Formal synthesis of fumonisin B1, a potent sphingolipid biosynthesis inhibitor

Article abstract of DOI:10.1016/j.tetlet.2012.04.030

The formal total synthesis of the important toxin fumonisin B₁ is achieved from simple raw materials in a convergent manner. The key functionalities are derived from MacMillan α-hydroxylation, sharpless asymmetric dihydroxylation and ring-closing metathesis.

Full text of DOI:10.1016/j.tetlet.2012.04.030

Tetrahedron Letters 53 (2012) 3233–3236
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Tetrahedron Letters
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Formal synthesis of fumonisin B1, a potent sphingolipid biosynthesis inhibitor
⇑
Srivari Chandrasekhar , Lella Sreelakshmi
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 February 2012
Revised 4 April 2012
Accepted 5 April 2012
Available online 21 April 2012
The formal total synthesis of the important toxin fumonisin B1 is achieved from simple raw materials in a
convergent manner. The key functionalities are derived from MacMillan
asymmetric dihydroxylation and ring-closing metathesis.
a-hydroxylation, sharpless
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
D
-Mannitol
Fumonisin B1
MacMillan -hydroxylation
Sphingolipid
a
Ring-closing metathesis
The parasitic fungi found on food grains produce several
secondary metabolites which cause a list of diseases including can-
cer. Fusarium is a very common class of fungi found on maize and a
few other grains.1 Metabolites of these fungi have shown carcino-
genic effects and esophageal cancer was noticed in the populations
in China and Africa when the maize has contamination with this
fungus.2 Fusarium verticillioides is one such species in corn and corn
products which induces ‘moldy corn poisoning’ syndrome in
horses and pigs, and in human has caused neural tube birth defects
besides esophageal cancer.3 Fumonisin B1 (1) is a powerful myco-
toxin isolated from these species and its structural identity has
been established (Fig. 1), based on extensive spectral studies and
correlation data.4 The fumonisins have a similar structural motif
as the sphingosine (2, Fig. 1) and are involved in the regulation
of cell growth, cell–cell communication and signaling pathways.
It was thought that sphingolipid biosynthesis disruption would
be an indirect way of controlling fumonisin formation.5 To under-
stand these cellular pathway similarities and also to design analogs
with modified properties, the synthesis of this mycotoxin has been
initiated in several research groups6 and to date, only one total
synthesis has been reported by McDonald and co-workers7.
Intrigued by structural similarities with sphingosine and our
own interest in the utilization of chiral synthons in the construc-
tion of asymmetric long-chain fatty acid class of molecules,8 we
embarked upon a total synthesis of fumonisin B1 involving chem-
istry amicable for generating analogs, scale up, and operational
simplicity.
A late-stage scaffold 3 (Scheme 1) reported by McDonald and
co-workers7 was our primary target whose retrosynthetic analysis
revealed that two building blocks, azido diol derivative 4, and alde-
hyde 5 could be stitched together by an alkynylation. Further, azi-
do diol 4 and aldehyde 5 can be synthesized from D-mannitol and
hexanal, respectively.
