An enantioselective convergent route to pamamycin 621A

Article abstract of DOI:10.1021/jo100774n

(Figure presented) An effective approach to the total synthesis of natural antibiotic pamamycin 621A is described, in which the stereogenic centers at the C-13 and C-15 were taken from a chiral building block derived from the inexpensive d-glucolactone while all others (except the C-10) were installed via chiral auxiliary-induced asymmetric Evans/Crimmins aldol reactions. In the synthesis of the smaller/lower fragment, an antiselective Evans aldol condensation was found to occur only if a stoichiometric (rather than catalytic as reported in the literature) amount of magnesium chloride was present. A previously unknown effect of the steric bulkiness of the pyridine base employed on the stereochemical outcome of the formation of the THF ring in the presence of a chiral auxiliary was also observed. The THF rings in the larger/upper fragment were similarly synthesized with a high level of stereoselectivity from a linear precursor carrying a chiral auxiliary via intramolecular O-alkylations, most notably even under acidic conditions. The basic dimethylamino functionality at the C-15 was installed at the final stage of the whole synthesis, with those otherwise unavoidable side reactions in the conversion of the azido group effectively circumvented through using a very mild yet largely forgotten tributyltin reduction protocol.

Full text of DOI:10.1021/jo100774n

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An Enantioselective Convergent Route to Pamamycin 621A
Guo-Bao Ren, Yi-Xian Huang, Ya-Ping Sun, Zhong-Han Li, and Yikang Wu*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
yikangwu@sioc.ac.cn
Received April 21, 2010
An effective approach to the total synthesis of natural antibiotic pamamycin 621A is described, in
which the stereogenic centers at the C-13 and C-15 were taken from a chiral building block derived
from the inexpensive D-glucolactone while all others (except the C-10) were installed via chiral
auxiliary-induced asymmetric Evans/Crimmins aldol reactions. In the synthesis of the smaller/lower
fragment, an antiselective Evans aldol condensation was found to occur only if a stoichiometric
(rather than catalytic as reported in the literature) amount of magnesium chloride was present. A
previously unknown effect of the steric bulkiness of the pyridine base employed on the stereochemical
outcome of the formation of the THF ring in the presence of a chiral auxiliary was also observed. The
THF rings in the larger/upper fragment were similarly synthesized with a high level of stereoselec-
tivity from a linear precursor carrying a chiral auxiliary via intramolecular O-alkylations, most
notably even under acidic conditions. The basic dimethylamino functionality at the C-15 was
installed at the final stage of the whole synthesis, with those otherwise unavoidable side reactions
in the conversion of the azido group effectively circumvented through using a very mild yet largely
forgotten tributyltin reduction protocol.
Introduction
weight of that compound were determined to be C36H63NO7
and 621 Da, respectively, no specific chemical structure was
given. The situation remained unchanged until 1988, when
Marumo and co-workers reported2a the isolation of another
compound from Streptomyces alboniger IFO12738, whose
chemical and biological behavior is very similar to that of the
pamamycin documented earlier. Because this new com-
pound has a molecular weight of 607 Da, it was subsequently
named pamamycin 607.
The name pamamycin appeared in the literature for the
first time in 1979, referring to a compound isolated from the
extracts of Streptomyces alboniger ATCC 12461 by McCann
and Pogell.1 Although the molecular formula and molecular
(1) McCann, P. A.; Pogell, B. M. J. Antibiot. 1979, 32, 673–678.
(2) (a) Kondo, S.; Yasui, K.; Natsume, M.; Katayama, M.; Marumo, S.
J. Antibiot. 1988, 41, 1196–1204. (b) Kondo, S.; Yasui, K.; Katayama, M.;
Marumo, S.; Kondo, T.; Hattori, H. Tetrahedron Lett. 1987, 28, 5861–5864.
(c) Natsume, M.; Kondo, S.; Marumo, S. J. Chem. Soc., Chem. Commun.
1989, 1911–1913. (d) Natsume, M.; Yasui, K.; Kondo, S.; Marumo, S.
Extensive spectroscopic analyses were performed on pa-
mamycin 607 (1, Figure 1), which allowed for the establishment
of not only the molecular framework but also the relative2b as
well as absolute2c configurations of the stereogenic centers.
Three years later, four additional compounds, pamamycins
635A, 635B, 649A, and 649B, were isolated2d by the same
Japanese group from the mother liquor of pamamycin 607.
€
Tetrahedron Lett. 1991, 32, 3087–3090. (e) Grafe, U.; Schlegel, R.;
Dornberger, K.; Ihn, W.; Ritzau, M.; Stengel, C.; Beran, M.; Guenther,
W. Nat. Prod. Lett. 1993, 3, 265–271. (f ) Nakanishi, S.; Kita, K.; Uosaki, Y.;
Yoshida, M.; Saitoh, Y.; Mihara, A.; Kawamoto, I.; Matsuda, Y. J. Antibiot.
1994, 47, 855–861. (g) Natsume, M.; Tazawa, J.; Yagi, K.; Abe, H.; Kondo,
S.; Marumo, S. J. Antibiot. 1995, 48, 1159–1164. (h) Natsume, M.; Tazawa, J.;
Yagi, K.; Abe, H.; Kondo, S.; Marumo, S. Tennen Yuki Kagobutsu Toronkai
Koen Yoshishu 1996, 38, 493-498; Chem. Abstr. 126:16551. (i) Hartl, A.;
Stelzner, A.; Schlegel, R.; Heinze, S.; H€ulsmann, H.; Fleck, W.; Grafe, U.
J. Antibiot. 1998, 51, 1040–1046.
€
€
Then, in 1993, Grafe and co-workers2e published their results
€
on isolation of pamamycin 621 (which is now usually referred
5048 J. Org. Chem. 2010, 75, 5048–5064
Published on Web 07/02/2010
DOI: 10.1021/jo100774n
r
2010 American Chemical Society

Ren et al.
JOCArticle
components, that this class of compounds possesses a range
of biological activities, including autoregulatory, aniono-
phoric, antibacterial, anti-tuberculosis, and antifungal acti-
vities,1,2a,d-i,3 further investigations are unfeasible because of
the difficulty acquiring a pure individual compound. These,
along with the intriguing structures, have invoked many
synthetic endeavors4 since the late 1990s.
The studies directed toward the synthesis of pamamycins
began to appear in 1988.5 However, despite the impressive
efforts by a number of groups, no total synthesis was
achieved throughout the whole 1990s. Then four elegant
total syntheses of pamamycin 607 were completed in 2001 by
Thomas,6a Lee,6b,c Metz,6d and Kang.6e In 2005, Metz dis-
closed the first synthesis of pamamycins 621A and 635B.7
Recently, another efficient synthesis6f of pamamycin 607
along with fragments of 593 and 621D was reported by
Hanquet and co-workers. In a previous publication,8 we
briefly communicated our results on pamamycin 621A. Here
we wish to detail the whole work.
FIGURE 1. Structures of the three pamamycins that have been
synthesized to date: 607 (1a), 621A (2a), and 635B (2b).
to as pamamycin 621A) from Streptomyces aurantiacus IMET
43917. A complete structure was also assigned to pamamycin
621(A) on the basis of chemical degradation and spectroscopic
analyses, which made 621A the second actually fully character-
ized member among the whole pamamycin family to date. The
other pamamycins so far documented in the literature were
assigned mainly according to the MS analysis data with an
inexplicit assumption that the framework and the stereochem-
istry are similar/comparable to those of 607 and 621A.
Another two homologues, MS-282a and MS-282b (both
with MW = 635 Da),2f were isolated from Streptomyces
tauricus ATCC27470 in 1994 by Nakanishi and co-workers.
In the subsequent year, an additional nine pamamycins,
namely, pamamycins 621B, 621C, 621D, 635A, 635B, 635C,
635D, 635E, and 635F, were identified by Natsumi et al.2g,h to
be the components of the extracts of Streptomyces alboniger
Results and Discussion
Our synthetic plan is outlined in Scheme 1. The target
framework was disconnected into two fragments, 3 and 4,
which in turn could be related to their open-chain counter-
parts 5 and 6 by disconnecting the C-O bonds at the THF
rings as the key steps in the whole synthesis. The linear pre-
cursor 5 was disconnected between C-20 and C-30 into simpler
units 7 and 8. Similarly, the precursor to the larger fragment
3 (i.e., 6) was disconnected into three smaller fragments: 7, 9,
and 10.
IFO12738. The latest four members in the family were re-
€
2i
ported by Grafe in 1998;the pamamycins 663, 677, 691, and
705; all of them were isolated from Streptomyces sp. HKI-
0118.
Although it has been shown, using the purified major
constituent 607 or the mixtures enriched in one of the other
The synthesis (Scheme 2) of the C-10 to C-110 fragment
(4, the smaller/lower fragment of 2a) emerged with an aldol
reaction of Evans’ N-propionyl oxazolidinone 7 with the
known9 enal 11 under the conditions10 of Crimmins, which led
to aldol 12 (dr 23:1). The isolated enantiopure 12 was then
€
(3) (a) Kozone, I.; Hashimoto, M.; Grafe, U.; Kawaide, H.; Abe, H.;
Natsume, M. J. Antibiot. 2008, 61, 98–102. (b) Lefevre, P.; Peirs, P.; Braibant,
M.; Fauville-Dufaux, M.; Vanhoof, R.; Huygen, K.; Wang, X.-M.; Pogell,
B.; Wang, Y.; Fischer, P.; Metz, P.; Content, J. J. Antimicrob. Chemother.
2004, 54, 824–827. (c) For reviews, see: Pogell, B. M. Cell. Mol. Biol. (Paris)
treated with MeNH(OMe) HCl/AlMe3 to deliver the known11
3
€
1998, 44, 461–463. (d) Grigoriev, P.; Berg, A.; Schlegel, R.; Grafe, U.
Bioelectrochem. Bioenerg. 1996, 39, 295–298. (e) Grafe, U.; Stengel, C.;
Weinreb amide 13. Further treatment with n-PrMgBr gave the
corresponding ketone 14, which on reduction with Me4NBH-
€
€
Mollmann, U.; Heinisch, L. Pharmazie 1994, 49, 343–346. (f ) Stengel, C.;
Reinhardt, G.; Grafe, U J. Basic Microbiol. 1992, 32, 339–345. (g) Chou,
€
12
(OAc)3 in MeCN/HOAc at -20 °C produced 1,3-anti-diol
W.-G.; Pogell, B. M. Biochem. Biophys. Res. Commun. 1981, 100, 344–350.
