An efficient stereoselective synthesis of penaresidin A from (E)-2-protected amino-3,4-unsaturated sulfoxide

Article abstract of DOI:10.1021/jo9022638

(Chemical Equation Presented) An efficient, modular, asymmetric synthesis of penaresidin A is disclosed. A β-protected amino-γ, δ-unsaturated sulfoxide was prepared by stereoselective addition of the lithio anion of (R)-methyl p-tolyl sulfoxide to an unsa

Full text of DOI:10.1021/jo9022638

pubs.acs.org/joc
An Efficient Stereoselective Synthesis of Penaresidin A from
(E)-2-Protected Amino-3,4-unsaturated Sulfoxide
Sadagopan Raghavan* and V. Krishnaiah
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
sraghavan@iict.res.in
Received October 21, 2009
An efficient, modular, asymmetric synthesis of penaresidin A is disclosed. A β-protected amino-γ,
δ-unsaturated sulfoxide was prepared by stereoselective addition of the lithio anion of (R)-methyl
p-tolyl sulfoxide to an unsaturated sulfinylimine. The pendant sulfoxide group was used as an
intramolecular nucleophile to functionalize an alkene regio- and stereoselectively to furnish a bromo-
hydrin, which was employed as the key intermediate in the preparation of the azetidine subunit of
penaresidin A. The stereogenic centers of the side chain were introduced by a regioselective opening
of an epoxide. Julia-Kocienski olefination was used to couple the azetidine and side chain sub-
units. The methodology disclosed herein is also useful for the synthesis of ribo- and arabino-
phytosphingosines and compounds possessing the amino alcohol moiety.
Introduction
to date rely on chiral pool starting materials (including
L-serine,3 D-glutamatic acid,4 D-xylose,5 D-glucose,6 and
D-arabinose,7) except one,8 which relied on Sharpless asym-
metric epoxidation and Sharpless asymmetric hydroxylation
reactions. The reported syntheses suffer from lengthy re-
action sequences, poor stereocontrol, or the need for specia-
lized techniques. We describe herein an efficient, highly
stereoselective, and modular asymmetric synthesis of penare-
sidin A.
Penaresidin A (1), penaresidin B (2), isolated from the
Okinawan sponge Penares sp.,1 and the related compound
penazetidine A (3), isolated from the Pacific sponge Penares
sollasi,2 Figure 1, are azetidine alkaloids structurally related
to phytosphingosines. Penaresidins A and B, tested as a
mixture,1 elevated the ATP-ase activity of myofibrils from
rabbit skeletal muscle to 181% of control and penazetidine
A showed specific rat brain protein kinase C inhibitory
activity.2
Results and Discussion
Penaresidin A is characterized by an azetidine diol subunit
separated from the hydroxy isobutyl subunit by a long alkyl
chain. The absolute configuration of the five stereogenic
centers was established by a combination of spectroscopic
and synthetic studies. The azetidine alkaloids have attracted
the attention of synthetic chemists due to their significant
biological activity, and unique structure: to date several
syntheses have been reported. Synthetic strategies reported
Our retrosynthetic analysis is depicted in Scheme 1. We
envisioned using the Julia-Kocienski olefination to couple
the azetidine 4 and the side chain subunit 5. The double bond
and the thiophenyl moiety in the coupled product can be
reduced and hydrogenolyzed respectively in a one-pot opera-
tion by treatment with Ra-Ni. Azetidine 4 can be obtained
(4) Yoda, H.; Oguchi, T.; Takabe, K. Tetrahedron Lett. 1997, 38, 3283–
(1) Kobayashi, J.; Cheng, J.; Ishibashi, M.; Walchli, M. R.; Yamamura,
S.; Ohizumi, Y. J. Chem. Soc., Perkin Trans. 1 1991, 1135–1137.
(2) Alvi, K. A.; Jaspars, M.; Crews, P. Bioorg. Med. Chem. Lett. 1994, 4,
2447–2450.
(3) (a) Ohshita, K.; Ishiyama, H.; Takahashi, Y.; Ito, J.; Mikami, Y.;
Kobayashi, J. Bioorg. Med. Chem. 2007, 15, 4910–4916. (b) Knapp, S.; Dong,
Y. Tetrahedron Lett. 1997, 38, 3813–3816. (c) Takikawa, H.; Maeda, T.; Seki,
M.; Koshino, H.; Mori, K. J. Chem. Soc., Perkin Trans. 1 1997, 97–111. (d)
Takikawa, H.; Maeda, T.; Mori, K. Tetrahedron Lett. 1995, 36, 7689–7692.
3284.
(5) Hiraki, T.; Yamagiwa, Y.; Kamikawa, T. Tetrahedron Lett. 1995, 36,
4841–4844.
(6) Beauhaire, J.; Ducrot, P.-H. C. R. Acad. Sci., Ser. IIc: Chim. 1999,
477–482.
(7) Yoda, H.; Uemura, T.; Takabe, K. Tetrahedron Lett. 2003, 44, 977–
979.
(8) (a) Liu, D.-G.; Lin, G.-Q. Tetrahedron Lett. 1999, 40, 337–340. (b)
Lin, G.-Q.; Liu, D.-G. Heterocycles 1998, 47, 337–348.
748 J. Org. Chem. 2010, 75, 748–761
Published on Web 12/21/2009
DOI: 10.1021/jo9022638
r
2009 American Chemical Society

Raghavan and Krishnaiah
JOCArticle
FIGURE 1. Structure of penaresidin and phytosphingosines.
SCHEME 1. Retrosynthetic Analysis of Penaresidin A
from the aminodiol derivative 6, which in turn can be derived
from bromohydrin 7. The bromohydrin 7 can be traced to
β-protected amino unsaturated sulfoxide 8. The sulfone 5
was envisaged to be obtained from epoxy alcohol 9, which
can be readily prepared from 1,3-propanediol (10). The
bromohydrin 7 was envisaged to be prepared by means of
a method we reported recently for the regio- and stereose-
lective oxidative vicinal heterofunctionalization of β-pro-
tected amino-γ,δ-unsaturated sulfoxides using N-bromo-
succinimide (NBS) as the electrophile and the sulfinyl group
as an intramolecular nucleophile.9
To begin with we needed to design a stereoselective route
to unsaturated sulfoxide 8. Barring one report10 prior to our
work,11 there was nothing known about the addition of
R-sulfinyl carbanions to imines derived from unsaturated
aldehydes. We have shown that the addition of the lithio
anion of (R)-methyl p-tolyl sulfoxide to the N-Ts imine of
cinnamaldehyde proceeded with modest stereocontrol
only.11 In this context, the account of Garcia-Ruano and
co-workers on the addition of sulfinyl carbanions to sulfi-
nylimines12 attracted our attention. A similar reaction be-
tween sulfinylimine 18 and sulfinyl carbanion was expected
to furnish sulfoxide 8 stereoselectively. We originally began
the synthesis of the unsaturated sulfinylimine 18 from 1,
9-nonanediol (11). Selective monoprotection of 11 as its
benzyl ether 12 followed by Swern oxidation13 furnished
the aldehyde 13. Wittig olefination stereoselectively afforded
the trans-ester 14, which was chemoselectively reduced with
alane14 to furnish allylic alcohol 15. Oxidation of 15 with the
Swern protocol yielded aldehyde 16, which was reacted with
(S)-tert-butyl sulfinamide15 17a (R=tBu) in the presence of
Ti(OEt)4 to furnish N-tert-butyl sulfinylimine 18a. Like-
wise, sulfinylimine 18b was prepared from 16 with use of
Davis’ reagent 17b (R=p-tolyl),17 Scheme 2.
Subsequently, sulfinylimine 18a was prepared readily and
convergently on a 20 mmol scale by a cross metathesis18
reaction between sulfinylimine 19,19 prepared from acrolein,
and benzyl ether 20, prepared from commercially available
16
(13) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480–2482.
(14) Eliel, E. L.; Rerick, M. N. J. Am. Chem. Soc. 1960, 82, 1367–1372.
(15) Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317–1320.
(16) (a) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli,
D. L.; Zhang, H. J. Org. Chem. 1999, 64, 1043. (b) Liu, G.; Cogan, D. A.;
Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278–1284.
(17) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll,
P. J. J. Org. Chem. 1997, 62, 2555–2563.
(9) Raghavan,S.; Rajender, A.; Joseph, S. C.; Rasheed, M. A.;Ravikumar,
K. Tetrahedron: Asymmetry 2004, 15, 365–379.
(10) Pyne, S. G.; Dikic, B. J. J. Org. Chem. 1990, 55, 1932–1936.
(11) (a) Raghavan, S.; Rajender, A. Tetrahedron Lett. 2004, 45, 1919–
1922. (b) Raghavan, S.; Rajender, A. Tetrahedron 2004, 60, 5059–5067.
(12) Garcia Ruano, J. L.; Alcudia, A.; Prado, M.; Barros, D.; Maestro,
M. C.; Fernandes, I. J. Org. Chem. 2000, 65, 2856–2862.
(18) (a) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360–11370. (b) Blackwell, H. E.; O’Leary,
D. J.; Chatterjee, A. K.; Washenfelder, R. A.; Bussmann, D. A.; Grubbs,
R. H. J. Am. Chem. Soc. 2000, 122, 58–71.
(19) Sulfinyl imine 19 is the starting material in our synthesis of nelfinavir.
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SCHEME 2. Preparation of Sulfinylimine 18
SCHEME 3. Preparation of Sulfinylimine 18a by Cross
Metathesis
TABLE 1. Diastereoselective C-N Bond Formationa
sulfinyl
imine
sulfin-
amide
temp,
°C
yield,
% (dr)b
9-decen-1-ol, using 1 mol % of Grubb’s catalyst20 21,
Scheme 3.
entry
sulfoxide
1
2
3
4
5
6
(R)-22
(R)-22
(S)-22
(S)-22
(R)-22
(R)-22
18a
18a
18a
18a
18b
18b
23a
23a
23b
23b
23c
23c
-78
0
-78
0
-78
0
94 (96:4)
86 (95:5)
96 (98:2)
88 (97:3)
91 (91:9)
82
(90:10)
94 (97:3)
89 (99:1)
With the aim of investigating the influence of N- and C-
sulfinyl groups in the creation of the new C-N stereogenic
center, imines 18a and 18b were independently reacted with
both (R)- and (S)-methyl p-tolyl sulfoxides21 at -78 and
0 °C, Table 1. An inspection of the table reveals that the
reaction proceeds with excellent stereoselectivity and the
ratio of diastereomers remained unchanged when the reac-
tion was carried out at 0 °C instead of -78 °C. However, the
reaction was cleaner when done at -78 °C. Also the stereo-
selectivity was better with (S)-sulfoxide, more so in the
reaction with 18b. In general tert-butyl sulfinamide fared
better as an auxiliary and since it is readily prepared by
asymmetric catalysis, further experiments were done with
18a. Though stereoselectivity was marginally better using
(S)-22, we chose to use only (R)-22 because the products
resulting from (R)-22 possess a syn relative configuration at
sulfur and nitrogen and these diastereomers have been
shown to afford bromohydrins with better stereoselectivity
than the diastereomers possessing the anti relative configu-
ration at sulfur and nitrogen.9
7
8
(S)-22
(S)-22
18b
18b
23d
23d
-78
0
aAll reactions were carried out on 0.25 mmol scale. bDiastereomer
ratio determined by HPLC.
hydrochloride 24 in the same pot with (R)- and (S)-methoxy-
phenylacetic acid 25 furnished amides 26 and 27, respec-
tively, Scheme 4. In full agreement with the model proposed
for the assignment of configuration to primary amines with a
stereogenic carbon at the R-position,23 the methylene pro-
tons directly bonded to sulfur appear downfield in amide 26
(δ 3.06 and 2.97) compared to 27 (δ 3.05 and 2.92). Also the
signal for olefinic and allylic protons appears upfield in 26
(δ 5.54, 5.43, and 1.95) compared to the corresponding
protons of 27 (δ 5.64, 5.48, and 2.0).
Proceeding with the synthesis, amine hydrochloride 24
was reacted with o-nitrobenzenesulfonyl chloride in the
presence of excess triethylamine to afford the sulfon-
amide 8 (P = o-Ns, 70% overall yield).24 Reaction of 8
with freshly recrystallized NBS, in toluene in the presence
of water, yielded bromohydrin 7 stereoselectively.25 The
The lithio anion of sulfoxide (R)-22 reacts with sulfinyli-
mine 18a probably through the intermediacy of the putative
transition state, TS, to furnish sulfinamide 23a (94% yield).
The “R” configuration expected for the newly created stereo-
genic center based on precedent12 was confirmed by compar-
ing the 1H NMR spectra of diastereomeric amides 26 and 27.
Thus removal of the N-sulfinyl moiety in 23a with 4 N HCl in
dioxane22 followed by treatment of the resulting amine
(23) Seco, J. M.; Quinoa, E.; Riguera, R. Tetrahedron: Asymmetry 2001,
12, 2915–2925.