The journey toward the synthesis of azido diol 4 began from a
known homoallyl triol derivative 69 which was subjected to hyd-
roboration using BH3ꢀDMS to provide primary alcohol 9 in 86%
yield (Scheme 2). Primary alcohol 9 was oxidized to aldehyde 10
which was employed in an organocatalytic MacMillan
ation to install the C-5 hydroxy group of the target molecule.10 This
task was achieved by subjecting the aldehyde 10 to 40 mol% -pro-
a-hydroxyl-
D
line and PhNO in DMSO, followed by the rapid reduction of alde-
hyde with NaBH4 to provide the unstable anilinoxy compound,
which was further treated with CuSO4ꢀ5H2O in MeOH to furnish
the diol derivative 11 in high diastereoselectivity (64% yield, 92:8
dr).11 The acetylenic functionality required to couple this fragment
with aldehyde 5 was introduced through an epoxide-opening
strategy. Thus, compound 11 was subjected to selective tosylation
at the primary alcohol site with one equivalent of p-TsCl in the
presence of dibutyltin oxide to provide tosylate 12, which under-
went a smooth epoxide formation in the presence of K2CO3 in
MeOH as solvent to generate epoxide 13. Addition of propargyl-
magnesium bromide to epoxide 13 provided homologated acety-
lenic alcohol 14 in 88% yield.12
Masking of the hydroxyl group in 14 with BnBr and NaH re-
sulted in benzyl ether 15 in 89% yield. The cyclohexyl ketal in 15
was deprotected with p-TsOH in MeOH to realize the diol 16 which
again was translated to epoxide 18 via tosylate 17 in 83% yield over
the two steps. The regioselective reductive opening of epoxide 18
⇑
Corresponding author. Tel.: +91 40 27193210; fax: +91 40 27160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.030

3234
S. Chandrasekhar, L. Sreelakshmi / Tetrahedron Letters 53 (2012) 3233–3236
O
CO2H
CO2H
OBn OBn
BnBr, NaH
THF
0 oC-rt, 12 h
89%
p-TsA, MeOH
O
OH OH
O
14
rt, 24 h, 84%
10
12
14
O
16
15
O
3
5
OH
NH2
OBn OBn
OBn OBn
K2CO3
O
MeOH
R2O
CO2H
O
HO2C
OR1
rt, 2 h
18
85% (two steps)
fumonisin B1 (1)
1
2
16
R = H, R = H
TsCl, NEt3
CH2Cl2, rt, 1h
OH
17 R1= H, R2= Ts
HO
NH2
i) MsCl, NEt3, CH2Cl2
rt, 2 h
OBn OBn
sphingosine (2)
LiAlH4, THF
4
50 o C, 7 h
96%
ii) NaN3, DMF
60 oC, 12 h
Figure 1. Structure of fumonisin B1 (1) and sphingosine (2).
OH
19
83% for two steps
Scheme 3. Synthesis of alkyne subunit 4.
OBn OBn
1. O3, CH2Cl2, -78 o
2. PPh3CHCO2Et,
C
Fumonisin B1 (1)
MeO
2 steps
N3
O
O
Hexanal
EtOOC
O
O
N
N
3
CH2Cl2, rt, 2h, 85%
20
DIBAL-H
CH2Cl2
HO
OBn OBn
rt, 3 h, 86%
22
21
O
O
OH
N3
5
4
AD mix-
β
, CH3SO2NH2
PMPCH(OMe)2
HO
CH2Cl2, 0 o
C
tBuOH-H2O (1:1)
OH
0
O
oC, 24 h, 90%
1h, 85%
OMPM
8
OBn
O
O
7
O
6
OMPM
O
DIBAL-H,CH2Cl2
rt, 2 h, 85%
R2O
O
O
OH
OR1
24
D-mannitol
HO
R1= H, R2= H
25 R1= H, R2= Ts
TsCl, NEt3
CH2Cl2, rt
90%
OH
23
OH
8
OMPM
Hexanal
, Mg, THF
Br
K2CO3, MeOH
rt, 1 h, 88%
-35 oC, 3 h, 88%
O
Scheme 1. Retrosynthetic analysis of fumonisin B1 (1).
26
OMPM
OMPM
acryloyl chloride
DIPEA, CH2Cl2
OBn
O
0 oc-rt, 3 h, 95%
OH
BH3.DMS, THF
oC-rt, 12 h, 90%
O
4 steps
OBn
28
27
D-Mannitol
O
0
O
6
Grubbs-ll (5 mol%)
7
toluene,110 oC
24 h, 85%
OBn
IBX
O
OH
O
O
O
THF-DMSO
rt, 3 h, 96%
O
Scheme 4. Synthesis of lactone 7.
10
9
OBn OR1
1. PhNO, D-proline
DMSO, then
to 19 using LiAlH4, followed by mesylation and SN2 displacement
of the mesylate in 19 with NaN3 afforded the azide 413 (Scheme 3).