(h) Chou, W.-G.; Pogell, B. M. Antimicrob. Agents Chemother. 1981, 20, 443–
454.
(4) For an excellent review, see: Metz, P. Top. Curr. Chem. 2005, 244,
215–249.
15. No traces of the corresponding syn isomer, which was
rather obvious if using NaBH4 as the reducing agent, could be
detected by 1H NMR.
(5) Walkup, R. D.; Park, G. Tetrahedron Lett. 1988, 29, 5505–5508. (b)
Walkup, R. D.; Kim, S. W.; Wagy, S. D. J. Org. Chem. 1993, 58, 6486–6490.
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Mandville, G.; Bloch, R. Eur. J. Org. Chem. 1999, 2303–2307. (k) Solladie,
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The diol 15 was transformed into 16 by sequential removal
of the TBS (tert-butyldimethylsilyl) protecting group with
TBAF (n-Bu4NF), formation of the acetonide using Me2C-
(OMe)2/CSA (10-camphorsulfonic acid), and refreeing the
(6) (a) Germay, O.; Kumar, N.; Thomas, E. J. Tetrahedron Lett. 2001, 42,
4969–4974. (b) Lee, E.; Jeong, E. J.; Kang, E. J.; Sung, L. T.; Hong, S. K.
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L. T.; Hong, S. K.; Lee, E. J. Am. Chem. Soc. 2002, 124, 14655–14662. (d)
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Chem. 2005, 70, 2329–2331.
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119, 7883–7884.
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SCHEME 1. General Features of Our Retrosynthetic Analysis
SCHEME 2
SCHEME 3
(Scheme 3). The resulting crude enal 17 was then subjected to
Evans’s antiselective aldol reaction conditions (MgCl2/
TMSCl13 (trimethylsilyl chloride)) to install the C-10/C-20.
However, completely to our surprise, the anticipated con-
densation essentially did not occur at all under the broadly
cited literature conditions (using only a catalytic amount of
MgCl2). We suspected that the failure might be caused by the
presence of the acetonide functionality, which might con-
sume some Mg ion and thus reduce the amount of effective
content of Mg ion required for the aldol reaction, as the
aldehydes in most (if not all) literature precedents were much
simpler/less functionalized. Therefore, we next tried to in-
crease the amounts of the added MgCl2 and Et3N.
The main results of the aldol reaction using stoichiometric
amounts of MgCl2 are outlined in Table 1. In the presence of
1 equiv (with respect to aldehyde 17) of MgCl2 and 4 equiv of
Et3N, the expected TMS protected aldol 18 was indeed
formed, which on cleavage of the silyl protecting group
provided aldol 19 in 31% yield (Table 1, entry 1). Addition
of NaSbF6 was reported13 to have a positive effect in the
literature cases. Therefore, we also attempted to improve the
yield by introducing NaSbF6. However, somewhat to our
surprise both the yield and the diastereoselectivity declined
allylic OH with 70% HOAc. The seemingly more direct
alternative, formation of the acetonide followed by desilyla-
tion, did not work so well, perhaps because the 1,3-anti-diol
cannot form a highly thermodynamically favored acetonide
as the corresponding syn diols: using either Me2C(OMe)2 or
CH2dCHMe(OMe) in CH2Cl2 in the presence of weak acid
catalyst PPTS (pyridium p-sulfonate, 0.1 equiv), the reaction
was very sluggish, while stronger acid catalysts such as CSA
(0.1 equiv) soon led to a complicated mixture.
Oxidation of the C-30 alcohol into the corresponding
aldehyde was readily achieved with Dess-Martin periodinane
(13) (a) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am.
Chem. Soc. 2002, 124, 392–393. For some recent applications, see: (b)
Davies, I. R.; Cheeseman, M.; Green, R.; Mahon, M. F.; Merritt, A.; Bull,
S. D. Org. Lett. 2009, 11, 2896–2899. (c) Balamurugan, D.; Muraleedharan,
K. M. Tetrahedron 2009, 65, 10074–10082. (d) Krygowski, E. S.;
Murphy-Benenato, K.; Shair, M. D. Angew. Chem., Int. Ed. 2008, 47,
1680–1684. (e) Evans, D. A.; Nagorny, P.; Reynolds, D. J.; McRae, K. J.
Angew. Chem., Int. Ed. 2007, 46, 541–544. (f ) Schnermann, M. J.; Romero,
F. A.; Hwang, I.; Nakamaru-Ogiso, E.; Yagi, T.; Boger, D. L. J. Am. Chem.
Soc. 2006, 128, 11799–11807.
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TABLE 1. Antiselective Aldol Reaction between 7 (2 equiv with respect
to 17) and 17 Performed in EtOAc in the Presence of TMSCl (3 equiv with
respect to 17) at Ambient Temperature with [17] = 0.5 M Unless
Otherwise Stated
TABLE 2. Treatment of 21 with Different Bases Leading to 4
entry
conditions
outcomes
1
2
3
4
5
6
7
2,6-lutidine/120 °C/3 h
2,6-lutidine/140-150 °C/3 h
2,6-luditine/rt/2 months
DBMPa (22)/130-140 °C/3 h
DBMPa (22)/toluene/120 °C/3 h
Py/110 °C/3 h
4 (83%, dr 11:1)
4 (90%, dr 10:1)
4 (traces)
4 (100%, dr 5:1)
4 (88%, dr 5:1)
4 (62%, dr g95:5)b
4 (traces)
entry
conditions
yield of 19 (dr)
1
MgCl2 (1 equiv)/Et3N (4 equiv)
MgCl2 (1 equiv)/Et3N (5 equiv)/
NaSbF6 (0.6 equiv)
MgCl2 (1 equiv)/Et3N (6 equiv)/4 A MS
MgCl2 (2 equiv)/Et3N (4 equiv)
MgCl2 (2 equiv)/Et3N (5 equiv)
MgCl2 (2 equiv)/Et3N (5 equiv)
MgCl2 (1 equiv)/Et3N (6 equiv)
31%
25% (5:1)
2a
˚
Py/rt/2 months
3
4
(traces)
45%
56% (13:1)
57% (10:1)
47% (12:1)
aDBMP = 2,6-di-tert-butyl-4-methylpyridine (22, Scheme 4). bNo
other isomer(s) could be seen by 1H NMR.
5
6a
7
In the beginning, the cyclization of 21 leading to 4 was
thought to be very similar to that in our14 nonactin synthesis.
The most satisfactory conditions (2,6-lutidine/120 °C) devel-
oped in that work were therefore simply adopted here. How-
ever, the product thus obtained turned out to be a mixture of
two diastereomers (dr 11:1, Table 2, entry 1) instead of a pure
enantiomer. At a slightly higher temperature (Table 2, entry 2),
the diastereomeric ratio began to drop further. If running the
reaction at ambient temperature, essentially no 4 was formed
even after 2 months (Table 2, entry 3).
a[17] = 0.25 M.
SCHEME 4
We suspected that the presence of the minor isomer might
stem from partial racemization at the stereogenic center R to
the carbonyl group. If this was the case, a sterically more
bulky base, which did not easily deprotonate the R-proton,
might help to reduce such side reactions. With this thought in
mind, we next synthesized 2,6-di-tert-butyl-4-methylpyri-
dine (22, Scheme 4) using a literature15 procedure. Somewhat
to our surprise, when the sterically more congested base 22
was utilized as base (also as solvent) in this reaction, the
diastereomeric ratio of the product declined to only 5:1
(Table 2, entry 4). Greatly reducing the amount of the added
22 by performing the reaction in toluene, also at a slightly
lower temperature, did not lead to any improvement in the dr
value but substantially lowered the yield of 4. Interestingly,
use of the least hindered base in the series (i.e., the pyridine
itself) eliminated the isomer completely. Thus, by heating 21
in neat pyridine at 110 °C for 3 h, 4 was obtained in 63% yield
as a single isomer (Table 2, entry 6). The unreacted 21 could
be recovered and recycled. However, it should be noted that
no 4 was formed at ambient temperature even after 2 months
(Table 2, entry 7).
With the smaller fragment 4 in hand, we next turned our
attention to the structurally more complex fragment 6, a key
precursor to the larger unit of pamamycin 621A (3). Accord-
ing to our general plan (Scheme 1), this linear precursor was
to be assembled from its subunits 9 (the C-11 to C-19
fragment) and 10 (the C-3 to C-10 fragment). The alkyne
fragment 9 was synthesized using a route shown in Scheme 5.
Starting from the known epoxide 23, which can be readily
prepared16,17 from inexpensive D-glucolactone using a practical
route developed by us earlier, via reaction with EtMgBr/
CuCN18 in THF, the alcohol 24 was obtained in 97% yield.
(Table 1, entry 2). In the presence of molecular sieves,
essentially no reaction occurred (Table 1, entry 3).
Use of more MgCl2 (2 equiv with respect to 17) under
otherwise the same conditions as in the entry 1 raised the
yield of 19 (via crude 18 without any purification) to 45%
(Table 1, entry 4). If the amount of the added Et3N increased
from 4 to 5 equiv, the yield could be further raised to 56%,
with a diastereomeric ratio of 13:1 (Table 1, entry 5). The
amount of solvent also seemed to have an effect on the
outcome of this reaction. At a lower concentration ([17] =
0.25 M), the dr value substantially dropped although the
yield essentially remained the same (Table 1, entry 6).
Finally, use of less MgCl2 (1 equiv) but more Et3N (6 equiv)
gave lower yield and diastereomeric selectivity (Table 1,
entry 7). Thus, the optimal conditions appeared to be those
in entry 5, which were employed later in preparative runs.
The C-C double bond in 19 was saturated by hydrogena-
tion over 10% Pd-C to deliver 20, which was subsequently
converted to the corresponding mesylate 21 via reaction with
MsCl/Et3N in CH2Cl2 (Scheme 4). The acetonide was then
removed with 1 N HCl in THF/MeOH to release the C-60/C-80
diol functionality, setting up the stage for the key step of THF ring
formation with concurrent configuration inversion at the C-30.