(24) The preparation of 8 by condensation of the lithio anion of 22 and N-
nosyl imine was not explored. The preparation of N-nosyl imine from the
corresponding R,β-unsaturated (enolizable) aldehyde is not straightforward.
Even if prepared, the new stereogenic center bearing amino substituent was
not expected to be introduced with good selectivity, see ref 11b.
(25) The structure of bromohydrin 7 was assigned based on precedent, see
ref 9.
(20) (a) Scholl, S.; Ding, S.; Lee, C. W.; Grubbs, R, H. Org. Lett. 1999, 1,
953–956. (b) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 1232, 6543–6554.
(21) Drago, C.; Caggiano, L.; Jackson, R. F. W. Angew. Chem., Int. Ed.
2005, 44, 7221–7223.
(22) Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 12–13.
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SCHEME 4. Stereoselective Formation of Sulfinamide 23a
SCHEME 6. Stereoselective Intramolecular 5-exo Epoxide
Opening
bromohydrin formation (compound 7 from 8 and 31 from
30), a π-complex and not epibromonium ion is involved. The
structure of diol 33 was proven by transformation to acetal
35 via a three-step sequence, including (a) 1,2-acetal forma-
tion, (b) Pummerer reaction, followed by one-pot hydrolysis
of the resulting intermediate to the corresponding aldehyde
and its subsequent reduction to an alcohol, and (c) acid-
catalyzed acetal exchange. The coupling constants of C2 H
and NOE studies on 35 confirm the structure assigned to it,
Scheme 7. The NOE observed with C3 H indicates a syn-
relationship between C2 and C3 substituents. The syn,anti
relation at C2-C3, C3-C4 of diol 33 relates to the relative
stereochemistry of corresponding carbons of arabino-phyto-
sphingosine. It is noteworthy that arabino-phytosphingosine
can be synthesized efficiently in a concise fashion starting
from an appropriate unsaturated sulfoxide X, following the
steps depicted in Scheme 6.
SCHEME 5. Stereoselective Formation of Aziridine 29 from
Bromohydrin 7
transformation of 7 to the key intermediate 6 requires
inversion of configurations at C3 and C4 and introduction
of the hydroxy group by bromine displacement. This was
intended to be achieved by epoxide formation, thus inverting
C3 stereocenter, followed by an acid-promoted regioselec-
tive26 intramolecular opening of the epoxide at C4 by the
sulfinyl moiety27 thereby inverting C4 stereocenter. In the
event, treatment of 7 with anhydrous potassium carbonate
did not afford any of the desired epoxide 28, but only the
aziridine 29, Scheme 5.
The epoxide could not be prepared in the presence of the
acidic N-H and we therefore considered bromohydrin forma-
tion from a protected sulfonamide derivative of 8. Thus
reaction of 8 with benzyl bromide with use of anhydrous
potassium carbonate as the base yielded sulfonamide 30.
Bromohydrin 31 was obtained as the only product regio-
and stereoselectively upon treatment of 30 with NBS. Epoxide
32 was obtained without incident from 31. The stage was now
set for preparing a derivative related to 6. Thus, treatment of32
Having been unsuccessful to effect epoxide opening in a
6-endo mode using an intramolecular nucleophile, we attem-
pted opening the epoxide intermolecularly. Epoxide 32 upon
Pummerer reaction afforded the intermediate 36, which
without isolation was hydrolyzed to aldehyde 37 and then
reduced in the same pot to yield alcohol 38. Intermolecular
opening of epoxide ring with aq 3 M sulfuric acid/dioxane29
proceeded cleanly at the less hindered carbon (C4) to furnish
triol 39, Scheme 8.30
1
The structure of 39 was proven by H NMR studies on
compound 40, obtained by acid-catalyzed acetal formation
followed by acetylation, Scheme 9. The signal for C2 H
appeared as a doublet of triplet with J values 4.9 and 11.3 Hz,
respectively. This points to a diaxial relationship between C2
H and C3 H and therefore also confirms the anti relationship
between C2 and C3 substituents in triol 39.
Proceeding, the primary hydroxyl group in 39 was selec-
tively protected as its tert-butyldiphenylsilyl ether to afford
41. Treatment of 41 with methanesulfonyl chloride furnished
exclusively the mesylate 42. The C3 hydroxy group in
42 was protected as its triethylsilyl ether 43, a derivative
of compound 6, using triethylsilyl triflate in the presence
of 2,6-lutidine. Deprotection of the nosyl group31 with
with BF3 Et2O at -78 °C and gradually warming to -10 °C
3
overnight afforded diol 33, resulting from a highly stereo- and
regioselective 5-exo opening, instead of the required diol 34,
expected to result from 6-endo opening, Scheme 6.
The colinear displacement of the epoxide by the sulfur
oxygen is probably more rapid in the 5-exo than the 6-endo
mode leading to the observed selectivity.28 In the case of
(26) A 6-endo nucleophilic opening of the epoxide was expected in a
fashion similar to 6-endo nucleophilic attack of the π-complexed bromonium
ion by the sulfinyl group in the formation of bromohydrin 7.
(27) Westwell, A. D.; Thornton Pett, M.; Rayner, C. M. J. Chem. Soc.,
Perkin Trans. 1 1995, 847–860.
ꢀ
(29) Ayad, T.; Genisson, Y.; Baltas, M.; Gorrichon, L. Chem. Commun.
2003, 582–583.
(28) For a related example of intramolecular epoxide opening, see:
Deslongchamps, P.page 167 in Stereoelectronic effects in Organic Chemistry;
Baldwin, J. E., Ed.; Pergamon Press: New York, 1983.
(30) Attempted opening of epoxide 32 with 3 N H2SO4/dioxane cleanly
yielded the diol 33 as the only product via intramolecular ring opening.
(31) Miller, S. C.; Scanlan, T. S. J. Am. Chem. Soc. 1997, 119, 2301–2302.
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SCHEME 7. Preparation of Acetal 35
SCHEME 8. Regio- and Stereoselective Intermolecular Epoxide Opening
SCHEME 9. Preparation of Acetal 40
SCHEME 10. Synthesis of Aldehyde 4
under the reaction conditions to furnish azetidine 45,
Scheme 10. Hydrogenolysis of the benzyl groups with
Pd(OH)2/C in the presence of di-tert-butyl dicarbonate
under an atmosphere of hydrogen in a mixture of EtOAc
and methanol afforded the carbamate 46 as a mixture of
rotamers (1H NMR in DMSO-d6 at 70 °C indicated a single
set of signals). The primary hydroxy group in 46 was oxidized
without incident with use of IBX to yield aldehyde 4.
Synthesis of the Side Chain Fragment. The attempted
synthesis of sulfone 5 began by subjecting 1,3-propanediol
(10) to reaction with 2-mercaptobenzothiazole (47) under
Mitsunobu conditions32 to furnish the mono sulfide 48. One-
pot IBX oxidation followed by Wittig olefination33 of the
resulting aldehyde afforded ester 49. Chemoselective reduc-
tion of the ester with DIBAL-H afforded allylic alcohol
50. Selective oxidation of the sulfide to sulfone 51 with
ammonium molybdate as the catalyst and H2O2 as the
(32) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc. Chim.
Fr. 1993, 130, 336–357. (b) Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.;
Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 856–878. For an illustration of this
approach in total synthesis see: (c) Bellingham, R.; Jarowicki, K.; Kocienski,
P. J.; Martin, V. Synthesis 1996, 285–296.
mercaptoethanol and DBU as the base afforded initially the
N-Bn compound 44, which underwent further cyclization
(33) Maiti, A.; Yadav, J. S. Synth. Commun. 2001, 31, 1499–1506.
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SCHEME 11. Preparation of Epoxy Sulfone 9
stoichiometric oxidant,34 followed by Sharpless epoxida-
tion35 furnished epoxy alcohol 9, Scheme 11. Attempted
opening of epoxy alcohol 9 with diethyl cuprate or ethyl-
magnesium bromide in the presence of cat. CuI did not
proceed at low temperatures (-78 to -10 °C), while warming
to 0 °C afforded a tarry material. Assuming the benzothia-
zolyl sulfone to be the cause for the unexpected outcome of
the cuprate opening reaction, we decided to introduce the
sulfone residue subsequent to epoxide opening.
Exploring an alternate route, homoallylic alcohol 52 was
converted to p-methoxybenzyl ether 53. Cross metathesis re-
action36 of 53 with cis-2-buten-1,4-diol (54) with Hoveyda-
Grubb’s catalyst 5537 furnished allylic alcohol 56. Sharpless
asymmetric epoxidation afforded epoxide 57, which was
regioselectively opened at C2 with ethylmagnesium bromide
promoted by cat. CuI38 to afford diol 58 (9:1 mixture of
1,3- to 1,2-diols). Protection of the diol as the benzylidene
acetal 59 followed by selective deprotection of the PMB
ether39 furnished alcohol 60. Treatment of 60 under Mitsu-
nobu conditions with N-phenyltetrazole thiol afforded sul-
fide 61, which was readily oxidized to sulfone 62 with
mCPBA. Attempted regioselective deprotection of the ben-
zylidene acetal with DIBAL-H,40 expecting to obtain pri-
mary alcohol 63 that was to be transformed to the coupling
partner 5, failed, instead a complex mixture of products were
obtained, Scheme 12. A probable explanation for the failure
to obtain desired products from sulfone 9 and 62 is the
competitive nucleophilic attack at the heterocyclic core of
these substrates. In an effort to validate this hypothesis,
sulfide 61 was subjected to reduction with DIBAL-H. The
reduction proceeded at rt to afford a product less polar
compared to the starting material, which turned out to be
the thiol 64. Thus the hydride addition to tetrazole moiety is
faster than reduction of acetal.
The alternate route involving deprotection of the acetal 62
under acidic conditions to furnish the corresponding diol
followed by selective conversion of the primary hydroxyl
group to a derivative of sulfone 5 was explored but aban-
doned due to the lengthy sequence of reactions. In the
meantime, we designed a new route to a different side chain
fragment. Diol 58 was selectively transformed to tosylate 65,
which was reduced with LAH41 to yield carbinol 66. Protec-
tion as its benzyl ether 67 followed by deprotection of the
PMB ether with DDQ afforded primary alcohol 68. Trans-
formation to sulfide 69 with Mitsunobu conditions followed
by oxidation with mCPBA afforded sulfone 70, Scheme 13.
Completion of the Synthesis. Having secured the azetidine
and side chain fragments, their union was examined. The
anion derived from 70, by treatment with KHMDS,42 was
reacted with aldehyde 4 to furnish predominantly the trans-
alkene 71. Reduction and concomitant hydrogenolysis of the
benzyl ether was effected by treatment with Pd(OH)2/C
under an atmosphere of hydrogen to afford alcohol 72,
Scheme 14. Deprotection of the silyl groups with TBAF
afforded triol 73. Removal of the carbamate group with
TFA/DCM furnished the amine salt, which was converted to
the tetraacetate 74 by treatment with excess acetic anhydride
in the presence of triethylamine. Tetraacetate 74 had physical
characteristics that were in excellent agreement with those
reported in the literature.3c The trifluoroacetic acid salt of
penaresidin A was converted to the free base by washing with
aq saturated NaHCO3, and purified with a mixture of t-
BuOH/CHCl3/AcOH/H2O as the eluent to furnish penare-
sidin A as its acetic acid salt, the spectral data of which
matched those reported in the literature.3c
(34) Blakemore, P. R.; Kocienski, P. J.; Marzcak, S.; Wicha, J. Synthesis
1999, 1209–1215.
(35) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–
5976.
(36) Using Grubbs catalyst 21, compound 53 isomerized to an internal
alkene, which underwent cross metathesis with 54 to furnish the p-methoxy-
benzyl ether of trans-but-2-ene diol. For a similar reaction, see: Virolleaud,
M. A.; Menant, C.; Fenet, B.; Piva, O. Tetrahedron Lett. 2006, 47, 5127–
5130.
In summary, we have employed an unsaturated tert-butyl-
sulfinylimine as precursor for the stereoselective preparation
(37) Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J. Organomet. Chem. 2001,
624, 327.
(38) Tius, M. A.; Fauq, A. H. J. Org. Chem. 1983, 48, 4131–4132.
(39) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885–888.
(40) Sviridov, A. F.; Ermolenko, M. S.; Yashunsky, D. V.; Borodkin, V.
S.; Kochetkov, N. K. Tetrahedron Lett. 1982, 23, 3835–3838.
(41) Rapoport, H.; Bonner, R. M. J. Am. Chem. Soc. 1951, 73, 2872–
2876.
(42) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett.
1991, 32, 1175–1178.