Synthesis of the right-hand side fragment 5 (Scheme 4) com-
menced from known Ender’s imine 20.14 Oxidation of imine 20
with O3, followed by exposure of the resulting aldehyde to ethoxy-
OR2
K2CO3, MeOH
rt, 1 h
O
NaBH4, EtOH, rt
2. CuSO4.5H2O, MeOH
rt, 64% for two steps
92:8 dr
O
88% ( two steps )
TsCl, NEt3
Bu2SnO
CH2Cl2, rt
1
2
11
12
R = H, R = H
R1= H, R2= Ts
carbonylmethylene triphenylphosphorane provided
a,b-unsatu-
rated ester 21 in 85% yield. DIBAL-H reduction of ester 21 to
alcohol 22 and Sharpless asymmetric dihydroxylation with AD
mix-b generated the triol 8 with >90% de.15 Protective group
manipulations were needed on triol 8 for further elaboration which
was achieved through conversion of triol 8 to p-methoxybenzalde-
hyde acetal 23 and reductive opening to 24 with DIBAL-H in 85%
OBn OH
O
OBn
HCCCH2Br
Mg,THF
O
O
O
-40 oC, 3 h
88%
14
O
13
Scheme 2. Synthesis of intermediate 14.

S. Chandrasekhar, L. Sreelakshmi / Tetrahedron Letters 53 (2012) 3233–3236
3235
OMPM
OBn OBn
Me
10% Pd-C, Na2CO3
EtOAc, H2, 95%
LiBH4, THF
0 oC-rt, 2 h
90%
O
7
O
O
N3
O
4
5
29
O
n-BuLi, THF
-78 oC, 2h
75%
OMPM
TBDMSCl, imidazole
CH2Cl2
OBn OBn
HO
0 oC-rt, 30 min, 94%
OH
30
N3
O
O
34 OH
(60:40)
1.DMP, CH2Cl2
0 oC-rt, 2 hr
OMPM
TBDMSO
TBDMSO
DMP, CH2Cl2
rt, 1h, 95%
2.LiI, Et2O, -40 oC
LiAlH4, -100 oC, 2 h
86% for 2 steps
OH
31
OBn OBn
OMPM
10% Pd-C, MeOH, H2
p-TSA, 30 min.
N3
O
3
O
O
OH
32
then pTSA, acetone
30 min, 88%
ref 7
DMP, CH2Cl2
0 oC - rt, 1 h, 82%
fumonisin B1 (1)
HO
5
O
O
Scheme 6. Coupling of fragment 4 and 5.
33
reduction of a,b-unsaturated lactone for C-12 methyl group taking
Scheme 5. Synthesis of aldehyde subunit 5.
advantage of the cyclic ring, and recurring epoxide opening strat-
egy for key C–C bond formations.
yield. Yet another time in the sequence, the 1,2-diol functionality
in 24 was converted into epoxide 26 via tosylate 25 in 88% yield.
Regioselective opening of the epoxide in 26 with 2-bromopropene
via Grignard formation to 27 was achieved in almost quantitative
yield.16 Acryloylation with acryloyl chloride and DIPEA in CH2Cl2
provided the diene 28, a ready precursor for ring closing metathe-
sis under the influence of second-generation Grubbs’ catalyst to
obtain the lactone 7 in 85% yield17 (Scheme 4).
Acknowledgment
LS thanks the Council of Scientific Industrial Research (CSIR),
New Delhi for the award of research fellowship. S.C.S thankful to
DST, New Delhi for funding the research grant (SR/S1/OC-65/2009).
References and notes
The C-12 methyl group with the required chirality was installed
by hydrogenation of the a,b-unsaturated lactone 7 with 10% Pd-C
1. Marasas, W. F. O.; Nelson, P. E.; Toussoun, T. A. Toxigenic Fusarium Species:
Identity and Mycotoxicology, 216; The Pennsylvania State University Press:
University Park, PA, 1984.