(14) Wu, Y.-K.; Sun, Y.-P. Org. Lett. 2006, 8, 2831–2834.
(15) Anderson, A. G.; Stang, P. J. J. Org. Chem. 1976, 41, 3034–3036.
(16) Wu, J.-Z.; Gao, J.; Ren, G.-B.; Zhen, Z.-B.; Zhang, Y.-H.; Wu, Y.-K.
Tetrahedron 2009, 65, 289–299.
(17) It is noteworthy that in the preparation of 23 by silylation of the
corresponding alcohol via treatment with TBSCl, use of the more commonly
employed CH2Cl2 as the solvent led to extremely slow reaction at different
concentrations with a large excess of the added base/silylating agent with or
without DMAP. Replacement of the TBSCl with TBSOTf did not result in
any improvement. In DMF, the reaction proceeded much faster, in general,
but relatively high substrate concentration (ca. 1 M) is recommended.
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JOCArticle
SCHEME 5
TABLE 3. Removal of the Acetonide Group in 25 under Different
Conditions
entry
conditions
yield for 26
a
a
a
1
2
3
CSA (0.2 equiv)/CH2Cl2/rt
CSA (0.1 equiv)/CH2Cl2/MeOH (10 equiv)/rt
p-TsOH (0.1 equiv)/ CH2Cl2/MeOH
(10 equiv)/rt
CAN (0.5 equiv)/MeOH/0 °C
3% CAN/KBrO3 (1.5 equiv)/CH3CN/H2O
(1:1)/60 °C
3% CAN/KBrO3 (1.5 equiv)/CH3CN/H2O
(1:1)/rt
3% CAN/borate buffer/CH3CN/H2O (1:1)/
60 °C
FeCl3-SiO2/CHCl3/rt
80% aq AcOH (as solvent)/rt
70% aq AcOH/THF/rt to 50 °C
50% aq CF3CO2H/CH2Cl2/rt/1 hd
-
-
-
a
a
4
5
-
-
a
6
7
-
(no reaction)
8
9
10
11
21%b
30%c
33%
90%
aA complex mixture was obtained. bAlong with 48% of recovered 25.
cAlong with 21% of recovered 25. dWith [25] = 0.03 M.
The fragment that corresponds to the C-3 to C-10 in the
target structure (cf. 10 in Scheme 1) was built up using two
chiral auxiliary-induced asymmetric aldol reactions24,10 to
install the four consecutive stereogenic centers. The synthesis
emerged with the condensation between 2823 and 725 under
the conditions of Crimmins10 (Scheme 6). The chiral aux-
iliary was then reductively cleaved with NaBH4/H2O26 in
THF to deliver the corresponding diol 30, which was conse-
quently transformed into the corresponding cyclic benzyl-
idene acetal 31 before further elaboration into alcohol 33.
Conversion of 30 into 31 was first attempted under con-
ventional conditions (CSA/PhCH(OMe)2) with CH2Cl2 as
the solvent. The reaction was very slow. To speed up the reac-
tion, we next performed the reaction in neat PhCH(OMe)2
under aspirator vacuum (to remove any MeOH formed).
Under such conditions, the desired 31 formed in 91% yield
within 1 h at ambient temperature. This protocol of acet-
alization also allowed for direct use of the crude mixture of
the diol 30 (and the concurrently generated chiral auxiliary
7), which was rather polar and difficult to separate from 7 on
silica gel.
Further elaboration of the diol via formation of the cyclic
acetal 31 followed a DIBAL-H reduction afforded a pair
of monoalcohols (ca. 1:13 as measured on the crude product
by 1H NMR) with the desired isomer as the major product.
The isolated pure alcohol 33 was then oxidized with Dess-
Martin periodinane to yield aldehyde 34, which was required
for a subsequent aldol condensation to introduce the C-8/
C-9 stereogenic centers. To facilitate conversion of the C-10
terminal into an aldehyde at a later stage, which was required
according to our synthetic plan, an oxazolidinethione auxi-
liary27 (35) was employed because treatment of such species
The newly formed hydroxyl group was masked as a MOM
ether by treatment with MOMCl/i-Pr2NEt, giving the de-
sired 25 in 98% yield.
Removal of the acetonide protecting group in 25 without
touching the TBS group was rather difficult. A variety of
conditions failed in the initial attempts (Table 3). Those most
commonly employed protocols for cleavage of acetonides,
such as p-TsOH or CSA (camphor-10-sulfonic acid)/CH2Cl2
(with or without added MeOH)/rt, all led to a complex
mixture (Table 3, entries 1-3). Use of CAN (ceric ammo-
nium nitrate)/KBrO319 also resulted in a complex mixture in
this case (Table 3, entries 4-6). In the presence of a borate
buffer,19 CAN failed to bring about any reactions (Table 3,
entry 7).
The reaction with FeCl3/SiO2/CHCl320 was better, giving
the desired diol 26 in 21% yield, along with 48% of recovered
starting 25 (Table 3, entry 8). Slightly higher yields were
obtained with 80% aqueous HOAc (as solvent) at ambient
temperature or 70% aqueous HOAc in THF at slightly eleva-
ted temperatures (Table 3, entries 9 and 10). Then we noticed a
relevant example reported by Smith21 and co-workers, which
used 50% F3CCO2H in CH2Cl2 to cleave 3-pentanonide
without touching the TBS in the same substrate. To our
delight, this set of conditions also worked very well for us.
After treatment of 25 with 50% F3CCO2H/CH2Cl2 at ambient
temperature for 1 h, the desired 26 was formed in 90% yield
(Table 3, entry 11).
The diol functionality was oxidatively cleaved with aq
22
NaIO4/SiO2 in CH2Cl2. The intermediate aldehyde was
treated with Ph3P/CBr4 to deliver the gem-dibromide 27,
which on further exposure to n-BuLi in THF at ca. -10 °C
provided the terminal alkyne 9.
(23) Marshall, J. A.; Schaaf, G.; Nolting, A. Org. Lett. 2005, 7, 5331–
5333.
(24) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127–2129. (b) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am.
Chem. Soc. 1991, 113, 1047–1049. (c) Crimmins, M. T.; Chaudhary, K. Org.
Lett. 2000, 2, 775–777. (d) Crimmins, M. T.; King, B. W.; Tabet, E. A.;
Chaudhary, K. J. Org. Chem. 2001, 66, 894–902.
(25) For a practical high-yielding route to such auxiliaries, see: Wu,
Y.-K.; Shen, X. Tetrahedron: Asymmetry 2000, 11, 4359–4363.
(26) Prashad, M.; Har, D.; Kim, H.-Y.; Repic, O. Tetrahedron Lett. 1998,
39, 7067–7070.
(18) Smith, A. B., III; Razler, T. M.; Pettit, G. R.; Chapuis, J.-C. Org.
Lett. 2005, 7, 4403–4406.
(19) Kojima, H.; Urano, Y.; Kikuchi, K.; Higuchi, T.; Hirata, Y.;
Nagano, T. Angew. Chem., Int. Ed. 1999, 38, 3207–3209.
(20) Kim, K. S.; Song, Y. H.; Lee, B. H.; Hahn, C. S. J. Org. Chem. 1986,
51, 404–407.
(21) Smith, A. B., III.; Doughty, V. A.; Sfouggatakis, C.; Bennett, C. S.;
Koyanagi, J.; Takeuchi., M. Org. Lett. 2002, 4, 783–786.
(22) Spanu, P.; Rassu, G.; Ulgheri, F.; Zanardi, F.; Battistini, L.;
Casiraghi, G. Tetrahedron 1996, 52, 4829–4838.
(27) For a convenient/practical synthesis of such auxiliaries, see: Wu,
Y.-K.; Yang, Y.-Q.; Hu, Q. J. Org. Chem. 2004, 69, 3390–3392.
5052 J. Org. Chem. Vol. 75, No. 15, 2010

Ren et al.
JOCArticle
SCHEME 6
SCHEME 7
To confirm the relative configurations of the four con-
secutive stereogenic centers in 36, the chiral auxiliary was
removed with MeOH/DMAP28 in CH2Cl2 (Scheme 7). The
resulting methyl ester (37) was treated with atmospheric H2/
Pd-C/MeOH followed by CSA to yield a six-membered
lactone (38), from which clear NOEs were observed between
the H-8/C-9 methyl group and the H-9/C-7 methyl group.
The coupling constants were also consistent with those
reported29 in the literature for similar lactones. The stereo-
chemistry of this fragment was thus fully secured.
To avoid potential complications in the carbanion addi-
tion reaction at a later stage of the synthesis, the hydroxyl
group in 36 must be masked first with a proper protecting
group. This protecting group was to be removed immediately
after the catenation of the fragments containing C-11 to C-18
(9) and C-3 to C-10 (vide infra). Therefore, TMS (trime-
thylsilyl) appears to be an ideal candidate, which has a small
molecular weight (and thus rather atom-economical com-
pared with other silyl groups) and can be cleaved under very
mild conditions.
TABLE 4. Aldol Reaction of 34 with 35 or ent-35 at -78 °C in CH2Cl2
under Different Conditions
entry auxiliary
conditions
yield of 36 (dr)
1
2
3
4
35 (R) TiCl4 (1 equiv)/TMEDA (2.5 equiv)
ent-35 (S) TiCl4 (2 equiv)/i-Pr2NEt (1.1 equiv)
traces
76% a (13.4:1)b
The silyl protection of the C-10 OH group was readily
achieved by treatment of 36 with TMSCl/2,6-lutidine in DMF
(Scheme 8). However, it was noted that, if using CH2Cl2 as the
solvent, essentially no reaction occurred. The chiral auxiliary
was then removed by a DIBAL-H reduction. The resulting
unstable aldehyde was directly treated with lithiated 9 at
-20 °C to deliver a pair of propargyl alcohols (i.e., 41a and
41b in a 2:3 ratio) in 100% yield.30 Use of zincated 9 (formed in
situ through metal exchange by addition of 0.5 or 1 equiv of
anhydrous ZnBr2 to the above-mentioned lithiated system
before introduction of the aldehyde) failed to deliver discern-
ible amounts of 41a/41b. With anhydrous MgCl2 to replace
ZnBr2 under otherwise identical conditions, the only detect-
able change was loss of the TMS protecting group in aldehyde
40. The Zn(OTf)2/(-)-NME/Et3N31 conditions, which showed
excellent enantioselectivity with other substrates, also failed to
give any products in our case.
ent-35 (S) TiCl4 (2 equiv)/(-)-spartiene (1.1 equiv) 85% a (10:1)b
35 (R)
TiCl4 (1 equiv)/(-)-spartiene (2.5 equiv) 94% (>95:5)c
aYield for 360. bAs determined by HPLC on the crude oil. cEssentially
no other diastereomers could be seen in the 1H NMR of the crude
product.
with DIBAL-H may directly lead to the corresponding alde-
hyde (with concurrent removal of the auxiliary) as shown24c,d
by Crimmins.