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SCHEME 12. Attempted Synthesis of Sulfone Related to 5
SCHEME 13. Synthesis of Sulfone 70
of β-protected amino-γ,δ-unsaturated sulfoxide. Oxidative
vicinal heterofunctionalization of the alkene mediated by the
pendant sulfinyl group afforded regio- and stereoselectively
a single bromohydrin. Regioselective intermolecular open-
ing of the epoxide, one-pot deprotection of the nosyl group,
tandem azetidine formation, and Julia-Kocienski olefina-
tion are key steps in the disclosed route. Cross metathesis
reaction and one-pot transformations have been used ad-
vantageously to decrease the number of steps requiring
isolation and also increase the efficiency. Penaresidin A has
been prepared in 20 steps by the longest linear sequence and
10.5% overall yield. The disclosed strategy elegantly demon-
strates the potential of the sulfinyl moiety as an intramole-
cular nucleophile to functionalize olefins and would be useful
for the synthesis of related phytosphingosines and other
amino diol containing natural products.
neat Ti(OEt)4 (2.5 equiv). The reaction mixture was stirred at
room temperature until TLC examination revealed complete
conversion of starting material. The reaction mixture was
cooled to 0 °C, diluted with dichloromethane, and quenched
by adding ice pieces. The resulting suspension was filtered
through Celite and the Celite pad was washed with hot ethyl
acetate. The filtrate was evaporated under reduced pressure and
the residue thus obtained was purified by column chromato-
graphy to furnish the sulfinylimine.
Compound 18a. Following the procedure detailed above,
aldehyde 16 (1.54 g, 5.61 mmol) was reacted with (S)-tert-butyl
sulfinamide 17a (747 mg, 6.2 mmol) to afford a crude product,
that was purified by column chromatography with use of 8%
EtOAc/hexane (v/v) as the eluent to afford the imine 18a (1.88 g,
5 mmol) in 89% yield as a pale yellow liquid. TLC: Rf 0.5 (20%
EtOAc/hexane). [R]25D þ243 (c 1, CHCl3). IR (neat): 3448, 3030,
1
2927, 1638, 1580, 1457, 1362, 1082, 736, 700 cm-1. H NMR
(300 MHz, CDCl3): δ 8.13 (d, J=9.1 Hz, 1H), 7.32-7.18 (m,
5H), 6.56-6.47 (m, 1H), 6.38 (dd, J=9.1, 15.8 Hz, 1H), 4.46 (s,
2H), 3.42 (t, J=6.8 Hz, 2H), 2.27 (q, J=6.8 Hz, 2H), 1.63-1.54
(qui, J=6.8 Hz, 2H), 1.53-1.43 (m, 2H), 1.41-1.22 (m, 8H),
1.19 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 163.8, 151.3, 138.4,
128.4, 128.0, 127.2, 127.1, 72.5, 70.1, 56.8, 32.7, 29.4, 29.0, 28.8,
Experimental Section
General Procedure for the Preparation of Sulfinylimines. To a
stirred solution of aldehyde (1 equiv) in anhydrous dichloro-
methane (0.2 M) was added sulfinamide (1.1 equiv) followed by
754 J. Org. Chem. Vol. 75, No. 3, 2010

Raghavan and Krishnaiah
JOCArticle
SCHEME 14. Synthesis of Penaresdin A 1
27.9, 25.9, 22.1. MS (ESI): 378 [M þ H]þ. HRMS (ESI): m/z
[M þ H]þ calcd for C22H36NO2S 378.2466, found 378.2484.
Compound 18b. Following the procedure detailed above,
aldehyde 16 (685 mg, 2.5 mmol) was reacted with (S)-p-toluene
sulfinamide 17b (426 mg, 2.75 mmol) to afford a crude product
that was purified by column chromatography with use of 8%
EtOAc/hexane (v/v) as the eluent to afford the imine 18b (937
mg, 2.28 mmol) in 91% yield as a viscous liquid. TLC: Rf 0.5
by the addition of aqueous saturated NH4Cl solution. The two
layers were separated and the aqueous layer was extracted with
ethyl acetate and the combined organic layers were successively
washed with water and brine and dried over Na2SO4. The
solvent was evaporated under reduced pressure to afford a
crude product that was purified by column chromatography
to afford the sulfinamide.
Compound 23a. Sulfinamide 23a (10.28 g, 19.36 mmol) was
prepared following the procedure detailed above from imine 18a
(7.76 mg, 20.6 mmol) and (R)-methyl p-tolyl sulfoxide 22 (3.17
mg, 20.6 mmol) in 94% yield after column chromatography with
use of 10% EtOAc/CHCl3 (v/v) as the eluent. Gummy liquid.
TLC: Rf 0.3 (60% EtOAc/hexane). [R]25D þ106.4 (c 1, CHCl3).
IR (neat): 3443, 3206, 2926, 2854, 1455, 1362, 1049, 810, 739, 698
cm-1. 1H NMR (300 MHz, CDCl3): δ 7.54 (d, J=7.5 Hz, 2H),
7.35-7.25 (m, 7H), 5.87-5.77 (m, 1H), 5.57 (dd, J=7.5, 15.1 Hz,
1H), 4.49 (s, 2H), 4.31-4.20 (m, 1H), 3.79 (d, J=5.3 Hz, NH),
3.46 (t, J=6.8 Hz, 2H), 3.19 (dd, J=6.8, 12.8 Hz, 1H), 2.85 (dd,
J=6.8, 12.8 Hz, 1H), 2.42 (s, 3H), 2.06 (q, J=6.8, Hz, 2H), 1.60
(qui, J=6.8, Hz, 2H), 1.44-1.25 (m, 10H), 1.22 (s, 9H). 13C
NMR (100 MHz, CDCl3): δ 141.4, 140.2, 138.2, 135.3, 129.7,
128.0, 127.9, 127.2, 127.0, 123.7, 72.5, 70.1, 63.6, 56.0, 54.8, 32.0,
29.5, 29.2, 29.1, 28.9, 28.6, 25.9, 22.4, 21.2. MS (LC-MSD): 532
[M þ H]þ. HRMS (ESI): m/z [M þ Na]þ calcd for C30H45NO3-
NaS2 554.2738, found 554.2724.
Compound 26. To a stirred solution of sulfinamide 23a (30 mg,
0.056 mmol) in MeOH (0.6 mL) was added HCl in dioxane (4 M,
28 μL, 0.11 mmol). The reaction mixture was stirred for 3 h and
then the solvent was evaporated under reduced pressure. The
residue was dissolved in dichloromethane (0.6 mL), DMAP (8
mg, 0.062 mmol) and (R)-methoxyphenylacetic acid (10 mg,
0.056 mmol) were added followed by DCC (14 mg, 0.067 mmol).
The reaction mixture was stirred for 30 min and then diluted
with diethyl ether (1.5 mL). The precipitated solids were filtered
through Celite and the solids were washed once with diethyl
ether (2 mL). The combined filtrates were evaporated under
reduced pressure to afford a crude product that was purified by
column chromatography with use of 35% EtOAc/hexane (v/v)
as the eluent to afford the amide 26 (27 mg, 0.048 mmol) in 86%
yield as a gummy liquid. TLC: Rf 0.3 (40% EtOAc/hexane). IR
(neat): 3296, 2925, 2854, 1669, 1518, 1454, 1199, 1099, 1039, 810,
736, 699 cm-1. 1H NMR (500 MHz, CD3CN): δ 7.54 (d, J=8.0
Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.36-7.30 (m, 10H), 5.56-5.51
(20% EtOAc/hexane). [R]25 þ320 (c 1, CHCl3). IR (neat):
D
3455, 3030, 2928, 2854, 1639, 1579, 1455, 1361, 1096, 809 cm-1
.
1H NMR (300 MHz, CDCl3): δ 8.25 (d, J=9.0 Hz, 1H), 7.53 (d,
J=8.3 Hz, 2H), 7.31-7.21 (m, 7H), 6.56-6.46 (m, 1H), 6.34 (dd,
J=9.0, 15.8 Hz, 1H), 4.45 (s, 2H), 3.40 (t, J=6.8 Hz, 2H), 2.39 (s,
3H), 2.24 (q, J=6.8 Hz, 2H), 1.61-1.52 (m, 2H), 1.50-1.40 (m,
2H), 1.36-1.25 (m, 8H). 13C NMR (75 MHz, CDCl3): δ 161.6,
152.0, 141.9, 141.2, 138.5, 129.8, 128.5, 128.3, 127.2, 127.1,
124.4, 72.6, 70.1, 32.7, 29.4, 28.9, 28.8, 27.8, 25.9, 21.1. MS
(ESI): 412 [M þ H]þ. HRMS (ESI): m/z [M þ H]þ calcd for
C25H34NO2S 412.2310, found 412.2326.
Preparation of Sulfinylimine 18a by Cross Metathesis. To the
mixture of benzyl ether 20 (13.9 g, 56.4 mmol) and imine 19 (2.98
g, 18.8 mmol) in anhydrous dichloromethane (94 mL) was
added Grubbs’s catalyst 21 (160 mg, 0.19 mmol). The flask
was fitted with a condenser and refluxed under nitrogen atmo-
sphere for 5 h. The reaction mixture was then allowed to cool to
room temperature and the solvent was removed under reduced
pressure. The residue thus obtained was purified by column
chromatography with use of 8% EtOAc/hexane (v/v) as the
eluent to furnish the sulfinylimine 18a (6.45 g, 17.1 mmol) in
91% yield.
General Procedure for the Preparation of Sulfinamides. A 250
mL round-bottomed flask equipped with a magnetic stirbar and
nitrogen inlet was charged with anhydrous THF (0.1 M) and
cooled at 0 °C. Diisopropylamine (1.6 equiv) was then added
followed by n-BuLi (1.6 equiv) dropwise over a period of 10 min.
The reaction mixture was stirred at this temperature for 20 min
and then cooled at -78 °C. A solution of aryl methyl sulfoxide (1
equiv) in anhydrous THF (0.2 M) was added dropwise via a
syringe to the above LDA solution and the mixture was stirred
for 30 min at the same temperature. To a stirred solution of
imine (1 equiv) in anhydrous THF (0.15 M) cooled at -78 °C
was added the solution of lithio anion of sulfoxide generated
above via a cannula and the reaction was quenched immediately
J. Org. Chem. Vol. 75, No. 3, 2010 755

Raghavan and Krishnaiah
JOCArticle
(m, 1H), 5.43 (dd, J=6.7, 15.4 Hz, 1H), 4.66-4.60 (m, 1H), 4.53
(s, 1H), 4.44 (s, 2H), 3.43 (t, J=6.7 Hz, 2H), 3.31 (s, 3H), 3.06
(dd, J=7.4, 13.4 Hz, 1H), 2.97 (dd, J=6.7, 13.4 Hz, 1H), 2.40 (s,
3H), 1.95 (q, J = 6.7 Hz, 2H), 1.55 (qui, J = 6.7 Hz, 2H),
1.36-1.19 (m, 10H). MS (ESI): 576 [M þ H]þ. HRMS (ESI):
m/z [M þ Na]þ calcd for C35H45NO4NaS 598.2967, found
598.2969.
Compound 27. Amide 27 (28 mg, 0.049 mmol) was prepared
following the procedure detailed above from sulfinamide 23a
(30 mg, 0.056 mmol) and (S)-methoxyphenylacetic acid (10 mg,
0.056 mmol) in 89% yield after column chromatography with
use of 30% EtOAc/hexane (v/v) as the eluent. Low melting solid.
TLC: Rf 0.35 (40% EtOAc/hexane). IR (KBr): 3309, 2928, 2852,
1650, 1515, 1452, 1196, 1096, 1031, 974, 808, 739, 697 cm-1. 1H
NMR (500 MHz, CD3CN): δ 7.54 (d, J=8.0 Hz, 2H), 7.44-7.27
(m, 12H), 5.67-5.62 (m, 1H), 5.48 (dd, J=6.7, 15.4 Hz, 1H),
4.58-4.51 (m, 1H), 4.56 (s, 1H), 4.45 (s, 2H), 3.44 (t, J=6.7 Hz,
2H), 3.30 (s, 3H), 3.05 (dd, J=7.4, 13.4 Hz, 1H), 2.92 (dd, J=7.4,
13.4 Hz, 1H), 2.40 (s, 3H), 2.00 (q, J=6.7 Hz, 2H), 1.55 (qui, J=
6.7 Hz, 2H), 1.37-1.23 (m, 10H). MS (ESI): 576 [M þ H]þ.
HRMS (ESI): m/z [M þ Na]þ calcd for C35H45NO4NaS
598.2967, found 598.2956.