2. (a) Sydenham, E. W.; Thiel, P. G.; Marasas, W. F. O.; Shephard, G. S.; Van
Schalkwyk, D. J.; Koch, K. R. J. Agric. Food. Chem. 1900, 38, 1990; (b) Chu, F. C.; Li,
G. Y. Appl. Environ. Microbiol. 1994, 60, 847; (c) Marasas, W. F. O. In Cancer of the
Oesophagus, 1; Pfeiffer, C. J., Ed.; GRC Press: Boca Raton, FL, 1982; p 29; (d)
Yang, C. S. Cancer Res. 1980, 40, 2633.
3. (a) Thiel, P. G.; Shephard, G. S.; Sydenham, E. W.; Marasas, W. F. O.; Nelson, P.
E.; Wilson, T. M. J. Agric. Food. Chem. 1991, 39, 109; (b) Harrison, L. R.; Colvin, B.
M.; Green, J. T.; Newman, L. E.; Cole, J. R. J. Vet. Diagn. InVest. 1990, 2, 217; (c)
Rhedder, J. P.; Marasas, W. F. O.; Thiel, P. G.; Sydenham, E. W.; Shephard, G. S.;
Van Schalkwyk, D. E.; Wang, P. Teratology J. Phytopathology 1992, 82, 353; (d)
Sadler, T. W.; Merrill, A. H.; Stevens, V. L.; Sullards, M. C.; Wang, Teratology
2002, 66, 169; (e) Hendricks, K. Epidemiology 1999, 10, 198.
4. (a) Blackwell, B. A.; Edwards, O. E.; ApSimon, J. W.; Fruchier, A. Tetrahedron Lett.
1995, 36, 1973; (b) Boyle, C. D.; Kishi, Y. Tetrahedron Lett. 1995, 36, 4579; (c)
Hoye, T. R.; Jimenez, J. I.; Shier, W. T. J. Am. Chem. Soc. 1994, 116, 9409; (d) Shier,
W. T.; Abbas, H. K.; Badria, F. A. Tetrahedron Lett. 1995, 36, 1571; (e) Poch, G. K.;
Powell, R. G.; Plattner, R. D.; Weisleder, D. Tetrahedron Lett. 1994, 35, 7707; (f)
Bezuidenhout, S. C.; Gelderblom, W. C. A.; Gorstallman, C. P.; Horak, R. M.;
Marasas, W. F. O.; Spiteller, G.; Vleggaar, R. Chem. Commun. 1998, 743; (g)
Gelderblom, W. C. A.; Jaskiewicz, K.; Marasas, W. F. O.; Thiel, P. G.; Horak, R. M.;
Vleggaar, R.; Kriek, N. P. J. Appl. Environ. Microbiol. 1998, 54, 1806.
5. Wang, E.; Norred, W. P.; Bacon, C. W.; Riley, R. T.; Merrill, A. H. J. Biol. Chem.
1991, 266, 14486.
which provided 29 as a single diastereomer18 (Scheme 5). The lac-
tone 29 was reduced with LiBH4 in THF to furnish diol 30 and fur-
ther was protected as silyl ether 31 with TBDMSCl and imidazole in
CH2Cl2 as solvent. The stereochemical inversion of the free hydro-
xyl group which translates to C-15 of the target molecule 3 was
achieved via a two step process, viz. oxidation, followed by the
reduction with LiAlH4 assisted by LiI at ꢁ40 °C, to achieve alcohol
32 (86% yield, 90% de).19,20 Protective group reorganization was
essential to reach the targeted aldehyde 5 through hydrogenation
and using p-TsOH (cat) to remove the MPM and silyl groups. The
resultant vicinal diol group was protected as an acetonide to re-
lease the primary alcohol 33 which provided spectroscopic correla-
tion with an intermediate in Kishi’s synthesis6a of fumoinisin B2
(Scheme 5). Oxidation of alcohol 33 under Dess-Martin conditions
provided aldehyde 5.