The aldol reaction was first performed under the “Evans-syn”
selective protocol24c of Crimmins, which used 35 (of R-configu-
ration) and 1.0 equiv of TiCl4 and 2.5 equiv of TMEDA (N,N0-
tetramethylethylenediamine). However, only traces of several
aldol products could be detected (Table 4, entry 1). Use of
Crimmins’ “non-Evans-syn” protocol gave better results. With
i-Pr2NEt as the base, the desired enantiopure 360 could be
obtained in 76% isolated yield with a diastereomeric ratio of
ca. 13.4 (360):1 (all other isomers) as determined on the crude oil
by HPLC (Table 4, entry 2). Even better yield was later obtained
when the i-Pr2NEt was replaced by (-)-sparteine(Table4, entry
3). Encouraged by the effect of (-)-sparteine in this run, we next
switched back to the Evans-syn recipe to see if it would work
equally well there. To our gratification, replacement of the
TMEDA with (-)-sparteine led to a tremendously improved
yield and diastereoselectivity (Table 4, entry 4).
The above-mentioned two (separated) alcohols were con-
verted (Scheme 9) into the corresponding acetonides by
(28) For the methodology, see: (a) Su, D.-W.; Wang, Y.-C.; Yan, T.-H.
Tetrahedron Lett. 1999, 40, 4197–4198. (b) Wu, Y.-K.; Sun, Y.-P.; Yang, Y.-Q.;
Hu, Q.; Zhang, Q. J. Org. Chem. 2004, 69, 61410–6144.
(29) Guindon, Y.; Brazeau, J.-F. Org. Lett. 2004, 6, 2566–2602.
(30) Elevated temperature or prolonged reaction time all resulted in
undesired desilylation of 41a/41b leading to 42a/42b.
(31) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806–1807.
J. Org. Chem. Vol. 75, No. 15, 2010 5053

Ren et al.
JOCArticle
SCHEME 8
SCHEME 9
sequential treatment, respectively, with F3CCO2H/CH2Cl2
and Me2C(OMe)2/PPTS (pyridinium p-sulfonate). In prin-
ciple, the acetonide derived from the 1,3-syn-diol is expected
to adopt a chair conformation with both substituents at the
C-8 and C-10 being in an equatorial position. However, the
acetonide from 1,3-anti-diol can be present only as a twisted
boat. The one with a chair conformation would allow for
observation of the NOEs depicted for 43a in Scheme 9. One
of the acetonides (derived from the more polar isomer of the
alcohols) indeed showed such NOEs and hence was assigned
to the structure of 43a, which has a syn relationship between
the C-8 and C-10 stereogenic centers. Consequently, the
other acetonide was assigned to 43b (derived from the less
polar alcohol, the major component). Such assignments are
also consistent with the empirical rules32 of Rychnovsky,
which says that the two methyl groups of the acetonide in a
chair conformation would have a large split in the 13C shifts
with the ketal carbon appearing below 100 ppm, while the
shifts for the two methyls in a twisted boat are rather close
to each other, with the ketal carbon showing up at >100
ppm.33a
the C-8. The carbonyl group was then reduced with Evans’s34
Me4BH(OAc)3, which is known to be highly 1,3-antiselective.
Unfortunately, in our case, the diastereoselectivity turned out
to be only 1:6. This, along with the fact that the two diols (42a
and 42b) are inseparable on silica gel, prompted us to seek
other alternatives.
Direct reduction of 44 was also attempted33b (Table 5). In
most cases, the major product was the desired isomer 41b.
With LiBHEt3 as the reducing agent, the 41a/41b ratio was
only 2:3, although the yield was excellent (Table 5, entry 1).
The selectivity could be raised to 1:2 by using NaBH4 in THF
in the presence of a small amount of water (entry 2). Better
selectivity was later observed with K-Selectride (KBH(i-Bu)3)
at 0 °C, but the yield was substantially lower (entry 3). Interes-
tingly, if performing the reduction at -78 °C under otherwise
the same conditions, a complex mixture was obtained (entry 4).
L-Selectride (LiBH(i-Bu)3) gave the most satisfactory results.
At -78 °C, the reduction gave alcohols 41a/41b in a ratio of
1:6.4 with the total yield being 93% (entry 5). The selectivity
was inverted when LiAlH(O-t-Bu)3 was employed as the
reductant (entry 6), while 9-BBN (9-borobicyclo[3.3.1]nonane)
failed to give any reduction at all at 0 °C.
To make full use of the undesired isomer 41a, the alcohol
was oxidized with Dess-Martin periodinane (Scheme 10).
The TMS protecting group in the resulting ketone 44 was
cleaved with 50% aq F3CCO2H to free the hydroxyl group at
The synthesis was then continued from the enantiopure
acetonide of correct configuration (43b), starting with a
DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone)-mediated
oxidative removal of the PMB (p-methoxybenzyl) protecting
group at the C-3 OH, as shown in Scheme 11. The phosphate
buffer (Na2HPO4/citric acid, pH 7) proved to be essential for
suppressing the otherwise unavoidable partial loss of the aceto-
nide protecting group. The allyl alcohol 46 was subsequently
(32) (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31,
945–948. (b) Rychnovsy, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58,
3511–3515.
(33) (a) Also compare many examples in: Evans, D. A.; Rieger, D. L.;
Gage, J. R. Tetrahedron Lett. 1990, 31, 7099–7100. For previous investiga-
tions on substrate-induced stereoselective reduction of propargyl ketones,
see; (b) Chakraborty, T. K.; Reddy, V. R.; Reddy, T. J. Tetrahedron 2003, 59,
8613–8622.
(34) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560-3578.
5054 J. Org. Chem. Vol. 75, No. 15, 2010

Ren et al.
JOCArticle
SCHEME 10
followed by heating in 2,6-lutidine also led to the same
product, though in a slightly lower yield. More surprisingly,
in the presence of added CSA, prolonged exposure of 51 to
H2/Pd-C/MeOH also gave a two THF ring containing
species, which was later proved to be identical to the 52b
prepared by removal of the MOM protecting group.
The high overall yield for the transformation of 51 to 52a
or 52b suggested that the unidentified side products in the
first two steps might be those with one of the two THF rings
already formed even before subjection to the basic 2,6-
lutidine conditions. Such a phenomenon (i.e., formation of
a THF ring from the corresponding alcohol mesylate pre-
cursor under acidic conditions) was not observed in our
earlier synthesis of nonactin.37
With 52a in hand, we proceeded with the remaining steps
of the synthesis, as depicted in Scheme 12. The chiral
auxiliary was removed with H2O2/LiOH in THF to deliver
the corresponding acid 3. The two fragments, 3 and 4, were
then combined with each other under Yamaguchi’s38 condi-
tions to afford 54. Use of MNBA (2-methyl-6-nitrobenzoyl
anhydride) protocol of Shiina39 gave a substantially lower
yield (71%).
TABLE 5. Reduction of Ketone 44 with Various Reductants
(cf. Scheme 10)
entry
conditions
41a/41b (% yield)
1
2
3
4
5
6
7
LiBHEt3/THF/-78 °C
NaBH4/THF/H2O/0 °C
K-Selectride/THF/0 °C
K-Selectride/THF/-78 °C
L-Selectride/THF/-78 °C
LiAlH(O-t-Bu)3/THF/-78 °C
9-BBN/THF/0 °C to rt
2:3 (96)
1:2 (94)
1:5 (74)
The auxiliary in 54 was subsequently cleaved with H2O2/
LiOH, affording hydroxyl acid 55 in 94% yield. Perhaps
because of the steric crowding around the C-1, the ester
linkage was not affected under the given conditions. Ring
closure of the 16-membered dilactone ring was much more
difficult than the coupling of 3 with 4. Under the same
a
-
1:6.4 (93)
2:1 (67)
b
-
aResulted in a complex mixture. bNo reaction occurred.
˚
conditions (53/DMAP/4 A MS/CH2Cl2/rt), no reaction
oxidized with Dess-Martin periodinane to yield the corres-
ponding aldehyde 47. The C-2/C-3 stereogenic centers were then
installed by a Crimmins10 aldol condensation, which delivered
enantiopure 48 in 90% isolated yield (along with ca. 3.9% of
other diastereomers).
Cleavage of the TBS protecting group on the C-13 OH was
troublesome. Many sets of conditions, including Me4NF/
THF, Me4NF/HOAc/THF, DDQ/THF-H2O, CAN/MeCN/
aq buffer (pH 7), and KF-H2O/TMSCl/MeCN,35 were tried
without success. Finally, the anticipated clean conversion of 48
into 49 was achieved with HF-py in THF.
The resulting alcohol 49 was subjected to H2/Pd-C/
EtOAc conditions to saturate the C-C double and triple
bonds. To avoid loss of the Bn group at this stage, addition36
of Et3N to the hydrogenation system was necessary. The
hydroxyl groups at the C-3 and C-13 were then activated
with MsCl to afford dimesylate 51.
Up to this point, the remaining task was to release the two
hydroxyl groups at C-6 and C-10 before attempting the key
step of construction of the two THF rings via intramolecular
etherification with concurrent configuration inversion at the
C-3 and C-13. This was initially attempted by removal of the
acetonide group with 50% aq F3CCO2H in CH2Cl2-MeOH
followed by hydrogenolysis over Pd-C in THF. The product
mixture was apparently more complex than we had expected.