1H), 4.50 (s, 2H), 3.91-3.82 (m, 1H), 3.68 (d, J=9.5 Hz, OH),
3.55 (d, J=5.1 Hz, 1H), 3.46 (t, J=6.6 Hz, 2H), 2.94-2.84 (m,
2H), 2.39 (s, 3H), 1.66-1.58 (m, 2H), 1.51-1.41 (m, 2H),
1.40-1.24 (m, 10H). 13C NMR (100 MHz, CDCl3): δ 147.5,
142.0, 139.5, 138.6, 134.0, 133.7, 133.2, 131.6, 130.1, 128.2,
127.5, 127.4, 125.1, 123.6, 72.8, 71.0, 70.4, 64.2, 62.2, 50.0,
34.0, 29.7, 29.4, 29.3, 29.2, 26.1, 25.0, 21.3. MS (ESI): 731 [M
þ Na]þ. HRMS (ESI): m/z [M þ Na]þ calcd for C32H41N2O7-
NaS2Br 731.1436, found 731.1456.
Compound 29. Anhydrous K2CO3 (83 mg, 0.6 mmol) was
added to a solution of bromohydrin 7 (354 mg, 0.5 mmol) in
anhydrous acetonitrile (2.5 mL). The reaction mixture was
stirred for 1 h when TLC examination revealed complete con-
version of starting material. Diethy ether (3 mL) was added to
the reaction mixture and the precipitated solids were filtered
through a pad of Celite. The filtrate was evaporated in vacuo to
afford a crude product that was purified by column chromatog-
raphy with use of 40% EtOAc/hexane (v/v) as the eluent to
afford the aziridine 29 (289 mg, 0.46 mmol) in 92% yield as a
gummy liquid. TLC: Rf 0.3 (45% EtOAc/hexane). [R]25D -88 (c
1, CHCl3). IR (neat): 3361, 2927, 2855, 1718, 1543, 1452, 1363,
1
1167, 1088, 1033, 740 cm-1. H NMR (400 MHz, CDCl3): δ
Compound 8. To a stirred solution of sulfinamide 23a (10.28 g,
19.36 mmol) in MeOH (97 mL) was added HCl in dioxane (4 M,
9.7 mL, 38.7 mmol). The reaction mixture was stirred for 3 h and
then the solvent was evaporated under reduced pressure. The
residue was dissolved in dichloromethane (97 mL) and Et3N (8.2
mL, 58.1 mmol) was added followed by o-nitrobenzenesulfonyl
chloride (5.14 g, 23.2 mmol) in portions. The reaction mixture
was stirred for 30 min and water (60 mL) was added. The clear
layers were separated and the aqueous layer was extracted once
with dichloromethane (60 mL). The combined organic layers
were washed with brine and dried over Na2SO4. The solvent was
evaporated under reduced pressure to afford a crude product
that was purified by column chromatography with use of 8%
EtOAc/CHCl3 (v/v) as the eluent to afford the sulfonamide 8
(8.26 g, 13.5 mmol) in 70% yield as a gummy liquid. TLC: Rf
0.35 (20% EtOAc/CHCl3). [R]25D þ14 (c 1, CHCl3). IR (neat):
3092, 2927, 2854, 1541, 1449, 1355, 1167, 1092, 1038, 737, 590
8.24-8.22 (m, 1H), 7.79-7.72 (m, 3H), 7.49 (d, J=8.1 Hz, 2H),
7.35-7.27 (m, 7H), 4.50 (s, 2H), 3.82-3.76 (m, 1H), 3.55 (q, J=
7.3 Hz, 1H), 3.46 (t, J=6.6 Hz, 2H), 3.34 (dd, J=7.3, 13.1 Hz,
1H), 3.25 (dd, J=6.6, 13.1 Hz, 1H), 3.21-3.18 (m, 1H þ OH),
2.40 (s, 3H), 1.64-1.53 (m, 4H), 1.50-1.21 (m, 10H). MS (ESI):
651 [M þ Na]þ. HRMS (ESI): m/z [M þ Na]þ calcd for
C32H40N2O7NaS2 651.2174, found 651.2189.
Compound 30. To a solution of sulfonamide 8 (4.76 g, 7.78
mmol) in anhydrous acetonitrile (39 mL) was added anhydrous
K2CO3 (1.3 g, 9.3 mmol) followed by neat benzyl bromide (1.1
mL, 9.3 mmol). The reaction mixture was stirred for 8 h when
TLC examination revealed complete conversion of starting
material. Diethyl ether (40 mL) was added to the reaction
mixture and the precipitated solids were filtered through a pad
of Celite. The filtrate was evaporated under reduced pressure to
afford a crude product that was purified by column chromato-
graphy with use of 30% EtOAc/hexane (v/v) as the eluent to
afford the sulfonamide 30 (5.2 g, 7.4 mmol) in 95% yield as a
gummy liquid. TLC: Rf 0.35 (50% EtOAc/hexane). [R]25D þ68
(c 1, CHCl3). IR (neat): 3029, 2928, 2854, 1543, 1453, 1367, 1163,
1092, 1045, 742, 700, 586 cm-1. 1H NMR (400 MHz, CDCl3): δ
7.96 (d, J=7.7 Hz, 1H), 7.69-7.59 (m, 3H), 7.36-7.30 (m, 8H),
7.29-7.22 (m, 6H), 5.64-5.56 (m, 1H), 5.50 (dd, J=7.7, 15.4 Hz,
1H), 4.69-4.65 (m, 1H), 4.65 (d, J=15.4 Hz, 1H), 4.49 (s, 2H),
4.46 (d, J=15.4 Hz, 1H), 3.46 (t, J=6.8 Hz, 2H), 2.89 (dd, J=3.4,
12.9 Hz, 1H), 2.65 (dd, J=11.2, 12.9 Hz, 1H), 2.40 (s, 3H), 1.95
(q, J=6.8 Hz, 2H), 1.61 (qui, J=6.8 Hz, 2H), 1.39-1.31 (m, 2H),
1.30-1.16 (m, 10H). 13C NMR (100 MHz, CDCl3): δ 147.7,
141.5, 140.6, 138.8, 138.7, 137.1, 133.8, 133.3, 131.8, 131.1,
129.9, 128.6, 128.3, 128.26, 127.8, 127.5, 127.4, 124.1, 124.0,
123.8, 72.7, 70.4, 61.2, 56.0, 49.6, 32.2, 29.8, 29.3, 29.27, 28.9,
28.5, 26.1, 21.3. MS (ESI): 703 [M þ H]þ. HRMS (ESI): m/z
[M þ Na]þ calcd for C39H46N2O6NaS2 725.2695, found 725.2694.
Compound 31. To a solution of sulfonamide 30 (5.2 g, 7.4
mmol) in toluene (37 mL) was added water (266 μL, 14.8 mmol)
followed by N-bromosuccinimide (1.6 g, 8.9 mmol). The reac-
tion mixture was stirred at room temperature for 2 h and then
quenched with aqueous saturated NaHCO3 solution (25 mL).
The two layers were separated and the aqueous layer was
extracted with EtOAc (2 ꢀ 25 mL). The combined organic
layers were successively washed with water and brine and dried
over Na2SO4. Evaporation of the solvent under reduced pres-
sure afforded a crude product that was purified by column
chromatography with use of 35% EtOAc/hexane (v/v) as the
eluent to furnish the bromohydrin 31 (4.6 g, 5.8 mmol) in 78%
yield as a gummy liquid. TLC: Rf 0.3 (50% EtOAc/hexane).
cm-1 1H NMR (400 MHz, CDCl3): δ 8.11-8.09 (m, 1H),
.
7.88-7.84 (m, 1H), 7.74-7.69 (m, 2H), 7.53 (d, J = 8.7 Hz,
2H), 7.36-7.25 (m, 7H), 5.76 (d, J=7.1 Hz, NH), 5.60-5.53 (m,
1H), 5.28 (dd, J=8.7, 15.8 Hz, 1H), 4.49 (s, 2H), 4.39-4.32 (m,
1H), 3.46 (t, J=7.1 Hz, 2H), 3.18 (dd, J=6.3, 13.4 Hz, 1H), 2.85
(dd, J=8.7, 13.4 Hz, 1H), 2.42 (s, 3H), 1.80 (q, J=6.3 Hz, 2H),
1.60 (qui, J=6.3 Hz, 2H), 1.37-1.07 (m, 10H). 13C NMR (100
MHz, CDCl3): δ 147.2, 141.2, 139.6, 138.2, 135.6, 133.9, 133.0,
132.2, 130.7, 129.5, 127.8, 127.1, 126.9, 125.4, 124.4, 123.8, 72.2,
69.9, 62.3, 52.8, 31.3, 29.2, 28.8, 28.7, 28.4, 28.0, 25.6, 20.9. MS
(LC-MSD): 613 [M þ H]þ. HRMS (ESI): m/z [M þ H]þ calcd
for C32H41N2O6S2 613.2406, found 613.2399.
Compound 7. To a solution of sulfonamide 8 (3.5 g, 5.72
mmol) in toluene (28 mL) was added water (206 μL, 11.4 mmol)
followed by N-bromosuccinimide (1.22 g, 6.86 mmol). The
reaction mixture was stirred at room temperature for 15 min
and then quenched by adding aqueous saturated NaHCO3
solution (20 mL). The two layers were separated and the
aqueous layer was extracted with EtOAc (2 ꢀ 20 mL). The
combined organic layers were successively washed with water
and brine and dried over Na2SO4. Evaporation of the solvent
afforded a crude product that was purified by column chroma-
tography with use of 35% EtOAc/hexane (v/v) as the eluent to
furnish the bromohydrin 7 (3.2 g, 4.52 mmol) in 79% yield as a
gummy liquid. TLC: Rf 0.35 (50% EtOAc/hexane). [R]25D -4.6
(c 1.5, CHCl3). IR (neat): 3359, 2927, 2855, 1711, 1540, 1357,
1167, 1086, 1029, 738 cm-1. 1H NMR (400 MHz, CDCl3): δ 8.32
(d, J=8.1 Hz, 1H), 7.91 (d, J=7.3 Hz, 1H), 7.83-7.73 (m, 2H),
7.35-7.25 (m, 9H), 5.80 (d, J=10.2 Hz, NH), 4.79-4.71 (m,
756 J. Org. Chem. Vol. 75, No. 3, 2010

Raghavan and Krishnaiah
JOCArticle
[R]25D -79 (c 1, CHCl3). IR (neat): 3402, 3029, 2929, 2855, 1712,
Compound 38. To a stirred solution of epoxide 32 (2 g, 2.78
mmol) in dichloromethane (14 mL) cooled at 0 °C was added
Et3N (1.6 mL, 11.1 mmol) followed by TFAA (1.6 mL, 11.1
mmol) dropwise. The reaction mixture was stirred for 1 h at 0 °C,
aqueous saturated NaHCO3 solution (12 mL) was added, and
the mixture was stirred further for 15 min. NaBH4 (630 mg, 16.7
mmol) was added to the reaction mixture in portions and
stirring was continued for 15 min. The two layers were separated
and the aqueous layer was extracted once with dichloromethane
(15 mL). The combined organic layers were washed with water
and brine and dried over Na2SO4. The solvent was evaporated
under reduced pressure to afford a crude product that was
purified by column chromatography with use of 35% EtOAc/
hexane (v/v) as the eluent to afford the hydroxy compound 38
(1.3 g, 2.17 mmol) in 78% yield as a gummy liquid. TLC: Rf 0.3
(55% EtOAc/hexane). [R]25D þ6.8 (c 1, CHCl3). IR (neat): 3441,
1543, 1367, 1164, 1090, 1032, 750, 702 cm-1. H NMR (300
1
MHz, CDCl3): δ 8.05 (d, J=7.7 Hz, 1H), 7.73-7.60 (m, 3H),
7.36-7.31 (m, 6H), 7.29-7.21 (m, 8H), 4.90-4.84 (m, 1H), 4.87
(d, J=16.4 Hz, 1H), 4.71 (d, J=16.4 Hz, 1H), 4.50 (s, 2H), 3.98
(dd, J=6.6, 8.1 Hz, 1H), 3.85 (dt, J=1.8, 8.1 Hz, 1H), 3.46 (t, J=
6.6 Hz, 2H), 3.26 (dd, J=6.0, 13.7 Hz, 1H), 2.91 (dd, J=5.5, 13.7
Hz, 1H), 2.39 (s, 3H), 1.61 (qui, J=6.6 Hz, 2H), 1.50-1.16 (m,
12H). 13C NMR (100 MHz, CDCl3): δ 147.4, 141.3, 139.2, 138.2,
137.0, 133.8, 132.4, 132.0, 131.6, 129.6, 128.3, 127.9, 127.5,
127.2, 127.0, 123.6, 123.3, 72.3, 71.0, 70.0, 60.4, 55.2, 49.5,
33.9, 29.3, 29.2, 29.04, 28.98, 28.8, 25.7, 24.5, 20.9. MS (ESI):
799 [M þ H]þ. HRMS (ESI): m/z [M þ Na]þ calcd for
C39H47N2O7NaS2Br 821.1905, found 821.1925.