The stage was now set to couple the two advanced building
blocks 4 and 5, which were assembled by exposing acetylene 4
to n-BuLi and the generated lithium acetylide was added onto alde-
hyde 5 to achieve the complete carbon frame 34 (75% yield) of the
target fumonisin B1 as a diastereomeric mixture (Scheme 6). For
operational and logical conclusions, the diastereomeric mixture
34 was oxidized with the Dess-Martin reagent to obtain 3 as a sin-
gle product whose spectral data were in full agreement with those
data reported by McDonald and co-workers7 during the only total
synthesis reported to date.
6. (a) Shi, Y.; Peng, L. F.; Kishi, Y. J. Org. Chem. 1997, 62, 5666; (b) Gurjar, M. K.;
Rajendran, V.; Rao, B. V. Tetrahedron Lett. 1998, 39, 3803; For the synthesis of
the related AAL toxins, see: (c) Oikawa, H.; Yamawaki, D.; Kagawa, T.; Ichihara,
A. Tetrahedron Lett. 1999, 40, 6621.
7. Pereira, C. L.; Chen, Y. H.; McDonald, F. E. J. Am. Chem. Soc. 2009, 131, 6066.
8. Prakesch, M.; Gree, D.; Chandrasekhar, S.; Gree, R. Eur. J. Org. Chem. 2005, 1221.
9. (a) Sharma, A.; Gamre, S.; Chattopadhyay, S. Tetrahedron Lett. 2007, 48, 3705;
(b) Venkataiah, M.; Somaiah, P.; Reddipalli, G.; Fadnavis, N. W. Tetrahedron:
Asymmetry 2009, 20, 2230.
In conclusion, we have demonstrated the formal total synthesis
of a very important toxin fumonisin B1 from simple commercially
available raw materials in a convergent manner.21 The noteworthy
achievements en route the synthesis, are the organocatalytic
hydroxylation to introduce C-5 hydroxyl group, stereoselective
10. (a) Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3696; (b)
Varseev, G. N.; Maier, M. E. Org. Lett. 2007, 9, 1461; (c) Brown, S. P.; Brochu, M.
P.; Sinz, C. J.; MacMillian, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808; (d)
Chandrasekar, S.; Mahipal, B.; Kavitha, M. J. Org. Chem. 2009, 74, 9531; (e)
Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247; (f) Hayashi, Y.; Yamaguchi, J.;
Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44, 8293.

3236
S. Chandrasekhar, L. Sreelakshmi / Tetrahedron Letters 53 (2012) 3233–3236
11. The diastereomeric ratio was determined by HPLC analysis using WATERS
column (mobile phase 40% CH3CN + 60% water (0.1%
74.1, 73.1, 70.6, 68.6, 59.5, 36.0, 32.8, 14.8, 14.1. IR (KBr): vmax 3302, 2929,
2870, 2107, 1257, 1064 cmꢁ1. MS (ESI): m/z 400 [M+Na]+. HRMS (ESI): [M+Na]+
HRC18 300 ꢂ 3.9 mm, 6
l
acetic acid)), flow rate 1.0 ml/min, major isomer tR 8.6 min, Minor isomer tR
9.3 min.
C23H27N3O2Na: calcd 400.1996; found, 400.2000. ½a D20
ꢃ : ꢁ31.5 (c 1.1, CHCl3).