However, heating the crude mixture in 2,6-lutidine at 120 °C
for 2 h led to the desired 52a in 93% isolated/overall yield.
The F3CCO2H-mediated hydrolysis of the acetonide is not
essential, as direct treatment of 51 with H2/Pd-C/MeOH
seemed to occur, even if using a large excess of 53 (2-10
equiv)/DMAP (10-20 equiv)/Et3N (12-24 equiv). If the
reaction was performed in MeCN instead of CH2Cl2, a
complex mixture that did not contain any 56 was obtained.
Similar results were also obtained with the Ph3P (4 equiv)/
PySSPy (4 equiv)/AgOTf (10 equiv)/toluene/rt conditions40
˚
and the MNBA (2.5 equiv)/DMAP (5 equiv)/4 A MS/
toluene/rt conditions. However, when the Yamaguchi ester-
ification was carried out in toluene at 80 °C (53 (10 equiv)/
DMAP (10 equiv)/Et3N (12 equiv)/80 °C), the anticipated
dilactone 56 was formed in 32% isolated yield. Using more
reagents at higher reaction temperature (53 (20 equiv)/
DMAP (20 equiv)/Et3N (24 equiv)/110 °C)) eventually
raised the yield of 56 to 66%.
The MOM protecting group was then removed with 10%
aq HBr41 in MeCN. The resultant alcohol 57 was converted
into the corresponding azide by treatment with Ph3P/
42
DEAD/(PhO)2P(O)N3 with concurrent inversion of the
configuration. In their synthesis of pamamycin 607, Kang7
(37) Such reactions typically occur under basic conditions. For some
examples (kindly provided by one of the reviewers) of related cyclization
under acidic conditions, see: (a) Chakraborty, T. K.; Das, S.; Raju, T. V.
J. Org. Chem. 2001, 66, 4091–4093. (b) Dehmlow, H.; Multzer, J.; Seilz, C.;
Strecker, A. R.; Kohlmann, A. Tetrahedron Lett. 1992, 33, 3607–3610. For a
recent review on stereoselective construction of THF rings, see: (c) Wolfe,
J. P.; Hay, M. B. Tetrahedron 2006, 63, 261–290.
(38) Yamaguchi, M.; Innaga, J.; Hirata, K.; Saeki, H.; Katsuki, T. Bull.
Chem. Soc. Jpn. 1979, 52, 1989–1993.
(39) (a) Shiina, I.; Kubota, M.; Ibuka, R. Tetrahedron Lett. 2002, 43,
7535–7539. (b) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org.
Chem. 2004, 69, 1822–1830.
(40) Kusaka, S.-i.; Dohi, S.; Doi, T.; Takahashi, T. Tetrahedron Lett.
2003, 44, 8857–8859.
(41) White, J. D.; Hrnciar, P. J. Org. Chem. 2000, 65, 2646–2650.
(42) Lal, B.; Pramanik, E. N.; Manhas, M. S.; Bose, A. K. Tetrahedron
Lett. 1977, 1977–1980.
(35) Peng, Y.; Li, W.-D. Z. Synlett 2006, 1165–1168.
(36) For a literature precedent of addition primary amine for similar
purposes, see: Czech, B. P.; Bartsch, R. A. J. Org. Chem. 1984, 49, 4076–
4078.
J. Org. Chem. Vol. 75, No. 15, 2010 5055

Ren et al.
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SCHEME 11
SCHEME 12
and co-workers have succeeded in reducing a similar azido
group to the corresponding dimethylamino group using
hydrogenation over Pd-C in MeOH followed by treatment
with 37% aq HCHO/HOAc. Unfortunately, application of
such a sequence to our substrate (58) led to a complicated
mixture that contained only traces of desired 2a. Combing
these two steps into one (i.e., performing the hydrogenation
in 37% aq HCHO/HOAc/MeOH) did not lead to any
5056 J. Org. Chem. Vol. 75, No. 15, 2010

Ren et al.
JOCArticle
discernible improvements. Exposure of 58 to Ph3P in THF
at 60 °C followed by treatment with NaBH3CN/37% aq
HCHO43 in MeCN in the presence of a NaOAc/HOAc
buffer appeared to be more promising, affording the desired
pamamycin 621A (2a) in ca. 66% yield. However, the 2a thus
obtained contained small amounts of unidentified side pro-
ducts, which were very difficult to get rid of. Careful moni-
toring of the whole process suggested that the problem most
likely stemmed from the azide reduction. Therefore, we
looked into the literature for other potential alternatives.
Then we noticed that Redlich44 and Roy once mentioned
an individual case of n-Bu3SnH-mediated reduction of a
carbohydrate-derived azide.45 Although this set of condi-
tions does not seem to have ever been tested on any complex
substrates, to our great delight, it resulted in a clean reduc-
tion of 58. The intermediate amine was then directly treated
with NaBH3CN in a mixture of 37% aq HCHO, and MeCN
containing a NaOAc/HOAc buffer provided the end product
2a in 92% overall yield.
It is noteworthy that the existence of a basic dimethyl-
amino group in the molecule makes 2a highly liable to pro-
tonation by traces of acids present in the NMR solvent. As
a consequence, serious line broadening and appearance of
“extra” signals are often observed, most notably in 1H
NMR. Such a phenomenon probably also exists with all
pamamycins, which made previous investigators measure
pamamycin 607’s NMR in the presence of F3CCO2D. How-
ever, addition of an acid cannot really/completely eliminate
the problem. In efforts to acquire “normal looking” spectra,
we found that stirring of the CDCl3 with K2CO3 for a few
hours before the supernatant was taken for preparing the
NMR solution was quite effective. After such a treatment,
the spectra were essentially the same as those compounds that
do not contain any basic functionalities. The optical rotation
measurements of pamamycin 621A (2a) are also interesting,
which are of opposite signs in CH2Cl2 and CHCl3. Although it
may not be surprising for two solvents of different nature/
polarity (such as CHCl3 and MeOH or acetone), for CH2Cl2
and CHCl3, it is quite unexpected because they are often
considered to be very similar to each other.
amounts of MgCl2 was observed, which was essential to the
success of the given substrate. The relative configuration of
the R-carbon in the aldol-derived cyclization precursors had
an influence on the THF ring formation, as shown by the
outcomes using pyridine bases of different steric bulkiness. In
the synthesis of the larger fragment, it is noteworthy that the
two THF rings could form from the mesylate alcohol precursor
even under acidic conditions.
The basic amino functionality was introduced at a very
late stage of the synthesis to minimize difficulties and inter-
ferences normally associated with the presence of such nitro-
gen atoms in the molecule. Reduction of the azido group into
an amino one was achieved using n-Bu3SnH in the absence of
AIBN, a reduction protocol that has never been tested in any
synthesis of a complex molecule.
1
The annoying interference (complication of the H and
13C NMR spectra) caused by the traces of acid in CDCl3 was
effectively eliminated by pretreatment of the NMR solvent
with powdered K2CO3, which made it possible to acquire
assignable “normal-looking” NMR spectra. An unusual
phenomenon of opposite rotation signs in CH2Cl2 and CHCl3
was observed for pamamycin 621A ([R]27 þ5.4 (c 0.4,
D
CH2Cl2) and [R]27D -5.4 (c 0.4, CHCl3), respectively).
Experimental Section46
(4R)-3-[(2R,3S,4E)-6-tert-Butyldimethylsilyloxy-3-hydroxy-
2-methylhex-4-enoyl]-4-phenyloxazolidin-2-one (12). TiCl4 (1.87
mL, 17.1 mmol) was added (via a syringe) dropwise to a solution
of 7 (3.571 g, 16.3 mmol) in dry CH2Cl2 (100 mL) stirred at 0 °C
(ice-water bath) under N2. After completion of the addition, the
mixture was stirred at the same temperature for 10 min before dry
TMEDA (6.10 mL, 40.8 mmol) was introduced dropwise. The
dark red-brown mixture was stirred at 0 °C for another 30 min. A
solution of aldehyde 11 (6.52 g, 32.58 mmol) in dry CH2Cl2
(20 mL) was added dropwise. After completion of the addition,
the mixture was stirred at the same temperature for 2 h. Aqueous
NH4Cl was added. The mixture was filtered through Celite
(washing with CH2Cl2 three times). The filtrate and washings
were combined, washed with water and brine, before being dried
over anhydrous Na2SO4. Removal of the solvent on a rotary
evaporator and column chromatography (1:4 EtOAc/PE) on
silica gel gave enantiopure aldol 12 as a colorless oil (5.769 g,
13.8 mmol, 84%): [R]25 -60.7 (c 1.21, CHCl3); 1H NMR (300
Conclusions
D
MHz, CDCl3) δ 7.32-7.19 (m, 5H), 5.75 (dt, J = 4.1, 15.5 Hz,
1H), 5.65 (dd, J = 5.7, 15.5 Hz, 1H), 5.38 (dd, J = 3.9, 8.6 Hz,
1H), 4.62 (t, J = 8.8 Hz, 1H), 4.43 (m, 1H), 4.18 (dd, J = 3.6, 9.0
Hz, 1H), 4.11 (d, J = 4.2 Hz, 2H), 3.82 (m, 1H), 2.76 (br, 1H), 1.08
(d, J = 6.9 Hz, 3H), 0.84 (s, 9H), 0.01 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 176.1, 153.2, 138.8, 131.5, 129.2, 128.7, 128.6, 125.5,
71.5, 69.8, 63.0, 57.5, 42.7, 25.8, 18.3, 10.8, -5.3; FT-IR (film)
3514, 2930, 2857, 1783, 1704, 1384, 1199, 838, 777, 700 cm-1; ESI-
MS m/z 442.3 ([M þ Na]þ); ESI-HRMS calcd for C22H33NO5Si-
Na ([M þ Na]þ) 442.2020, found 442.2014.
A total synthesis of natural antibiotic pamamycin 621A
was achieved through a convergent route in a highly enantio-
selective manner. The THF rings, which are characteristic of
the compounds of this family, were constructed from linear
precursors via O-alkylations of hydroxyl groups with mesy-
lates located at carbons β to a carbonyl group as the
alkylating agents under carefully chosen conditions without
suffering otherwise readily occurring side reactions, such as
R-racemization and β-elimination.