Compound 32. Anhydrous K2CO3 (0.97 g, 7 mmol) was added
to a solution of bromohydrin 31 (4.6 g, 5.8 mmol) in anhydrous
acetonitrile (29 mL). The reaction mixture was stirred for 6 h
when TLC examination revealed complete conversion of start-
ing material. Diethyl ether (25 mL) was added to the reaction
mixture and the precipitated solids were filtered through a pad
of Celite. The filtrate was evaporated under reduced pressure to
afford a crude product that was purified by column chromato-
graphy with use of 35% EtOAc/hexane (v/v) as the eluent to
afford the epoxide 32 (3.9 g, 5.5 mmol) in 95% yield as a gummy
3028, 2930, 2856, 1543, 1454, 1366, 1163, 1097, 882, 740 cm-1
.
1H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 8.2 Hz, 1H),
7.67-7.53 (m, 3H), 7.41 (d, J = 6.3 Hz, 2H), 7.34-7.22 (m,
8H), 4.87 (d, J=15.3 Hz, 1H), 4.50 (s, 2H), 4.49 (d, J=15.3 Hz,
1H), 3.80-3.72 (m, 3H), 3.46 (t, J=7.0 Hz, 2H), 2.89-2.86 (m,
1H), 2.40-2.38 (m, 1H), 1.97-1.90 (m, 1H), 1.65-1.57 (m, 3H),
1.39-1.21 (m, 10H). 13C NMR (75 MHz, CDCl3): δ 147.5,
138.4, 137.0, 133.4, 133.35, 131.6, 131.0, 128.5, 128.4, 128.2,
127.8, 127.4, 127.3, 123.9, 72.6, 70.3, 61.4, 60.0, 57.7, 56.7, 49.0,
31.1, 29.5, 29.2, 29.1, 29.05, 25.9, 25.3. MS (ESI): 597 [M þ H]þ.
HRMS (ESI): m/z [M þ Na]þ calcd for C32H40N2O7NaS
619.2453, found 619.2465.
liquid. TLC: Rf 0.3 (50% EtOAc/hexane). [R]25 -89 (c 1,
D
CHCl3). IR (neat): 3453, 3028, 2929, 2855, 1714, 1544, 1455,
1367, 1164, 1090, 1045, 927, 741, 582 cm-1. 1H NMR (400 MHz,
CDCl3): δ 8.08 (d, J=8.1 Hz, 1H), 7.74-7.64 (m, 3H), 7.45 (d,
J=7.3 Hz, 2H), 7.36-7.30 (m, 7H), 7.29-7.17 (m, 5H), 4.78 (d,
J = 15.4 Hz, 1H), 4.71 (d, J = 15.4 Hz, 1H), 4.50 (s, 2H),
4.17-4.11 (m, 1H), 3.46 (t, J=6.6 Hz, 2H), 2.84 (dd, J=9.5,
13.9 Hz, 1H), 2.69 (dd, J=4.4, 13.9 Hz, 1H), 2.64-2.57 (m, 2H),
2.38 (s, 3H), 1.65-1.57 (m, 2H), 1.39-1.16 (m, 12H). 13C NMR
(100 MHz, CDCl3): δ 147.3, 141.0, 139.6, 138.2, 136.7, 133.8,
132.2, 131.6, 131.2, 129.4, 128.4, 128.3, 127.8, 127.7, 127.0,
126.9, 123.8, 123.2, 72.3, 70.0, 57.9, 57.8, 57.0, 54.8, 49.6, 30.8,
29.4, 29.0, 28.9, 28.8, 25.8, 25.1, 21.0. MS (LC-MSD): 719 [M þ
H]þ. HRMS (ESI): m/z [M þ H]þ calcd for C39H47N2O7S2
719.2824, found 719.2834.
Compound 39. To a solution of hydroxy compound 38 (1.3 g,
2.17 mmol) in dioxane (11 mL) was added aqueous H2SO4
solution (3 M, 2.2 mL, 6.5 mmol). The reaction mixture was
stirred for 8 h at 70 °C and then allowed to cool to room
temperature. EtOAc (15 mL) was added and an excess of
aqueous saturated NaHCO3 solution was added dropwise.
The organic layer was separated and the aqueous layer was
extracted with EtOAc (2 ꢀ 15 mL). The combined organic
extracts were successively washed with water and brine, dried
over Na2SO4, and concentrated to dryness under reduced
pressure. The residue thus obtained was purified by column
chromatography with use of 45% EtOAc/hexane (v/v) as the
eluent to afford the triol 39 (1.18 g, 1.93 mmol) in 89% yield as a
gummy liquid. TLC: Rf 0.2 (65% EtOAc/hexane). [R]25D þ1.5 (c
1.1, CHCl3). IR (neat): 3399, 3029, 2929, 2855, 1543, 1455, 1368,
1161, 1096, 1027, 740 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.92
(d, J=8.2 Hz, 1H), 7.67-7.54 (m, 3H), 7.42 (d, J=6.7 Hz, 2H),
7.34-7.23 (m, 8H), 4.83 (d, J=15.6 Hz, 1H), 4.64 (d, J=15.6 Hz,
1H), 4.50 (s, 2H), 4.12 (dt, J=2.9, 6.7 Hz, 1H), 3.85 (dd, J=5.9,
11.9 Hz, 1H), 3.79-3.74 (m, 2H), 3.55-3.51 (m, 1H), 3.46 (t, J=
6.7 Hz, 2H), 1.64-157 (m, 2H), 1.44-1.14 (m, 12H). 13C NMR
(100 MHz, CDCl3): δ 147.5, 138.4, 137.3, 133.4, 133.35, 131.6,
131.3, 128.4, 128.3, 128.2, 127.6, 127.5, 127.4, 124.0, 76.6, 73.3,
72.7, 70.4, 59.9, 59.3, 49.8, 32.3, 29.5, 29.3, 29.2, 26.0, 25.8. MS
(ESI): 615 [M þ H]þ. HRMS (ESI): m/z [M þ Na]þ calcd for
C32H42N2O8NaS 637.2559, found 637.2588.
Compound 33. To a stirred solution of epoxide 32 (1.9 g, 2.65
mmol) in anhydrous dichloromethane (13 mL) cooled at -78 °C
was added neat BF3 Et2O (1 mL, 8 mmol) under an inert
3
atmosphere. Stirring was continued for 2 h before the reaction
mixture was warmed to -10 °C. After being stirred at this
temperature for 8 h, the reaction mixture was quenched with
aqueous saturated NaHCO3 solution (8 mL). The two layers
were separated and the aqueous layer was extracted once with
dichloromethane (10 mL). The combined organic layers were
successively washed with water and brine and dried over
Na2SO4. Evaporation of the solvent under reduced pressure
afforded a crude product that was purified by column chromato-
graphy with use of 30% EtOAc/hexane (v/v) as the eluent to
furnish the diol 33 (1.76 g, 2.4 mmol) in 90% yield as a gummy
liquid. TLC: Rf 0.3 (55% EtOAc/hexane). [R]25 -58 (c 0.8,
CHCl3). IR (neat): 3377, 3030, 2928, 2855, 1543, 1453, 1367,
.
1162, 1086, 1025, 937, 855, 738 cm-1 1H NMR (400 MHz,
D
Compound 41. To a stirred solution of a mixture of the triol 39
(1 g, 1.63 mmol) and imidazole (224 mg, 3.3 mmol) in anhydrous
dichloromethane (8 mL) was added TBDPS-Cl (0.5 mL, 1.95
mmol) at ambient temperature. The reaction mixture was stirred
for 6 h at room temperature and then water (6 mL) was added.
Two layers were separated and the aqueous phase was extracted
once with dichloromethane (8 mL). The combined organic
extracts were successively washed with brine and dried over
Na2SO4. Evaporation of the solvent under reduced pressure
afforded a crude product that was purified by column chromato-
graphy with use of 20% EtOAc/hexane (v/v) as the eluent to afford
the silyl ether 41 (1.32 g, 1.55 mmol) in 95% yield as a gummy
CDCl3): δ 8.23-8.21 (m, 1H), 7.73-7.67 (m, 3H), 7.46 (d, J=7.3
Hz, 2H), 7.34-7.18 (m, 12H), 4.85 (d, J = 16.1 Hz, 1H),
4.78-4.74 (m, 2H), 4.50 (s, 2H), 3.72-3.66 (m, 1H), 3.46 (t,
J=6.6 Hz, 2H), 3.38-3.32 (m, 1H), 3.03 (dd, J=4.4, 13.9 Hz,
1H), 2.84 (dd, J=7.3, 13.9 Hz, 1H), 2.53 (d, J=4.4 Hz, OH), 2.38
(s, 3H), 1.60 (qui, J = 6.6 Hz, 2H), 1.41-1.09 (m, 12H). 13C
NMR (100 MHz, CDCl3): δ 147.8, 141.6, 139.6, 138.6, 138.0,
133.9, 133.0, 132.8, 132.1, 129.9, 128.8, 128.4, 128.3, 127.8,
127.6, 127.4, 124.1, 123.6, 77.3, 72.8, 72.3, 70.4, 57.5, 54.4,
49.8, 32.7, 29.7, 29.5, 29.3, 26.1, 25.5, 21.3. MS (ESI): 737
[M þ H]þ. HRMS (ESI): m/z [M þ Na]þ calcd for C39H48N2O8-
NaS2 759.2749, found 759.2720.
liquid. TLC: Rf 0.25 (30% EtOAc/hexane). [R]25 þ16 (c 1,
D
CHCl3). IR (neat): 3562, 3068, 3029, 2931, 2856, 1544, 1460,
J. Org. Chem. Vol. 75, No. 3, 2010 757

Raghavan and Krishnaiah
JOCArticle
1430, 1367, 1163, 1108, 822, 742 cm-1
.
1H NMR (400 MHz,
Compound 45. To a stirred solution of disilyl ether 43 (1.37 g,
1.31 mmol) in acetone (7 mL) was added DBU (0.58 mL, 3.9
mmol) followed by 2-mercaptoethanol (0.18 mL, 2.6 mmol).
The reaction mixture was stirred for 8 h at room temperature
and then acetone was evaporated under reduced pressure. The
residue thus obtained was suspended in water (8 mL) and
extracted with CHCl3 (3 ꢀ 10 mL). The combined organic
extracts were successively washed with water and brine and
dried over Na2SO4. Evaporation of the solvent in vacuo af-
forded a crude product that was purified by column chromato-
graphy with use of 5% EtOAc/hexane (v/v) as the eluent to
furnish the azetidine 45 (908 mg, 1.19 mmol) in 91% yield as a
gummy liquid. TLC: Rf 0.3 (10% EtOAc/hexane). [R]25D þ28 (c
1.1, CHCl3). IR (neat): 3028, 2930, 2855, 1589, 1492, 1457, 1363,
1213, 1110, 1008, 736, 701 cm-1. 1H NMR (400 MHz, CDCl3): δ
7.70-7.66 (m, 4H), 7.43-7.32 (m, 8H), 7.30-7.16 (m, 8H), 4.50
(s, 2H), 4.48-4.45 (m, 1H), 3.90 (d, J=14.3 Hz, 1H), 3.81 (d, J=
14.3 Hz, 1H), 3.75-3.69 (m, 2H), 3.67-3.62 (m, 1H), 3.44 (t, J=
6.3 Hz, 2H), 3.40-3.36 (m, 1H), 1.62-1.55 (m, 2H), 1.39-1.16
(m, 12H), 1.06 (s, 9H), 0.90 (t, J=7.9 Hz, 9H), 0.53 (q, J=7.9 Hz,
6H). 13C NMR (75 MHz, CDCl3): δ 140.3, 138.7, 135.6, 135.5,
133.4, 133.2, 129.5, 128.2, 128.0, 127.7, 127.6, 127.5, 127.4,
127.3, 126.2, 72.7, 70.4, 66.5, 66.0, 63.6, 53.6, 29.8, 29.7, 29.4,
29.3, 26.8, 26.6, 26.1, 24.9, 19.1, 6.7, 4.7. MS (ESI): 764 [M þ
H]þ. HRMS (ESI): m/z [M þ H]þ calcd for C48H70NO3Si2
764.4894, found 764.4902.
Compound 46. To a mixture of azetidine 45 (908 mg, 1.19
mmol) and (Boc)2O (312 mg, 1.43 mmol) in a mixture of EtOAc
and MeOH (1:1, 6 mL) was added Pd(OH)2 (91 mg, 10% by wt).
