@iict.res.in
Scheme 1. Retrosynthetic analysis of clavulazine.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.006

7150
S. P. Kumar et al. / Tetrahedron Letters 47 (2006) 7149–7151
OH
N3
O
O
a
a
b
b
OR1
9 + 10
H
O
O
HO
O
O
11a-c
c
2
3
R1=Bn
O
O
N3
N3
c
O
c
O
OR1
OR1
O
OH
R1=MOM
MsO
O
OH
N3
12a-c
13c
5
4
c
d
Scheme 2. Reagents and conditions: (a) Zn, THF, allyl bromide, satd
NH4Cl, 0 °C, 2 h, 74%; (b) NaH, dry THF, allyl bromide, 0 °C, 3 h,
86%; (c) 2 N HCl, THF, rt, 3 h, 90%.
R1=TBDPS
N
N
H2N
H2N
O
e
O
As depicted in Scheme 2, Zn mediated5a–d addition of al-
lyl bromide at 0 °C to the chiral synthon (R)-2,3-O-iso-
propylideneglyceraldehyde5e–g 2 proceeded with a good
enantioselectivity (95% ee) to give homoallylic alcohol
3. Allylation of the hydroxyl group using allyl bromide
and NaH at 0 °C afforded 4.6 Diol 5 was prepared from
4 by treatment with THF and 2 N HCl at 0 °C to rt7a
(Scheme 2).
OMOM
OMOM
OMOM
15
14
f
N
N
N
O
O
g
OH
N
16
1
Alcohol 6 was produced from 5 by oxidation with
NaIO4 and satd NaHCO3 in DCM at 0 °C,7b followed
by NaBH4 reduction in methanol. The primary hydroxyl
group in 6 was protected using benzyl bromide,
TBDPSCl, and MOM-Cl. For the preparation of 13,
when the primary alcohol was protected with Bn or with
TBDPSCl the azide formation was sluggish. We found
that the MOM group was the most effective for the con-
version of 12 to azide 13. Alcohol 6 was treated with
methoxymethyl chloride and DIPEA in THF to furnish
protected alcohol 7c.8 Exposure of 7c to Grubbs’ first
generation catalyst 16 in DCM at room temperature
proceeded efficiently to give pyran 8c9 in a modest yield.
This was next epoxidized with m-CPBA to afford regio-
isomers 9c and 10c (60:40)10 (Scheme 3).
Scheme 4. Reagents and conditions: (a) (i) for 11a, NaN3, EtOH:H2O
(3:1), NH4Cl, 80 °C, 8 h, 57%; (ii) for 11b, NaN3, EtOH:H2O (3:1),
NH4Cl, 80 °C, 9 h, 58%; (iii) for 11c, NaN3, EtOH:H2O (3:1), NH4Cl,
80 °C, 6 h, 62%; (b) (i) for 12a, CH3SO3Cl, dry TEA, dry DCM, 0 °C,
3 h, 82%; (ii) for 12b, CH3SO3Cl, dry TEA, dry DCM, 0 °C, 4 h, 85%;
(iii) for 12c, CH3SO3Cl, dry TEA, dry DCM, 0 °C, 2 h, 88%; (c) NaN3,
dry DMF, 100 °C, overnight, 59%; (d) Pd–C, H2, EtOH, 4 h, rt, 78%;
˚
(e) 40% glyoxal, 4 A molecular sieves, EtOH, 80 °C, 36 h; (f) DDQ, dry
toluene, 80 °C, 24 h; (g) 2 N HCl, THF, 0 °C–rt, 1 h (for 3 steps, the
overall yield was 15%).
Epoxides 9c and 10c were opened with NaN3, etha-
nol:water (3:1) and NH4Cl under reflux to furnish azido
alcohol 11c as a mixture of diastereoisomers. The free
hydroxyl group in 11c was converted to the metha-
nsulfonyl derivative 12c with MsCl and TEA at 0 °C.
Subsequent treatment with sodium azide in dry DMF
at 100 °C afforded diazide 13c in a 59% yield.11
O
O
a
b
5
OH
OR1
7a R1 = Bn
6
PCy3
Ru
7b R1 = TBDPS
7c R1 = MOM
Cl
Cl
Hydrogenation of 13 in the presence of Pd–C in absolute
ethanol was uneventful and led to diamine 14.12 Cycliza-
Ph
˚
tion of diamine 13 with 40% glyoxal and 4 A molecular
PCy3
16
sieves in ethanol at reflux for 36 h afforded 15.13 Crude
14 was aromatized by dehydrogenation with DDQ in
toluene for 24 h at 80 °C to afford 16.14 Final deprotec-
tion of the MOM group with 2 N HCl in THF furnished
(S)-clavulazine (1) (Scheme 4).
O
d
OR1
c
8a-c
O
O
O
O
+
OR1
OR1
9a-c
10a-c
In summary, the first total synthesis of (S)-clavulazine
was accomplished via 15 steps from D-mannitol. Spec-
tral data are provided in Ref. 15.