The mesylates were derived from corresponding aldols pre-
pared under either syn- or antiselective conditions developed
by Evans and/or Crimmins. In the antiselective aldol conden-
sation, a previously unreported effect of using stoichiometric
N-Methoxy-N-methyl-(2R,3S,4E)-6-tert-butyldimethylsilyloxy-
3-hydroxy-2-methylhex-4-enamide (13). MeAl3 (2.0 M in toluene,
9.0 mL, 18.0 mmol) was added slowly to a solution of MeONH-
Me HCl (1.758 g, 18.0 mmol) in dry THF (10 mL) stirred at 0 °C
3
under argon (balloon). The solid dissolved gradually with the gas
evolvement. Stirring was continued at 0 °C for 15 min and at
ambient temperature for 15 min before the bath was recooled to
-15 °C. A solution of 12 (2.511 g, 6.0 mmol) in dry THF (5 mL)
was introduced dropwsie. Stirring was continued at -15 °C until
(43) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497–4513.
(44) Redlich, H.; Roy, W. Liebigs. Ann. Chem. 1981, 1215–1222.
(45) There are also other reports on n-Bu3SnH reduction of azides, but
they all required AIBN (2,20-azobis(2-methylpropionitrile)) to initiate the
reactions: (a) Hays, D. S.; Fu, G. J. Org. Chem. 1998, 63, 2796–2797. and the
refs cited therein. (b) Poopeiko, N. E.; Pricota, T. I.; Mikhailopulo, I. A.
Synlett 1991, 342–342.
(46) Those steps that are not given in this section were reported in the
Supporting Information for ref 8.
J. Org. Chem. Vol. 75, No. 15, 2010 5057

Ren et al.
JOCArticle
TLC showed completion of the reaction. The reaction mixture was
poured into aq saturated potassium sodium tartrate (15 mL),
followed by addition of Et2O (50 mL). The mixture was stirred at
ambient temperature until it separated into two layers. The phases
were separated. The aqueous layer was back-extracted with Et2O
(3ꢀ50 mL). The combined ethereal layers were washed with water
and brine before being dried over anhydrous Na2SO4. Removal of
the solvent on a rotary evaporator and column chromatography
(1:2 Et2O/PE) on silica gel afforded the known Weinreb amide
continued at ambient temperature for 10 min before the mixture
was concentrated on a rotary evaporator. The residue was
chromatographed (EtOAc) on silica gel to give a colorless oil,
which was directly dissolved in THF (6 mL). With stirring, aq
HOAc (70%) was added in portions. The reaction (removal of
the undesired Me2C(OMe) group on the allylic OH) was moni-
tored by TLC. When the reaction was complete, aq saturated
NaHCO3 was added to neutralize the acid. The mixture was
extracted with Et2O (3 ꢀ 100 mL). The organic phase waswashed
in turn with water and brine and dried over Na2SO4. Removal of
the solvent and chromatography on silica gel (1:13 EtOAc/PE)
gave alcohol 16 as a colorless oil (512 mg, 2.24 mmol, 75% from
15): [R]24D þ9.8 (c 0.95, CHCl3); 1H NMR (300 MHz, CDCl3) δ
5.83 (dt, J = 15.6, 5.3 Hz, 1H), 5.68 (dd, J = 6.1, 15.5 Hz, 1H),
4.43 (t, J = 5.8 Hz, 1H), 4.14 (d, J = 5.0 Hz, 2H), 3.29-3.25 (m,
1H), 1.72-1.61 (m, 2H), 1.51-1.41 (m, 3H), 1.35 (s, 6H), 0.92 (t,
J = 7.0 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 130.7, 129.2, 100.6, 74.3, 69.9, 63.2, 40.8, 36.7, 25.3,
23.9, 19.1, 14.0, 12.7; FT-IR (film) 3416, 2986, 2873, 1380, 1222,
929 cm-1; ESI-MS m/z 251.3 ([M þ Na]þ); ESI-HRMS calcd for
C13H24O3Na ([M þ Na]þ) 251.1618, found 251.1628.
1311 as a colorless oil (1.806 g, 5.73 mmol, 96%): [R]26 -17.0
D
1
(c 1.95, CHCl3) (lit.11 [R]26 -17.3 (c 1.96, CHCl3)); H NMR
D
(300 MHz, CDCl3) δ 5.87 (m, 1H), 5.67 (m, 1H), 4.44 (m, 1H),
4.20 (m, 2H), 3.78 (br, 1H), 3.71 (s, 3H), 3.20 (s, 3H), 2.96 (m, 1H),
1.17 (d, J = 7.3 Hz, 3H), 0.90 (s, 9H), 0.08 (s, 6H).
(5R,6S,7E)-9-tert-Butyldimethylsilyloxy-6-hydroxy-5-methyl-
non-7-en-4-one (14). n-PrMgBr (1.5 M, in THF, 20.0 mL, 30.0
mmol) was added to a solution of the Weinreb amide 13 (3.125 g,
9.92 mmol) in dry THF (30 mL) stirred at 0 °C under argon
(balloon). The mixture was stirred at the same temperature until
TLC showed completion of the reaction. Aqueous saturated
NH4Cl was added. The mixture was extracted with Et2O (3 ꢀ
50 mL). The combined ethereal layers were washed with water
and brine before being dried over anhydrous Na2SO4. Removal
of the solvent on a rotary evaporator and column chromato-
graphy (1:6 EtOAc/PE) on silica gave ketone 14 (2.769 g, 9.22
mmol, 93%) as a colorless oil: [R]28D þ0.11 (c 1.00, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 5.88-5.63 (m, 2H), 4.49-4.43 (m,
1H), 4.21 (dt, J = 4.3, 1.3 Hz, 2H), 2.83 (d, J = 3.5 Hz, 1H), 2.67
(dq, J = 3.9, 7.0 Hz, 1H), 2.49 (dt, J = 3.1, 7.4 Hz, 2H),
1.67-1.58 (m, 2H), 1.15 (d, J = 7.3 Hz, 3H), 0.92 (t, J = 7.3 Hz,
3H), 0.91 (s, 9H), 0.09 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
215.4, 131.3, 129.1, 71.8, 63.0, 50.6, 44.1, 25.9, 18.4, 16.9, 13.7,
10.7, -5.2; FT-IR (film) 3465, 2958, 2931, 2858, 1707, 1463,
1255, 837, 777 cm-1; ESI-MS m/z 323.2 ([M þ Na]þ); ESI-
HRMS calcd for C16H32O3SiNa ([M þ Na]þ) 323.2013, found
323.2011.
(4R)-3-[(2S,3S,4E)-3-Hydroxy-2-methyl-5-((4S,5S,6S)-2,2,5-
trimethyl-6-propyl-1,3-dioxan-4-yl)-pent-4-enoyl]-4-phenyloxa-
zolidin-2-one (19). Dess-Martin periodinane (1.742 g, 4.11
mmol) and NaHCO3 (518 mg, 6.17 mmol) were added in turn
to a solution of alcohol 16 (469 mg, 2.06 mmol) in dry CH2Cl2
(10 mL) stirred at 0 °C. Stirring was continued until TLC showed
completion of the reaction. Et2O was added. The mixture was
filtered through Celite. The filtrate was concentrated on a rotary
evaporator. The residue was chromatographed (1:8 EtOAc/PE)
on silica gel to afford the intermediate unstable aldehyde 17 (428
mg, 1.89 mmol, 92%) as a yellowish oil, on which a diagnostic 1H
NMR was briefly acquired before performing the next step: 1H
NMR (300 MHz, CDCl3) δ 9.60 (d, J = 7.9 Hz, 1H), 6.73 (dd,
J = 4.3, 15.9 Hz, 1H), 6.35 (dd, J = 7.8, 16.0 Hz, 1H), 4.70 (m,
1H), 3.29 (m, 1H), 1.88 (m, 1H), 1.61-1.44 (m, 2H), 1.37 (s, 3H),
1.36 (s, 3H), 0.93 (t, J = 7.0 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H).
Et3N (0.35 mL, 2.50 mmol) was added dropwise to a solution
of the acyloxazolidinone 7 (219 mg, 1.0 mmol) and anhydrous
MgCl2 (105 mg, 1.0 mmol) in dry EtOAc (1.0 mL) stirred at
ambient temperature. To the resulting mixture a solution of
aldehyde 17 (142 mg, 0.63 mmol) obtained above in dry EtOAc
(1.0 mL) was added, followed by Me3SiCl (0.19 mL, 1.50 mmol).
The mixture was stirred at ambient temperature for 24 h before
being diluted with Et2O and filtered through Celite (washing
with Et2O). The filtrate and washings were combined and
concentrated on a rotary evaporator. The residue (crude TMS
ether 18) was dissolved in THF (18 mL) and H2O (2 mL). To this
solution was added DDQ (30 mg, 0.136 mmol). The mixture was
stirred at ambient temperature until TLC showed completion of
the reaction. Aqueous saturated NaHCO3 was then added. The
mixture was extracted with Et2O (3 ꢀ 50 mL). The combined
ethereal layers were washed with aq saturated NaHSO3 (twice),
H2O, and brine before being dried over anhydrous Na2SO4.
Removal of the solvent by rotary evaporation left a yellowish
oil, which was chromatographed (1:3 EtOAc/PE) on silica gel to
give aldol 19 as a colorless oil (156 mg, 0.351 mmol, 56% from
17, 52% from 16).
(4S,5S,6S,7E)-1-tert-Butyldimethylsilyloxy-5-methylnon-2-
ene-4,6-diol (15). A solution of ketone 14 (2.365 g, 7.88 mmol) in
dry CH3CN (5 mL) was added dropwise to a solution of
Me4NBH(OAc)3 (16.7 g, 63.0 mmol) in dry CH3CN (20 mL)
and glacial HOAc (20 mL) stirred at -20 °C. The mixture was
stirred at the same temperature for 14 h, when TLC showed
completion of the reduction. Aqueous potassium sodium tar-
trate (1.0 M, 50 mL) was added, followed by Et2O. The aqueous
layer was made slightly alkaline (ca. pH 8) by addition of
K2CO3. The phases were separated. The aqueous phase was
back-extracted with Et2O (5 ꢀ 100 mL). The organic phases
were washed with water and brine and dried over Na2SO4.