The reaction mixture was evacuated, subsequently filled with
H2, and stirred for 12 h at atmospheric pressure. The solid
catalyst was filtered through a small pad of Celite and washed
with ethyl acetate. Evaporation of the solvent in vacuo afforded
a crude product that was purified by column chromatography
with use of 15% EtOAc/hexane (v/v) as the eluent to furnish the
hydroxy compound 46 (717 mg, 1.05 mmol) in 88% yield as a
viscous liquid. TLC: Rf 0.3 (30% EtOAc/hexane). [R]25D þ47 (c
1, CHCl3). IR (neat): 3430, 2930, 2862, 1683, 1408, 1246, 1111,
1010, 745 cm-1. 1H NMR (400 MHz, CDCl3) (mixture of two
rotamers): δ 7.69-7.61 (m, 8H), 7.46-7.33 (m, 12H), 4.65-4.52
(m, 2H), 4.42-4.38 (m, 1H), 4.31-4.17 (m, 2H), 4.08-4.01 (m,
1H), 3.96-3.75 (m, 3H), 3.70-3.56 (m, 5H), 1.60-1.52 (m, 4H),
1.46 (s, 9H), 1.40-1.23 (m, 33H), 1.06 (s, 18H), 0.99-0.95 (m,
9H), 0.94-0.87 (m, 9H), 0.62-0.57 (m, 6H), 0.55-0.48 (m, 6H).
13C NMR (75 MHz, CDCl3) (mixture of two rotamers): δ 155.1,
154.8, 135.5, 133.3, 133.0, 132.9, 129.6, 127.5, 78.9, 78.8, 71.3,
70.7, 65.8, 65.3, 65.1, 64.9, 62.6, 62.5, 61.1, 59.7, 32.6, 32.5, 29.7,
29.5, 29.3, 28.4, 28.3, 28.1, 26.7, 25.8, 25.7, 19.2, 6.6, 5.7, 4.5, 4.3.
MS (ESI): 706 [M þ Na]þ. HRMS (ESI): m/z [M þ Na]þ calcd
for C39H65NO5NaSi2 706.4299, found 706.4298.
CDCl3): δ 7.95 (d, J=8.0 Hz, 1H), 7.58-7.50 (m, 6H), 7.46-7.33
(m, 10H), 7.28-7.19 (m, 7H), 4.79 (d, J=16.1 Hz, 1H), 4.64 (d, J=
16.1 Hz, 1H), 4.50 (s, 2H), 4.29 (dt, J=1.4, 6.5 Hz, 1H), 3.87-3.80
(m, 2H), 3.73 (dd, J=2.2, 6.5 Hz, 1H), 3.46 (t, J=6.5 Hz, 2H), 3.32
(t, J=6.6 Hz, 1H), 1.60 (qui, J=6.5 Hz, 2H), 1.41-1.12 (m, 12H),
0.96 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 147.8, 138.5, 137.4,
135.5, 135.4, 133.6, 133.1, 132.1, 131.4, 131.0, 129.9, 129.8, 128.5,
128.3, 128.2, 127.7, 127.66, 127.4, 127.3, 123.9, 77.47, 72.9, 72.7,
70.3, 61.4, 60.4, 50.2, 32.9, 29.6, 29.3, 29.2, 26.7, 26.0, 25.5, 18.8.
MS (ESI): 852.9 [M þ H]þ. HRMS(ESI):m/z[M þ Na]þ calcd for
C48H60N2O8NaSiS 875.3737, found 875.3757.
Compound 42. In a 25 mL round-bottomed flask equipped
with a magnetic stirbar, rubber septum, and nitrogen inlet were
placed silyl ether 41 (1.32 g, 1.55 mmol) and Et3N (0.44 mL, 3.1
mmol) in anhydrous dichloromethane (10 mL). The reaction
mixture was cooled at 0 °C and MsCl (1 M in CH2Cl2, 2.3 mL,
2.3 mmol) was added dropwise over a period of 10 min. The
resulting mixture was stirred for 15 min at 0 °C and then water (6
mL) was added. The clear layers were separated and the aqueous
phase was extracted once with dichloromethane (8 mL). The
combined organic extracts were successively washed with water
and brine and dried over Na2SO4. Evaporation of the solvent
under reduced pressure afforded a crude product that was
purified by flash column chromatography with use of 2%
EtOAc/CHCl3 (v/v) as the eluent to afford the mesylate 42
(1.3 g, 1.4 mmol) in 90% yield as a gummy liquid. TLC: Rf 0.25
(4% EtOAc/CHCl3). [R]25 þ2 (c 1, CHCl3). IR (neat): 3551,
D
3068, 3030, 2931, 2856, 1544, 1461, 1430, 1351, 1169, 1108, 910,
738 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.87 (d, J=8.0 Hz,
1H), 7.61-7.53 (m, 6H), 7.48-7.33 (m, 10H), 7.29-7.19 (m,
7H), 4.85 (d, J=15.3 Hz, 1H), 4.68-4.62 (m, 1H), 4.61 (d, J=
15.3 Hz, 1H), 4.50 (s, 2H), 4.20-4.11 (m, 2H), 4.02-3.93 (m,
2H), 3.46 (t, J=6.5 Hz, 2H), 2.83 (s, 3H), 1.64-1.57 (m, 2H),
1.38-1.13 (m, 12H), 0.96 (s, 9H). 13C NMR (75 MHz, CDCl3): δ
147.8, 138.6, 136.8, 135.6, 135.55, 134.7, 133.6, 133.2, 132.3,
132.1, 131.6, 131.0, 130.0, 129.9, 128.7, 128.4, 128.2, 127.9,
127.8, 127.5, 127.4, 123.9, 84.0, 75.0, 72.7, 70.4, 62.2, 60.2,
50.3, 38.1, 30.2, 29.6, 29.3, 29.1, 26.7, 26.5, 26.0, 24.9, 18.8.
MS (ESI): 953 [M þ Na]þ. HRMS (ESI): m/z [M þ Na]þ calcd
for C49H62N2O10NaSiS2 953.3512, found 953.3490.
Compound 43. To a stirred solution of mesylate 42 (1.3 g, 1.4
mmol) in anhydrous dichloromethane (7 mL) cooled at 0 °C was
added 2,6-lutidine (0.4 mL, 3.5 mmol) followed by TES-OTf
(0.48 mL, 2.1 mmol) dropwise over a period of 10 min. The
resulting mixture was stirred for 15 min at 0 °C and then diluted
with water (6 mL). The two layers were separated and the
aqueous layer was extracted once with dichloromethane (6
mL). The combined organic layers were washed with brine,
dried over Na2SO4, and concentrated to dryness under reduced
pressure to afford a crude product that was purified by column
chromatography with use of 8% EtOAc/hexane (v/v) as the
eluent to afford the disilyl ether 43 (1.37 g, 1.31 mmol) in 94%
yield as a gummy liquid. TLC: Rf 0.5 (20% EtOAc/hexane).
Compound 4. To a solution of hydroxy compound 46 (717 mg,
1.05 mmol) in dichloromethane (7 mL) cooled at 0 °C was added
IBX (353 mg, 1.26 mmol) in DMSO (2.1 mL) and the reaction
mixture was allowed to warm to room temperature gradually
and stirred further for a period of 1 h when TLC examination
revealed completion of the reaction. The reaction mixture was
then diluted with dichloromethane (5 mL) and the precipitated
solid was filtered through a pad of Celite. The filtrate was
washed successively with water (2 ꢀ 10 mL) and brine and dried
over anhydrous Na2SO4. Evaporation of the solvent in vacuo
afforded a crude product that was purified by column chromato-
graphy with use of 8% EtOAc/hexane (v/v) as the eluent to
furnish the aldehyde 4 (640 mg, 0.94 mmol) in 90% yield as a
[R]25 -20 (c 1.05, CHCl3). IR (neat): 3067, 3029, 2933, 2858,
D
1
1546, 1460, 1357, 1171, 1111, 1005, 908, 740 cm-1. H NMR
(300 MHz, CDCl3): δ 7.97-7.77 (m, 1H), 7.62-7.57 (m, 5H),
7.47-7.32 (m, 10H), 7.30-7.15 (m, 8H), 4.89-4.74 (m, 1H),
4.69-4.55 (m, 3H), 4.50 (s, 2H), 4.19-4.04 (m, 2H), 3.90-3.71
(m, 1H), 3.47 (t, J=6.7 Hz, 2H), 2.89 (s, 3H), 1.67-1.58 (m, 2H),
1.41-1.17 (m, 12H), 0.99 (s, 9H), 0.69 (t, J = 8.3 Hz, 9H),
0.40-0.24 (m, 6H). 13C NMR (75 MHz, CDCl3): δ 148.5, 138.6,
135.5, 135.4, 133.3, 133.2, 132.5, 131.3, 130.9, 130.8, 129.9,
129.8, 129.2, 128.5, 128.2, 127.7, 127.69, 127.4, 127.3, 123.4,
85.0, 74.9, 72.7, 70.4, 61.7, 60.2, 48.7, 38.1, 31.4, 29.6, 29.4, 29.3,
29.2, 26.8, 26.0, 25.4, 18.8, 6.6, 4.5. MS (ESI): 1062 [M þ
(NH4)þ]þ. HRMS (ESI): m/z [M þ (NH4)þ]þ calcd for
C55H80N3O10Si2S2 1062.4818, found 1062.4819.
viscous liquid. TLC: Rf 0.4 (20% EtOAc/hexane). [R]25 þ46 (c
D
1, CHCl3). IR (neat): 3060, 2932, 2864, 1696, 1462, 1398, 1245,
1
1110, 1008, 702 cm-1. H NMR (300 MHz, CDCl3) (mixture of
two rotamers): δ 9.76 (s, 2H), 7.74-7.61 (m, 8H), 7.46-7.33 (m,
12H), 4.65-4.55 (m, 2H), 4.45-4.38 (m, 1H), 4.28-4.16 (m, 2H),
758 J. Org. Chem. Vol. 75, No. 3, 2010

Raghavan and Krishnaiah
JOCArticle
4.08-4.00 (m, 1H), 3.92-3.80 (m, 2H), 3.72-3.64 (m, 1H),
3.61-3.53 (m, 1H), 2.46-2.37 (m, 4H), 1.69-1.54 (m, 4H), 1.46
(s, 9H), 1.41-1.22 (m, 33H), 1.08 (s, 9H), 1.06 (s, 9H), 0.97-0.83
(m, 18H), 0.56-0.46 (m, 12H). 13C NMR (75 MHz, CDCl3)
(mixture of two rotamers): δ 202.5, 155.0, 154.8, 135.6, 133.4,
133.2, 133.0, 132.9, 129.6, 129.5, 127.6, 78.7, 71.3, 70.7, 65.8, 65.4,
65.2, 64.8, 61.2, 59.8, 43.8, 29.6, 29.2, 29.0, 28.5, 28.3, 28.1, 27.0,
26.8, 26.7, 25.8, 22.0, 19.2, 6.6, 4.6. MS (ESI): 682 [M þ H]þ.
HRMS (ESI): m/z [M þ Na]þ calcd for C39H63NO5NaSi2
704.4142, found 704.4144.
Compound 66. To a stirred suspension of LAH (228 mg, 6
mmol) in anhydrous THF (15 mL) cooled at 0 °C was added the
solution of tosylate 65 (2.13 g, 5.04 mmol) in anhydrous THF
(10 mL) under nitrogen atmosphere. The reaction mixture was
stirred at the same temperature for 20 min. After diluting the
reaction mixture with diethyl ether (20 mL), it was quenched by
adding small ice pieces. The resulting suspension was filtered
through a pad of Celite, then the residue was washed with
diethyl ether (3 ꢀ 15 mL). The filtrates were concentrated under
reduced pressure and the residue was purified by column
chromatography with use of 13% EtOAc/hexane (v/v) as the
eluent to furnish the alcohol 66 (1.14 g, 4.53 mmol) in 90% yield
Compound 58. To a suspension of CuI (209 mg, 1.1 mmol) in
anhydrous THF (150 mL) cooled at -78 °C was added EtMgBr
(2 M in diethyl ether, 22 mL, 44 mmol) under nitrogen atmo-
sphere. After the reaction mixture was stirred for 30 min
at -78 °C, epoxide 57 (2.62 g, 11 mmol) in anhydrous THF
(20 mL) was added dropwise. The reaction mixture was allowed
to warm to -30 °C gradually and stirred further until no
remaining starting material could be detected by TLC (ca.
3 h). The reaction was quenched with a mixture of NH4Cl and
NH4OH (9:1, 30 mL) and stirred for 1.5 h. The clear layers were
separated and the aqueous layer was extracted with EtOAc (2 ꢀ
40 mL). The combined organic extracts were washed with brine,
dried over Na2SO4, and concentrated under reduced pressure.
The residue, a mixture of 1,3- and 1,2-diols (9:1), was dissolved
in THF (25 mL) then cooled to 0 °C and a solution of NaIO4
(706 mg, 3.3 mmol) in water (8 mL) was added dropwise. The
reaction mixture was allowed to attain rt and stirred further for a
period of 6 h. The precipitated solids were filtered through
Celite, then the filtrate was diluted with EtOAc and washed
with water and brine and dried over anhydrous Na2SO4.