(4R,6R)-6-((1R,2R)-1-(4-Methoxybenzyloxy)-2-methylhexyl)-4-methyl-tetrahydro
pyran-2-one (29): colourless oil. 1H NMR (300 MHz, CDCl3): d 7.23 (d, J = 8.4 Hz,
2H), 6.82 (d, J = 8.4 Hz, 2H), 4.63 (d, J = 10.9 Hz, 1H), 4.52 (d, J = 11.1 Hz, 1H),
4.48–4.40 (m, 1H), 3.79 (s, 3H), 3.18–3.12 (m, 1H), 2.69–2.57 (m, 1H), 2.06–
1.95 (m, 2H), 1.90–1.73 (m, 2H), 1.51–1.14 (m, 7H), 1.04 (d, J = 6.0 Hz, 3H), 0.95
(d, J = 6.7 Hz, 3H), 0.89 (t, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 170.9,
159.0, 130.5, 129.3, 113.6, 84.5, 81.3, 73.9, 55.1, 38.1, 33.9, 33.1, 31.2, 29.2,
26.5, 22.8, 21.6, 16.2, 14.0. IR (KBr): vmax 2956, 2929, 2872, 1737, 1514, 1247,
771 cmꢁ1. MS (ESI): m/z 371 [M+Na]+. HRMS (ESI): [M+Na]+ C21H32NaO4: calcd
12. (a) Nakayama, Y.; Biju Kumar, G.; Kobayashi, Y. J. Org. Chem. 2000, 65, 707; (b)
Sommer, S.; Kuhn, M.; Waldmann, H. Adv. Synth. Catal. 2008, 350, 1736.
13. The spectroscopic data of an intermediate azide 4 was in full agreement with
the data of an intermediate reported by McDonald and co-workers7.
14. Waalboer, D. C. J.; van Kalkeren, H. A.; Schaapman, M. C.; van Delft, F. L.; Rutjes,
F. P. J. T. J. Org. Chem. 2009, 74, 8878.
15. The diastereoselectivity of triol was determined by its 1H and 13C NMR
spectroscopic data.
16. Ahmed, A.; Hoegenauer, E. K.; Enev, V. S.; Hanbauer, M.; Kaehlig Ohler, H. E.;
Mulzer, J. J. Org. Chem. 2003, 68, 3026.
17. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
18. Guinchard, X.; Roulland, E. Org. Lett. 2009, 11, 4700.
19. Forsyth, C. J.; Jianyan, X.; Nguyen, S. T.; Samdal, I. A.; Briggs, L. R.; Rundberget,
T.; Sandvik, M.; Miles, C. O. J. Am. Chem. Soc. 2006, 128, 15114.
20. The diastereomeric excess was determined by HPLC analysis using Zorbax
371.2193; found, 371.2228. ½a D20
ꢃ
: 14.0 (c 2.2, CHCl3).
(S)-4-((4S,5R)-5-((R)-Hexan-2-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-methylbutan-
1-ol (33): colourless oil. 1H NMR (400 MHz, CDCl3): d 4.16–4.11(m, 1H), 3.76–
3.70 (m, 2H), 3.68–3.63 (m, 1H), 1.91–1.83 (m, 1H), 1.80–1.57 (m, 4H), 1.52–
1.44 (m, 1H), 1.42 (s, 3H), 1.40–1.26 (m, 3H), 1.32 (s, 3H), 1.26–1.18 (m, 2H),
1.16–1.08 (m, 1H), 0.98 (d, J = 6.5 Hz, 3H), 0.90 (d, J = 7.4 Hz, 3H), 0.82 (d,
J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 107.4, 82.7, 75.4, 61.1, 38.3, 36.8,
SBC3 150 ꢂ 4.6 mm, 5
l
column (mobile phase 80% CH3CN + 20% water), flow
33.4, 32.0, 28.6, 28.4, 26.1, 25.9, 22.9, 21.2, 15.7, 14.1. IR (KBr):
2928, 2858, 1462, 1375, 1243, 1220, 1056 cmꢁ1. MS (ESI): m/z 273 [M+H]+.
: ꢁ40.4 (c 1.3, CHCl3).
vmax 3388, 2955,
rate 1.0 ml/min, major isomer tR 4.8 min, Minor isomer tR 5.4 min.