Removal of the solvent and chromatography on silica gel (1:5
EtOAc/PE) gave diol 15 as a colorless oil (2.220 g, 7.35 mmol,
94%): [R]23 -20.1 (c 1.05, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 5.78-5.72 (m, 2H), 4.43 (m, 1H), 4.20 (s, 2H), 3.62
(m, 1H), 3.08 (br, 1H), 2.84 (br, 1H), 1.70 (m, 1H), 1.59-1.24 (m,
4H), 0.95-0.82 (m, 15H), 0.06 (s, 6H); 13C NMR (100 MHz,
CHCl3) δ 130.6, 130.1, 74.9, 74.0, 63.2, 42.3, 37.6, 25.9, 18.6,
18.4, 14.1, 12.1, -5.2; FT-IR (film) 3398, 1463, 1254, 838, 776
cm-1; ESI-MS m/z 325.3 ([M þ Na]þ); ESI-HRMS calcd for
C16H34O3SiNa ([M þ Na]þ) 325.2169, found 325.2166.
(2E)-3-((4S,5S,6S)-2,2,5-Trimethyl-6-propyl-1,3-dioxan-4-yl)-
prop-2-en-1-ol (16). A solution of TBAF (1.0 M in THF, 6.0 mL,
6.0 mmol) and diol 15 (906 mg, 3.0 mmol) in dry THF (6.0 mL)
was stirred at ambient temperature until TLC showed comple-
tion of the reaction. The mixture was concentrated on a rotary
evaporator. The residue was chromatographed on silica gel
(EtOAc) to give the intermediate triol as a yellowish oil (551
mg, 2.93 mmol), to which were added Me2C(OMe)2 (10 mL) and
CSA (65 mg, 0.287 mmol). The mixture was stirred at ambient
temperature for 48 h. Et3N (2 mL) was added. Stirring was
Data for 18 (purified by chromatography (1:6 EtOAc/PE) on
1
silica gel): [R]24 -11.5 (c 1.85, CHCl3); H NMR (300 MHz,
D
CDCl3) δ 7.39-7.26 (m, 5H), 5.50 (m, 2H), 5.43 (dd, J = 4.4, 9.0
Hz, 1H), 4.67 (t, J = 9.0 Hz, 1H), 4.36-4.26 (m, 2H), 4.21 (dd,
J = 4.0, 8.8 Hz, 1H), 3.93 (m, 1H), 3.23 (m, 1H), 1.63 (m, 1H),
1.59-1.50 (m, 4H), 1.32 (s, 3H), 1.31 (s, 3H), 1.01 (d, J = 6.8 Hz,
3H), 0.90 (t, J = 7.0 Hz, 3H), 0.75 (d, J = 7.0 Hz, 3H), -0.17 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 174.9, 153.4, 139.2, 131.6,
130.7, 129.1, 128.5, 126.2, 100.4, 75.3, 74.2, 70.0, 69.7, 57.7, 44.6,
41.0, 36.6, 25.1, 23.8, 19.1, 14.0, 13.9, 12.8, 0.08; FT-IR (film)
5058 J. Org. Chem. Vol. 75, No. 15, 2010

Ren et al.
JOCArticle
2959, 2874, 1783, 1708, 1495, 1457, 1382, 1250, 842 cm-1; ESI-
Removal of the organic solvent on a rotary evaporator and
column chromatography (1:3 EtOAc/PE) on silica gel gave diol
MS m/z 540.2 ([M þ Na]þ); ESI-HRMS calcd for C28H43NO6-
SiNa ([M þ Na]þ) 540.2752, found 540.2781.
26 as a colorless oil (730 mg, 2.17 mmol, 92%): [R]25 þ28.7
D
Data for 19: [R]26 -19.2 (c 0.90, CHCl3); H NMR (300
(c 4.80, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.69 (d, J = 6.7
Hz, 1H), 4.66 (d, J = 6.7 Hz, 1H), 3.85 (m, 1H), 3.81-3.70 (m,
2H), 3.62 (m, 2H), 3.40 (s, 3H), 3.39 (m, 1H), 2.42 (m, 1H),
1.92-1.62 (m, 2H), 1.52 (m, 2H), 1.40 (m, 2H), 0.92 (t, J = 7.4Hz,
3H), 0.90 (s, 9H), 0.09 (d, J = 3.8 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 95.6, 74.3, 73.6, 71.0, 63.6, 55.9, 38.4, 37.0, 25.7, 18.2,
17.9, 14.2, -4.4, -4.8; FT-IR (film) 3446, 2920, 2861, 2822, 1471,
836, 778 cm-1; ESI-MS m/z 359.2 ([M þ Na]þ); ESI-HRMS calcd
for C16H36O5SiNa ([M þ Na]þ) 359.2224, found 359.2234.
(3R,5S)-1,1-Dibromo-3-tert-butyldimethylsilyloxy-5-methoxy-
methoxyoctene (27). An aqueous solution of NaIO4 (0.65 M,
37.27 mmol) was added dropwise to a mixture of diol 26 (8.364 g,
24.9 mmol) and silica gel (300-400 mesh, 15.0 g) in CH2Cl2
(150 mL) and was vigorously stirred at ambient temperature.
After completion of the addition, stirring was continued for 1 h at
the same temperature before another portion of NaIO4 solution
(same as above, 37.27 mmol) was introduced dropwise. When
TLC showed completion of the reaction, the mixture was filtered
through Celite (washing with CH2Cl2). The filtrate and washings
werecombinedandwashedinturnwithwater andbrine anddried
over anhydrous Na2SO4. Removal of the solvent and chroma-
tography on silica gel (1:4 Et2O/PE) yielded the unstable inter-
mediate aldehyde (7.255 g, 23.9 mmol, 96%) as a colorless oil,
which was used immediately dissolved indry CH2Cl2 (20mL) and
added dropwsie to a solution of PPh3 (37.88 g, 143.0 mmol) and
CBr4 (23.73 g, 71.5 mmol) in dry CH2Cl2 (120 mL) stirred at 0 °C.
When the reaction was complete as shown by TLC, the mixture
was poured into hexanes (1000 mL) and then filtered through
Celite. The solvents were removed by rotary evaporation. The
residual was filtered through Celite again. The filtrate was con-
centrated on a rotary evaporator. The residue was chromato-
graphed (1:30 Et2O/PE) on silica gel to afford the gem-dibromide
1
D
MHz, CDCl3) δ 7.38-7.27 (m, 5H), 5.63-5.61 (m, 2H), 5.44
(dd, J = 3.9, 8.7 Hz, 1H), 4.69 (t, J = 8.8 Hz, 1H), 4.37 (t, J =
4.0 Hz, 1H), 4.24 (dd, J = 4.0, 8.8 Hz, 1H), 4.18 (m, 1H), 3.99
(m, 1H), 3.24 (m, 1H), 2.38 (d, J = 6.3 Hz, 1H), 1.64-1.58 (m,
2H), 1.45-1.38 (m, 3H), 1.33 (s, 6H), 1.14 (d, J = 7.3 Hz, 3H),
0.92 (t, J = 6.6 Hz, 3H), 0.74 (d, J = 6.5 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 175.7, 153.7, 138.7, 131.2, 131.0, 129.1, 128.6,
125.7, 100.6, 75.4, 74.2, 69.9, 69.7, 58.0, 43.5, 40.8, 36.6, 25.2,
23.8, 19.1, 14.3, 13.9, 12.6; FT-IR (film) 3503, 3033, 2935, 2874,
1782, 1705, 1382, 1222, 700 cm-1; ESI-MS m/z 468.3 ([M þ
Na]þ); ESI-HRMS calcd for C25H35NO6Na ([M þ Na]þ)
468.2357, found 468.2355.
(1S,3S)-1-tert-Butyldimethylsilyloxy-1-((4R)-2,2-dimethyl-
1,3-dioxolan-4-yl)-hexan-3-ol (24). PrMgBr (1.3 M in THF, 8.6
mL, 11.2 mmol) was added to a suspension of CuCN (10 mg,
0.11 mmol) in dry THF (7 mL) stirred at 0 °C under N2. The
stirring was continued at 0 °C for 10 min, which led to a clear
solution. The bath was then cooled to -10 °C. A solution of
epoxide 23 (1.190 g, 3.93 mmol) in THF (7 mL) was introduced
dropwise. After completion of the addition, the stirring was
continued at the same temperature for 12 h. Aqueous saturated
NH4Cl was added. The mixture was extracted with Et2O (4 ꢀ
50 mL). The organic layers were combined and washed in turn
with water and brine before being dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation and
column chromatography (1:5 Et2O/PE) on silica gel gave alco-
hol 24 as a colorless oil (1.266 g, 3.81 mmol, 97%): [R]25D þ21.9
(c 2.30, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.11-4.03 (m,
2H), 3.92-3.78 (m, 3H), 2.59 (br s, 1H), 1.74-1.67 (m, 2H), 1.42
(s, 3H), 1.36 (s, 3H),1.48-1.36 (m, 4H), 0.93 (t, J = 6.9 Hz, 3H),
0.85 (s, 9H), 0.09 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 109.4,
78.7, 71.4, 67.9, 67.3, 42.7, 40.1, 26.6, 25.8, 25.4, 18.8, 17.9, 14.1,
-4.1, -4.5; FT-IR (film) 3585, 2956, 2932, 838, 776 cm-1; ESI-
MS m/z 355.1 ([M þ Na]þ); ESI-HRMS calcd for C17H36SiO4-
Na ([M þ Na]þ) 355.2275, found 355.2275.