Evaporation of the solvent in vacuo afforded a crude product
that was purified by column chromatography with use of 35%
EtOAc/hexane (v/v) as the eluent to afford the 1,3-diol 58 (2.5 g,
9.35 mmol) in 85% yield as a viscous oil. TLC: Rf 0.4 (50%
EtOAc/hexane). [R]25D þ1.8 (c 1, CHCl3). IR (neat): 3400, 2958,
2873, 1612, 1513, 1461, 1248, 1090, 1034, 820 cm-1. 1H NMR
(400 MHz, CDCl3): δ 7.24 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz,
2H), 4.46 (s, 2H), 3.90-3.85 (m, 2H), 3.80 (s, 3H), 3.75 (qui,
J = 4.7 Hz, 1H), 3.69-3.62 (m, 2H), 1.98-1.88 (m, 1H),
1.79-1.72 (m, 1H), 1.45-1.35 (m, 3H), 0.94 (t, J = 6.7 Hz,
3H). 13C NMR (75 MHz, CDCl3): δ 159.1, 129.7, 129.2, 113.7,
75.2, 72.9, 69.0, 63.5, 55.1, 46.4, 34.6, 21.1, 11.6. MS (ESI): 269
[M þ H]þ. HRMS (ESI): m/z [M þ Na]þ calcd for C15H24O4Na
291.1572, found 291.1563.
as a viscous liquid. TLC: Rf 0.4 (30% EtOAc/hexane). [R]25
D
þ3.9 (c 1, CHCl3). IR (neat): 3466, 2959, 2870, 1612, 1513, 1461,
1248, 1090, 1035, 821 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.25
(d, J=8.1 Hz, 2H), 6.87 (d, J=8.1 Hz, 2H), 4.45 (s, 2H), 3.80 (s,
3H), 3.70 (qui, J=4.7 Hz, 2H), 3.65-3.59 (m, 1H), 2.74 (d, J=
2.7 Hz, OH), 1.82-1.73 (m, 1H), 1.68-1.61 (m, 1H), 1.57-1.47
(m, 1H), 1.43-1.35 (m, 1H), 1.20-1.09 (m, 1H), 0.93-0.88 (m,
6H). 13C NMR (75 MHz, CDCl3): δ 159.2, 130.2, 129.3, 113.8,
74.1, 72.9, 69.2, 55.1, 40.4, 33.7, 25.6, 13.7, 11.9. MS (ESI): 253
[M þ H]þ. HRMS (ESI): m/z [M þ Na]þ calcd for C15H24O3Na
275.1623, found 275.1626.
Compound 67. To a suspension of the sodium hydride (60% in
Nujol, 272 mg, 6.8 mmol) in anhydrous THF (8 mL) cooled at
0 °C was added n-tetrabutylammonium iodide (166 mg, 0.45
mmol) followed by dropwise addition of a solution of the
alcohol 66 (1.14 g, 4.53 mmol) in anhydrous THF (15 mL).
The reaction mixture was stirred allowing it to attain rt gradu-
ally over a period of 30 min. The reaction mixture was recooled
and neat benzyl bromide (0.65 mL, 5.43 mmol) was added
dropwise. The reaction mixture was stirred at room temperature
for 20 h under an atmosphere of nitrogen and then quenched
with aqueous NH4Cl solution (15 mL). The two layers were
separated and the aqueous layer was extracted with ethyl acetate
(2 ꢀ 15 mL). The combined organic layers were washed succes-
sively with water and brine and dried over Na2SO4. The solvent
was evaporated under reduced pressure to afford a crude
product that was purified by column chromatography with
use of 6% EtOAc/hexane (v/v) as the eluent to afford the benzyl
ether 67 (1.24 g, 3.62 mmol) in 80% yield as a viscous liquid.
TLC: Rf 0.4 (15% EtOAc/hexane). [R]25 -34 (c 1.1, CHCl3).
D
IR (neat): 3030, 2959, 2931, 2869, 1612, 1513, 1459, 1360, 1247,
1093, 1035, 819, 738 cm-1 1H NMR (400 MHz, CDCl3): δ
.
7.32-7.25 (m, 5H), 7.25 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz,
2H), 4.52 (d, J=11.7 Hz, 1H), 4.42 (d, J=11.7 Hz, 1H), 4.40 (s,
2H), 3.79 (s, 3H), 3.56-3.52 (m, 2H), 3.48-3.44 (m, 1H),
1.80-1.75 (m, 2H), 1.65-1.52 (m, 2H), 1.17-1.08 (m, 1H),
0.91-0.88 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 159.0,
139.0, 130.5, 129.2, 128.1, 127.5, 127.2, 113.6, 79.9, 72.4, 71.8,
66.9, 55.0, 37.7, 31.0, 24.7, 14.6, 12.0. MS (ESI): 365 [M þ Na]þ.
HRMS (ESI): m/z [M þ Na]þ calcd for C22H30O3Na 365.2092,
found 365.2089.
Compound 65. To a stirred solution of 1,3-diol 58 (1.5 g, 5.6
mmol) in dichloromethane (28 mL) was added NEt3 (1.6 mL,
11.2 mmol) followed by TsCl (1.6 g, 8.4 mmol). The reaction
mixture was stirred at room temperature for 20 h and then
quenched with aqueous saturated NaHCO3 solution. The two
layers were separated and the aqueous layer was extracted once
with EtOAc (20 mL). The combined organic extracts were
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue thus obtained was purified by
column chromatography with use of 25% EtOAc/hexane (v/v)
as the eluent to afford the tosylate 65 (2.13 g, 5.04 mmol) in 90%
yield as a gummy liquid. TLC: Rf 0.35 (40% EtOAc/hexane).
Compound 68. DDQ (985 mg, 4.34 mmol) was added portion-
wise over a period of 10 min to a solution of benzyl ether 67 (1.24
g, 3.62 mmol) in a mixture of dichloromethane (17.1 mL) and
water (0.9 mL) cooled at 0 °C. The reaction mixture was stirred
at the same temperature for 30 min and then diluted with
dichloromethane (15 mL). The precipitated solid was filtered,
then the filtrate was washed successively with aqueous saturated
NaHCO3 solution (2 ꢀ 20 mL), water, and brine and dried over
anhydrous Na2SO4. Evaporation of the solvent in vacuo af-
forded a crude product that was purified by column chroma-
tography with use of 15% EtOAc/hexane (v/v) as the eluent to
yield the alcohol 68 (755 mg, 3.4 mmol) in 94% yield as a gummy
[R]25 þ4.8 (c 1, CHCl3). IR (neat): 3489, 2961, 2872, 1609,
D
1
1513, 1358, 1247, 1177, 1093, 953, 817 cm-1. H NMR (400
MHz, CDCl3): δ 7.78 (d, J=7.9 Hz, 2H), 7.32 (d, J=7.9 Hz, 2H),
7.22 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 4.43 (s, 2H),
4.17-4.09 (m, 2H), 3.81 (s, 3H), 3.79-3.77 (m, 1H), 3.69 (qui,
J = 4.7 Hz, 1H), 3.61-3.56 (m, 1H), 2.43 (s, 3H), 1.79-1.67
(m, 2H), 1.60-1.53 (m, 1H), 1.47-1.39 (m, 1H), 1.38-1.28 (m,
1H), 0.84 (t, J=7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 158.9, 144.4, 132.5, 129.5, 129.48, 129.0, 127.5, 113.4, 72.5,
70.2, 69.4, 68.6, 54.8, 44.9, 33.5, 21.2, 19.8, 10.9. MS (ESI): 445
[M þ Na]þ. HRMS (ESI): m/z [M þ Na]þ calcd for C22H30O6-
NaS 445.1660, found 445.1665.
liquid. TLC: Rf 0.4 (30% EtOAc/hexane). [R]25 -38 (c 1.1,
D
CHCl3). IR (neat): 3393, 3031, 2960, 2874, 1457, 1377, 1062,
738, 697 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.37-7.27 (m,
J. Org. Chem. Vol. 75, No. 3, 2010 759

Raghavan and Krishnaiah
JOCArticle
5H), 4.61 (d, J = 11.7 Hz, 1H), 4.47 (d, J = 11.7 Hz, 1H),
3.76-3.72 (m, 2H), 3.52 (qui, J=4.4 Hz, 1H), 1.79-1.68 (m,
3H), 1.67-1.58 (m, 1H), 1.14-1.05 (m, 1H), 0.94-0.89 (m, 6H).
13C NMR (75 MHz, CDCl3): δ 138.4, 127.9, 127.2, 127.0, 81.3,
71.2, 59.8, 36.9, 32.5, 24.0, 14.5, 11.7. MS (ESI): 245 [M þ Na]þ.
HRMS (ESI): m/z [M þ Na]þ calcd for C14H22O2Na 245.1517,
found 245.1521.
gummy liquid. TLC: Rf 0.4 (10% EtOAc/hexane). [R]25D þ40 (c
1, CHCl3). IR (neat): 2928, 2879, 1697, 1459, 1398, 1244, 1109,
1007, 737, 701 cm-1. 1H NMR (400 MHz, CDCl3) (mixture of
two rotamers): δ 7.71-7.62 (m, 10H), 7.44-7.29 (m, 20H),
5.52-5.37 (m, 4H), 4.65-4.55 (m, 4H), 4.51-4.44 (m, 2H),
4.43-4.38 (m, 1H), 4.25-4.17 (m, 2H), 4.07-4.01 (m, 1H),
3.91-3.81 (m, 2H), 3.71-3.66 (m, 1H), 3.61-3.55 (m, 1H),
3.30-3.23 (m, 2H), 2.23-2.17 (m, 4H), 2.06-1.94 (m, 4H),
1.92-1.70 (m, 4H), 1.61-1.53 (m, 4H), 1.51-141 (m, 4H), 1.45
(s, 9H), 1.40-1.25 (m, 29H), 1.22-1.15 (m, 2H), 1.06 (s, 18H),
0.93-0.85 (m, 30H), 0.55-0.48 (m, 12H). 13C NMR (75 MHz,
CDCl3) (mixture of two rotamers): δ 155.1, 154.8, 139.2, 135.6,
133.5, 133.3, 133.1, 133.0, 132.6, 132.5, 129.7, 129.6, 129.5,
128.1, 127.6, 127.5, 127.2, 126.8, 82.8, 78.8, 71.7, 71.4, 70.7,
65.9, 65.5, 65.3, 65.0, 61.3, 59.9, 37.6, 34.3, 32.7, 29.8, 29.7,
29.50, 29.4, 29.2, 28.9, 28.5, 28.4, 28.1, 27.1, 26.8, 26.77, 25.9,
25.6, 19.3, 14.2, 11.9, 6.7, 4.6. MS (ESI): 892 [M þ Na]þ. HRMS
(ESI): m/z [M þ Na]þ calcd for C53H83NO5NaSi2 892.5707,
found 892.5726.
Compound 69. To a stirred solution of alcohol 68 (755 mg, 3.4
mmol) in anhydrous THF (17 mL) were added N-phenyltetra-
zolethiol (667 mg, 3.74 mmol) and triphenylphosphine (981 mg,
3.74 mmol). The resulting mixture was cooled at 0 °C and
diethylazodicarboxylate (0.58 mL, 3.74 mmol) was added drop-
wise under an atmosphere of nitrogen. The reaction mixture was
allowed to warm to room temperature gradually and stirred
further for 4 h. Evaporation of the solvent under reduced
pressure afforded a crude product that was purified by column
chromatography with use of 10% EtOAc/hexane (v/v) as the
eluent to afford the sulfide 69 (1.17 g, 3.06 mmol) in 90% yield as
a gummy liquid. TLC: Rf 0.4 (25% EtOAc/hexane). [R]25D -34
(c 1.3, CHCl3). IR (neat): 3452, 3063, 2961, 2930, 2873, 1596,
Compound 72. To a solution of alkene 71 (756 mg, 0.87 mmol)
in a mixture of EtOAc and MeOH (1:1, 4 mL) was added
Pd(OH)2 (76 mg, 10% by wt). The reaction mixture was
evacuated, subsequently filled with H2, and stirred for 2 h at
atmospheric pressure. The solid catalyst was filtered through a
small pad of Celite and washed with ethyl acetate. Evaporation
of the solvent in vacuo afforded a crude product that was
purified by column chromatography with use of 12% EtOAc/
hexane (v/v) as the eluent to furnish the hydroxy compound 72
(609 mg, 0.78 mmol) in 90% yield as a viscous oil. TLC: Rf 0.5
1
1499, 1457, 1387, 1243, 1019, 1068, 759, 694 cm-1. H NMR
(400 MHz, CDCl3): δ 7.57-7.53 (m, 5H), 7.35-7.29 (m, 5H),
4.58 (d, J=11.7 Hz, 1H), 4.47 (d, J=11.7 Hz, 1H), 3.52-3.38 (m,
3H), 2.09-1.92 (m, 2H), 1.77-1.68 (m, 1H), 1.66-1.56 (m, 1H),
1.15-1.05 (m, 1H), 0.93-0.89 (m, 6H). 13C NMR (100 MHz,
CDCl3): δ 154.2, 138.4, 133.4, 129.8, 129.5, 128.1, 127.5, 127.3,
123.4, 81.4, 71.5, 36.9, 30.1, 29.8, 24.2, 14.7, 11.9. MS (ESI):
383 [M þ H]þ. HRMS (ESI): m/z [M þ Na]þ calcd for
C21H26N4ONaS 405.1725, found 405.1741.