Scheme 3. Reagents and conditions: (a) NaIO4, NaHCO3, DCM,
0 °C–rt, 8 h, then NaBH4, MeOH, 15 min, 93%; (b) (i) for 7a, BnBr,
NaH, dry THF, 0 °C, 4 h, 82%; (ii) for 7b, TBDPSCl, imidazole, dry
THF, 0 °C, 2 h, 85%; (iii) for 7c, DIPEA, MOMCl, dry DCM, 0 °C,
2 h, 78%; (c) (i) for 8a, Grubbs’ catalyst, dry DCM, rt, 4 h, 77%; (ii) for
8b, Grubbs’ catalyst, dry DCM, rt, 6 h, 80%; (iii) for 8c, Grubbs’
catalyst, dry DCM, rt, 3 h, 73%; (d) (i) m-CPBA, NaHCO3, dry DCM,
5 h, 65%, 33:32 (9a, 10a); (ii) m-CPBA, NaHCO3, dry DCM, 6 h, 62%,
32:30 (9b, 10b); (iii) m-CPBA, NaHCO3, dry DCM, 4 h, 60%, 35:25
(9c, 10c).
Acknowledgements
S.P.K. is thankful to CSIR, New Delhi, for the award of
a fellowship, and to Dr. J. S. Yadav, Director IICT, for
his support and encouragement.

S. P. Kumar et al. / Tetrahedron Letters 47 (2006) 7149–7151
7151
15. All new compounds were fully characterized on the basis
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0.01, CHCl3); EIMS (relative intensity) m/z: 172 (M+, 15),
157 (5), 101 (40), 83 (5), 69 (10), 59 (35), 43 (100); 1H
NMR (CDCl3, 300 MHz): d 5.09–5.75 (m, 1H), 5.16–5.06
(m, 2H), 3.99–3.83 (m, 3H), 3.73–3.66 (m, 1H), 2.35–2.31
(m, 2H), 1.93 (1H, –OH), 1.39 (s, 3H), 1.32 (s, 3H);
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70.5, 65.7, 38.1, 27.0, 25.7; (7c) ½aꢀD ꢁ0.71 (c 0.01, CHCl3);
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neat) 3450, 3078, 2928, 1642, 1438, 1149, 1113, 1045; H
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(m, 4H), 4.61 (s, 2H), 4.15–4.02 (m, 2H), 3.53 (m, 3H),
3.35 (s, 3H), 2.32 (q, 2H, J = 7.55 Hz); 13C NMR (CDCl3,
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25
1111, 1038; (8c) ½aꢀD ꢁ1.52 (c 0.01, CHCl3); EIMS
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(s, 2H), 4.21–4.18 (m, 2H), 3.75–3.67 (m, 1H), 3.54–3.52
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25
96.56, 72.44, 70.23, 65.66, 55.04, 27.03; (9c) ½aꢀD ꢁ18.5
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4H), 3.32 (s, 3H), 3.01 (d, 1H, J = 3.7 Hz), 1.92–1.74 (m,
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25
55.0, 49.0, 48.7, 25.8; (12c): ½aꢀD ꢁ16.8 (c 0.01, CHCl3);
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(d, 1H, J = 2.26 Hz), 3.98–3.86 (m, 2H), 3.61–3.52
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13C NMR (CDCl3, 75 MHz): 96.9, 74.8, 71.3, 70.0, 65.3,
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EIMS (relative intensity) m/z: 242 (M+, 18), 198 (23), 153
(20), 108 (13), 92 (25), 45 (100); 1H NMR
(CDCl3, 200 MHz):
d 4.60 (s, 2H), 4.13 (dd, 1H,
J = 1.60, 12.82 Hz), 3.63–3.48 (m, 6H), 3.33 (s, 3H),
1.90–1.81 (m, 2H); 13C NMR (CDCl3, 75 MHz): 96.6,
70.6, 69.5, 64.2, 58.6, 58.4, 55.2, 32.1; (1): colorless solid,
25
mp 98–99 °C; ½aꢀD ꢁ96.2 (c 0.17, CHCl3), [lit.1 ꢁ99.4 (c
0.17, CHCl3)]; EIMS (relative intensity) m/z: 166 (M+, 60),
148 (15), 135 (100), 107 (90), 80 (26), 52 (13); 1H
NMR (CDCl3, 300 MHz): d 8.38 (d, 1H, J = 2.5 Hz),
8.35 (d, 1H, J = 2.5 Hz), 4.99 (d, 1H, J = 16.4 Hz),
4.85 (d, 1H, J = 16.4), 4.01 (m, 1H), 3.85 (dd, 1H,
J = 6.9, 12.6 Hz), 3.82 (dd, 1H, J = 6.7, 12.0 Hz), 3.01
(m, 2H), 2.05 (d, –OH, J = 7.5 Hz); 13C NMR
(CDCl3, 75 MHz): 150.2, 149.9, 145, 145.2, 75.8, 68.3,
61.0, 31.8.