21. Spectroscopic data for representative compounds:
½ ꢃ
a 2D0
(2S,4S)-4-(Benzyloxy)-4-((R)-1,4-dioxaspiro[4.5]decan-2-yl)butane-1,2-diol (11):
viscous liquid.1H NMR (500 MHz, CDCl3): d 7.34–7.24 (m, 5H), 4.66–4.59 (m,
2H), 4.08 (q, J = 6.2 Hz, 1H), 4.05–4.01 (m, 1H), 3.89–3.83 (m, 1H), 3.83–3.77
(m, 1H), 3.71–3.66 (m, 1H), 3.58–3.49 (m, 1H), 3.39 (dd, J = 6.9, 11.0 Hz, 1H),
1.75–1.68 (m, 1H), 1.65–1.51 (m, 9H), 1.44–1.34 (m, 2H). 13C NMR (75 MHz,
CDCl3): d 137.8, 128.4, 128.0, 127.9, 110.0, 77.5, 77.3, 72.8, 69.0, 66.9, 66.4,
36.1, 34.6, 34.5, 25.0, 23.9, 23.7. IR (KBr): vmax 3399, 2935, 2861, 1099, 1070,
772 cmꢁ1. MS (ESI): m/z 359 [M+Na]+. HRMS (ESI): [M+Na]+ C19H28O5Na: calcd
(2R,9R,11S,12S)-12-Azido-9,11-bis(benzyloxy)-1-((4S,5R)-5-((R)-hexan-2-yl)-2,2-
dimethyl-1,3-dioxolan-4-yl)-2-methyltridec-5-yn-4-one (3): colourless oil. 1H
NMR (600 MHz, CDCl3): d 7.28–7.18 (m, 10H), 4.58 (d, J = 11.5 Hz, 1H), 4.53
(d, J = 11.5 Hz, 1H), 4.35 (d, J = 11.0 Hz, 1H), 4.33 (d, J = 11.5 Hz, 1H), 4.07–4.04
(m, 1H), 3.73–3.68 (m, 2H), 3.61–3.57 (m, 2H), 2.67 (q, J = 8.4, 11.0 Hz, 1H),
2.49–2.32 (m, 4H), 1.93–1.81 (m, 2H), 1.77–1.66 (m, 1H), 1.65–1.58 (m, 2H),
1.50–1.45 (m, 1H), 1.42 (s, 3H), 1.39–1.17 (m, 12 H), 1.15–1.09 (m, 1H), 1.02 (d,
J = 6.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz,
CDCl3):d 187.7, 138.2, 138.0, 128.4, 127.8, 127.7, 107.5, 93.1, 82.6, 81.4, 78.3,
75.5, 74.0, 73.1, 70.7, 59.3, 51.3, 35.8, 33.5, 32.1, 32.0, 28.7, 28.5, 26.6, 26.2,
23.0, 20.9, 15.7, 14.6, 14.5, 14.1. IR (KBr): vmax 2955, 2926, 1855, 2107, 1671,
359.1851; found, 359.1834. ½a D20
ꢃ
: 3.72 (c 1.8, CHCl3).
((2S,3S,5R)-2-Azidonon-8-yne-3,5-diyl)bis(oxy)bis(methylene)dibenzene (4): 1H
NMR (600 MHz, CDCl3): colourless oil.
d 7.35–7.27 (m, 10H), 4.60 (d,
J = 8.1 Hz, 1H), 4.58 (d, J = 8.5 Hz, 1H), 4.40 (d, J = 11.3 Hz, 1H), 4.35 (d,
J = 11.3 Hz, 1H), 3.79–3.75 (m, 1H), 3.61–3.57 (m, 2H), 2.37–2.24 (m, 2H), 1.99
(t, J = 2.6 Hz, 1H), 1.90–1.80 (m, 2H), 1.78–1.65 (m, 2H), 1.28 (d, J = 6.3 Hz, 3H).
13C NMR (75 MHz, CDCl3): d 138.4, 138.1, 128.3, 127.8, 127.7, 127.6, 84.1, 78.5,
1219, 1059, 772 cmꢁ1. HRMS (ESI): [M+NH4]+ C39H59N4O5: calcd 663.4480;
found, 663.4474. ½a D20
ꢃ
: ꢁ32.4 (c 0.5, CHCl3). [Lit.Val.7
[a
]
D: ꢁ34.8 (c 0.6,
25
CHCl3)].