(25% EtOAc/hexane). [R]25 þ36 (c 0.8, CHCl3). IR (neat):
Compound 70. To a stirred solution of sulfide 69 (1.17 g, 3.06
mmol) in dichloromethane (15 mL) cooled at 0 °C was added
mCPBA (2.27 g, 9.2 mmol). The reaction mixture was allowed to
warm to room temperature gradually and stirred further for a
period of 4 h when TLC examination revealed complete con-
version of starting material. The reaction was quenched with an
aqueous saturated NaHSO3 solution (15 mL) and stirred for 20
min. The two layers were separated, then the organic layer was
washed with saturated NaHCO3 solution, water, and brine and
dried over Na2SO4. The solvent was evaporated under reduced
pressure to furnish a crude product that was purified by column
chromatography with use of 10% EtOAc/hexane (v/v) as the
eluent to afford the sulfone 70 (1.2 g, 2.9 mmol) in 95% yield as a
gummy liquid. TLC: Rf 0.4 (25% EtOAc/hexane). [R]25D -12 (c
1.1, CHCl3). IR (neat): 3031, 2963, 2931, 2875, 1595, 1497, 1342,
D
3452, 2928, 2858, 1695, 1461, 1404, 1245, 1111, 1008, 738, 703
cm-1. 1H NMR (300 MHz, CDCl3) (mixture of two rotamers): δ
7.72-7.63 (m, 8H), 7.47-7.33 (m, 12H), 4.65-4.56 (m, 2H),
4.44-4.37 (m, 1H), 4.27-4.16 (m, 2H), 4.08-4.00 (m, 1H),
3.91-3.81 (m, 2H), 3.71-3.64 (m, 1H), 3.60-3.57 (m, 1H),
3.55-3.48 (m, 2H), 1.91-1.80 (m, 2H), 1.51-1.38 (m, 18H),
1.36-1.15 (m, 44H), 1.08 (s, 9H), 1.06 (s, 9H), 0.93-0.85 (m,
30H), 0.56-0.46 (m, 12H). 13C NMR (75 MHz, CDCl3)
(mixture of two rotamers): δ 155.2, 154.8, 135.7, 133.5, 133.1,
133.0, 129.7, 129.6, 127.6, 78.8, 74.8, 71.4, 70.8, 65.9, 65.5, 65.3,
65.0, 61.3, 59.9, 39.9, 34.5, 29.9, 29.7, 29.6, 28.5, 28.4, 28.1, 27.1,
26.8, 26.3, 26.0, 25.9, 19.3, 13.2, 11.9, 6.7, 4.7. MS (ESI): 782
[M þ H]þ. HRMS (ESI): m/z [M þ Na]þ calcd for C46H79NO5-
NaSi2 804.5394, found 804.5381.
1151, 1070, 762, 693 cm-1 1H NMR (400 MHz, CDCl3): δ
.
Compound 73. To a stirred solution of disilyl ether 72 (609 mg,
0.78 mmol) in anhydrous THF (4 mL) cooled at 0 °C was added
tetrabutylammonium fluoride (1 M in THF, 2.3 mL, 2.3 mmol)
dropwise. The reaction mixture was allowed to warm to room
temperature gradually and stirred further for a period of 1 h
when TLC examination revealed complete conversion of start-
ing material. The solvent was evaporated under reduced pres-
sure and the residue thus obtained was purified by column
chromatography with use of 45% EtOAc/hexane (v/v) as the
eluent to afford the triol 73 (283 mg, 0.66 mmol) in 85% yield as
a gummy liquid. TLC: Rf 0.2 (65% EtOAc/hexane). [R]25D þ17
(c 0.7, CHCl3). IR (neat): 3386, 2926, 2855, 1666, 1413, 1369,
1252, 1159, 1094, 1032, 769 cm-1. 1H NMR (300 MHz, CDCl3):
δ 4.29-4.06 (m, 3H), 3.88-3.73 (m, 2H), 3.56-3.48 (m, 1H),
1.88-1.71 (m, 2H), 1.59-1.15 (m, 21H), 1.45 (s, 9H), 0.93-0.85
(m, 6H). 13C NMR (75 MHz, CDCl3): δ 156.7, 80.3, 74.9, 71.5,
65.7, 64.9, 64.2, 39.9, 34.4, 29.64, 29.6 29.5, 29.4, 28.4, 27.8,
26.2, 25.9, 25.88, 13.1, 11.8. MS (ESI): 430 [M þ H]þ. HRMS
(ESI): m/z [M þ Na]þ calcd for C24H47NO5Na 452.3351, found
452.3368.
7.71-7.57 (m, 5H), 7.34-7.26 (m, 5H), 4.57 (d, J=11.7 Hz, 1H),
4.47 (d, J=11.7 Hz, 1H), 3.85-3.77 (m, 1H), 3.72-3.65 (m, 1H),
3.44 (qui, J=4.4 Hz, 1H), 2.21-2.05 (m, 2H), 1.76-1.66 (m,
1H), 1.64-1.56 (m, 1H), 1.16-1.06 (m, 1H), 0.96-0.91 (m, 6H).
13C NMR (75 MHz, CDCl3): δ 153.3, 138.1, 132.9, 131.3, 129.5,
128.3, 127.64, 127.61, 125.0, 80.7, 71.5, 53.1, 37.0, 24.0, 22.9,
14.9, 11.8. MS (ESI): 437 [M þ Na]þ. HRMS (ESI): m/z
[M þ Na]þ calcd for C21H26N4O3NaS 437.1623, found 437.1628.
Compound 71. To a stirred solution of sulfone 70 (468 mg,
1.13 mmol) in anhydrous THF (11 mL) cooled at -78 °C was
added KHMDS (15% in toluene, 3 mL, 2.26 mmol) under
nitrogen atmosphere and the reaction mixture was stirred at
the same temperature for 1 h. A solution of aldehyde 4 (640 mg,
0.94 mmol) in anhydrous THF (3 mL) was added dropwise via a
syringe over a period of 10 min. The reaction mixture was stirred
for 15 min at -78 °C and then water (6 mL) was added. The clear
layers were separated and the aqueous phase was extracted once
with EtOAc (8 mL). The combined organic extracts were
successively washed with water and brine and dried over
Na2SO4. Evaporation of the solvent under reduced pressure
afforded a crude product that was purified by column chroma-
tography with use of 5% EtOAc/hexane (v/v) as the eluent to
afford the alkene 71 (756 mg, 0.87 mmol) in 93% yield as a
Compound 74. To a stirred solution of triol 73 (283 mg, 0.66
mmol) in dichloromethane (2 mL) cooled at 0 °C was added
TFA (1 mL) dropwise. The reaction mixture was allowed to
warm to room temperature gradually and stirred further until no
760 J. Org. Chem. Vol. 75, No. 3, 2010

Raghavan and Krishnaiah
JOCArticle
remaining starting material could be detected by TLC (ca. 3 h).
The solvent was evaporated under reduced pressure, the
residue thus obtained was dissolved in dichloromethane (3 mL),
and Et3N (0.75 mL, 5.3 mmol) and DMAP (16 mg, 0.13 mmol)
were added followed by dropwise addition of acetic anhydride
(0.37 mL, 4 mmol). The reaction mixture was stirred for 1 h and
water (3 mL) was added. The clear layers were separated and the
aqueous phase was extracted once with CHCl3 (4 mL). The
combined organic extracts were successively washed with water
and brine and dried over Na2SO4. Evaporation of the solvent
under reduced pressure afforded a crude product that was
purified by column chromatography with use of 15% EtOAc/
hexane (v/v) as the eluent to afford the tetraacetate 74 (293 mg,
0.59 mmol) in 90% yield as a viscous liquid. TLC: Rf 0.4 (30%
EtOAc/hexane). [R]25D þ40 (c 0.8, CHCl3) ([R]27D þ38 (c 0.378,
CHCl3)).3c IR (neat): 2927, 2856, 1744, 1655, 1414, 1374, 1237,
1042, 953, 755, 603 cm-1. 1H NMR (600 MHz, CDCl3) (mixture
of two rotamers): δ 5.26 (dd, J=4.0, 7.1 Hz, 1H), 5.14 (dd, J=
3.4, 6.8 Hz, 1H), 4.87-4.84 (m, 2H), 4.71 (dd, J=3.4, 11.7 Hz,
1H), 4.61 (dd, J = 3.4, 11.7 Hz, 1H), 4.47-4.43 (m, 2H),
4.39-4.36 (m, 2H), 4.35-4.33 (m, 1H), 4.29 (dd, J=2.8, 12.4
Hz, 1H), 2.14 (s, 3H), 2.13 (s, 3H), 2.12 (s, 3H), 2.10 (s, 3H), 2.06
(s, 6H), 1.93 (s, 3H), 1.90 (s, 3H), 1.81-1.69 (m, 4H), 1.56-1.46
(m, 6H), 1.41-1.36 (m, 2H), 1.35-1.19 (m, 32H), 1.15-1.10 (m,
2H), 0.90-0.87 (m, 12H). 13C NMR (75 MHz, CDCl3) (mixture
of two rotamers): δ 171.0, 170.5, 170.4, 170.35, 170.2, 170.1,
170.0, 77.0, 67.4, 66.6, 66.4, 65.0, 64.8, 63.2, 62.3, 61.0, 38.0,
31.4, 29.6, 29.5, 29.4, 29.1, 26.9, 25.7, 25.5, 25.2, 21.2, 21.0, 20.8,
20.7, 20.6, 13.9, 11.7. MS (ESI): 498 [M þ H]þ. HRMS (ESI):
m/z [M þ Na]þ calcd for C27H47NO7Na 520.3250, found
520.3257.
remaining starting material could be detected by TLC (ca. 2 h).
The reaction mixture was diluted with dichloromethane (0.5
mL) and an excess of aqueous saturated NaHCO3 solution was
added dropwise. The organic layer was separated and the
aqueous layer was extracted with EtOAc (2 ꢀ 1 mL). The
combined organic extracts were successively washed with brine
and dried over Na2SO4. Evaporation of the solvent under
reduced pressure afforded a crude product that was purified
by column chromatography with use of t-BuOH/CHCl3/AcOH/
H2O (6:6:1:1 v/v) as the eluent to afford penaresidin A AcOH
3
(6.5 mg, 0.0073 mmol) in 88% yield as an oil. TLC: Rf 0.5
(6:6:1:1 t-BuOH/CHCl3/AcOH/H2O). [R]25 -15.5 (c 0.25,
MeOH). IR (neat): 3427, 2924, 2854, 1565, 1410, 1123, 654
D
cm-1 1H NMR (500 MHz, CD3OD): δ 4.54-4.49 (m, 1H),
.
4.21-4.14 (m, 1H), 4.07-4.01 (m, 1H), 3.86-3.78 (m, 2H),
3.46-3.41 (m, 1H), 1.96-1.80 (m, 2H), 1.91 (s, 3H), 1.53-1.45
(m, 1H), 1.44-1.23 (m, 19H), 1.21-1.14 (m, 1H), 0.91 (t, J=7.3
Hz, 3H), 0.86 (t, J=6.2 Hz, 3H). 13C NMR (75 MHz, CD3OD):
δ 180.1, 75.5, 69.8, 66.5, 65.2, 59.9, 41.5, 35.4, 30.9, 30.8, 30.75,
30.7, 30.6, 30.5, 28.0, 27.5, 27.1, 26.3, 14.0, 12.3. MS (ESI): 330
[M þ H]þ. HRMS (ESI): m/z [M þ H]þ calcd for C19H40NO3
330.3008, found 330.2994.
Acknowledgment. S.R. is thankful to Dr. J. M. Rao, Head,
Organic Division I and Dr. J. S. Yadav, Director, IICT for
constant support and encouragement. V.K. is thankful to CSIR,
New Delhi for a fellowship. Financial assistance from DST
(New Delhi) is gratefully acknowledged.
Supporting Information Available: Experimental details for
the preparation of compounds 12-16, 19, 20, 23b, 23c, 23d, 35,
40, 48-51, 9, 53, 56, 57, 59-62, and copies of 1H and 13C NMR
spectra of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Penaresidin A. To a stirred solution of triol 73 (8 mg, 0.019
mmol) in dichloromethane (0.13 mL) cooled at 0 °C was added
TFA (0.07 mL) dropwise. The reaction mixture was allowed to
warm to room temperature gradually and stirred further until no
J. Org. Chem. Vol. 75, No. 3, 2010 761