27 as a colorless oil (10.25 g, 22.4 mmol, 94%): [R]24 -27.2
D
(c 3.15, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.41 (d, J = 7.4
Hz, 1H), 4.69 (d, J = 6.7 Hz, 1H), 4.62 (d, J = 6.7 Hz, 1H), 4.43-
4.35 (m, 1H), 3.67-3.59 (m, 1H), 3.38 (s, 3H), 1.90-1.81 (m, 1H),
1.64-1.58 (m, 1H), 1.57-1.45 (m, 2H), 1.44-1.32 (m, 2H), 0.93
(1S,3S)-1-tert-Butyldimethylsilyloxy-1-((4R)-2,2-dimethyl-1,3-
dioxolan-4-yl)-3-methoxymethoxyhexane (25). MOMCl (1.52 mL,
19 mmol) was introduced dropwise to a solution of alcohol 24
(1.250 g, 3.80 mmol), DMAP (114 mg, 0.95 mmol), and i-Pr2NEt
(6.6 mL, 38.0 mmol) in dry CH2Cl2 (13 mL) stirred at 0 °C under
N2. The stirring was continued at ambient temperature until TLC
showed completion of the reaction. Aqueous saturated NaHCO3
(10 mL) was added. The mixture was extracted with Et2O (4 ꢀ
50 mL). The organic layers were combined and washed in turn
with water and brine, before being dried over anhydrous Na2SO4.
Removal of the solvent by rotary evaporation and column
chromatography (1:15 Et2O/PE) on silica gel gave the MOM
ether 25 as a yellowish oil (1.392 g, 3.70 mmol, 98%): [R]25D þ11.8
(c 2.26, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.67 (d, J = 6.6
Hz, 1H), 4.64 (d, J = 6.6 Hz, 1H), 4.09 (m, 1H), 3.98 (t, J = 6.8
Hz, 1H), 3.91-3.74 (m, 3H), 3.38 (s, 3H), 1.77-1.66 (m, 2H),
1.64-1.59 (m, 2H), 1.52-1.34 (m, 2H), 1.44 (s, 3H), 1.38 (s, 3H),
0.92 (t, J = 6.4 Hz, 3H), 0.90 (s, 9H), 0.09 (s, 6H); 13C NMR (75
MHz, CDCl3) δ 108.9, 95.4, 78.8, 74.2, 69.7, 66.1, 55.6, 40.3, 37.2,
26.6, 25.9, 25.4, 18.3, 18.0, 14.2, -4.2, -4.4; FT-IR (film) 2955,
2930, 1256, 1045, 838, 777 cm-1; ESI-MS m/z 399.2 ([M þ Na]þ);
ESI-HRMS calcd for C19H40SiO5Na ([M þ Na]þ) 399.2537,
found 399.2555.
(t, J = 7.2 Hz, 3H), 0.89 (s, 9H), 0.08 (d, J = 6.9 Hz, 6H); 13
C
NMR (75 MHz, CDCl3) δ 141.8, 95.8, 88.6, 74.3, 70.9, 55.6, 41.5,
36.7, 25.7, 18.3, 17.9, 14.2, -4.4, -5.0; FT-IR (film) 2956, 2930,
2821, 1621, 837, 777 cm-1; ESI-MS m/z 481.1 ([M þ Na]þ); ESI-
HRMScalcdfor C16H32SiO3Br2Na ([M þ Na]þ) 481.0380, found
481.0387.
(3R,5S)-3-tert-Butyldimethylsilyloxy-5-methoxymethoxyoc-
tyne (9). n-BuLi (2.5 M, in hexanes, 20.9 mL, 52.2 mmol) was
added via syringe to a solution of the gem-dibromide 27 (9.57 g,
20.9 mmol) in dry THF (100 mL) stirred at -10 °C under N2.
After completion of the addition, stirring was continued at the
same temperature for 30 min before aq saturated NH4Cl was
introduced. The mixture was extracted with Et2O (3 ꢀ 100 mL).
The organic phases were combined and washed with water and
brine anddried overanhydrous Na2SO4. Rotaryevaporation and
column chromatography (1:15 Et2O/PE) on silica gel gave the
alkyn 9 (6.14 g, 20.5 mmol, 98%) as a yellowish oil: [R]24D -16.8
(c 3.05, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.66 (s, 2H), 4.54
(ddd, J = 2.1, 6.0, 8.1 Hz, 1H), 4.82-4.72 (m, 1H), 3.39 (s, 3H),
2.44 (d, J = 2.0 Hz, 1H), 1.99-1.77 (m, 2H), 1.60-1.44 (m, 2H),
1.42-1.30 (m, 2H), 0.93 (t, J = 6.9 Hz, 3H), 0.91 (s, 9H), 0.14 (d,
J = 8.5 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 95.6, 85.1, 74.6,
72.8, 60.5, 55.6, 43.6, 36.8, 25.7, 18.3, 18.1, 14.1, -4.6, -5.1; FT-
IR (film) 3312, 2958, 2823, 1472, 838, 778 cm-1; EI-MS m/z (%)
255 ([Μ - CH2OCH3]þ, 0.82), 211 (6), 161 (9), 143 (19), 89 (99),
45 (100); EI-HRMS calcd for C14H27O2Si ([M - CH2OCH3]þ)
255.1780, found 255.1789.
(2R,3S,5S)-3-tert-Butyldimethylsilyloxy-5-methoxymethoxy-
octane-1,2-diol (26). A solution of acetonide 25 (890 mg, 2.37
mmol) and CF3CO2H (50% aq solution, 3.4 mL) in CH2Cl2 (78
mL) was stirred at ambient temperature for 1 h. The mixture was
diluted with Et2O (300 mL), washed with aq saturated NaHCO3
(20 mL), water, and brine, and dried over anhydrous Na2SO4.
J. Org. Chem. Vol. 75, No. 15, 2010 5059

Ren et al.
JOCArticle
(4R)-3-[(2R,3S,4E)-3-Hydroxy-2-methyl-6-(4-methoxybenzy-
loxy)-hex-4-enoyl]-4-phenyloxazolidin-2-one (29). Freshly dis-
tilled TiCl4 (5.7 mL, 52.0 mmol) was added (via a syringe)
dropwise to a solution of acyloxazolidinone 7 (10.95 g, 50.0
mmol) in dry CH2Cl2 (300 mL) stirred at 0 °C under N2. The
resulting yellow solution was stirred the same temperature for
10 min before neat TMEDA (20.8 mL, 130.0 mmol) was added
dropwise (resulting in a dark red-brown solution). After stirring
at 0 °C for another 20 min, a solution of aldehyde 28 (10.4 g,
50.5 mmol) in dry CH2Cl2 (20 mL) was introduced via a syringe.
The stirring was continued at 0 °C for 10 h. Aqueous NH4Cl was
added. The voluminous yellow precipitates were filtered off
through Celite. The filtrate was washed in turn with water and
brine and dried over anhydrous Na2SO4. Rotary evaporation
and column chromatography (1:2 EA/PE) on silica gel afforded
ESI-MS m/z 377.2 ([M þ Na]þ); ESI-HRMS calcd for C22H26-
O4Na ([M þ Na]þ) 377.1723, found 377.1733. Anal. Calcd for
C22H26O4: C, 74.55; H, 7.39. Found: C, 74.52; H, 7.44.
(2S,3S,4E)-1-Benzyloxy-2-methyl-6-(4-methoxybenzyloxy)-
hex-4-en-3-ol (32) and (2S,3S,4E)-3-Benzyloxy-2-methyl-6-(4-
methoxybenzyloxy)-hex-4-en-1-ol (33). DIBAL-H (1.0 M, in
cyclohexane, 134.8 mL, 134.8 mmol) was added dropwise to a
solution of (11.93 g, 33.6 mmol) in dry CH2Cl2 (80 mL) stirred at
0 °C under N2. After completion of the addition, the cooling
bath was removed and the stirring was continued at ambient
temperature until TLC showed completion of the reaction.
Aqueous saturated potassium sodium tartrate (100 mL) was
added, followed by Et2O (300 mL). The mixture was stirred at
ambient temperature for 2 h. The phases were separated. The
aqueous layer was back-extracted with Et2O. The organic
phases were combined and washed in turn with water and brine
and dried over anhydrous Na2SO4. Removal of the solvent by
rotary evaporation followed by column chromatography (1:4
EtOAc/PE) on silica gel gave 32 (less polar) and 33 (more polar)
(1:13 as determined by 1H NMR before chromoatography, 11.4
g altogether after chromatography, 32.1 mmol, 95% in total).
The two alcohols are separable on silica gel; on preparative
scales, one chromatography normally could afford 85-91% of
the enantiopure 32, along with a mixture of 32 and 33.
the aldol 29 (17.9 g, 42.1 mmol, 84%) as a yellowish oil: [R]29
-58.9 (c 3.75, CHCl3); H NMR (400 MHz, CDCl3) δ 7.39-
D
1
7.25 (m, 7H), 6.87 (d, J=8.8 Hz, 2H), 5.86 (dt, J =15.7, 5.3 Hz,
1H), 5.76 (dd, J=15.7, 5.4 Hz, 1H), 5.40 (dd, J =8.9, 3.7 Hz,
1H), 4.65 (t, J = 8.9 Hz, 1H), 4.50 (m, 1H), 4.44 (s, 2H), 4.21 (dd,
J = 8.9, 3.8 Hz, 1H), 4.00 (d, J=5.4 Hz, 2H), 3.93-3.91 (m, 1H),
3.80 (s, 3H), 2.90 (br, 1H), 1.15 (d, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 176.0, 159.1, 153.3, 138.8, 131.8, 130.2,
129.3, 129.2, 128.7, 128.6, 125.5, 113.7, 71.72, 71.65, 69.8, 69.6,
57.5, 55.2, 42.6, 11.0; FT-IR (film) 3504, 2936, 1775, 1702, 1513,
1383, 1248, 1034, 978, 705 cm-1; ESI-MS m/z 448.2 ([M þ
Na]þ); ESI-HRMS calcd for C24H27NO6Na ([M þ Na]þ)
448.1731, found 448.1731.
Data for 32 (the less polar component, yellowish oil): [R]27
D
þ3.2 (c 1.50, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.34-7.25
(m, 7H), 6.87 (d, J = 8.6 Hz, 2H), 5.88-5.71 (m, 2H), 4.50 (s,
2H), 4.44 (s, 2H), 4.29-4.25 (m, 1H), 4.00 (d, J = 5.1 Hz, 2H),
3.80 (s, 3H), 3.50 (m, 2H), 2.90 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 159.2, 138.0, 133.4, 130.5, 129.4, 128.5, 127.8, 127.7,
113.8, 74.5, 73.8, 73.5, 71.7, 70.0, 55.3, 38.5, 11.8; FT-IR (film)
3448, 2933, 2856, 1612, 1513, 1454, 1248, 820, 699 cm-1; ESI-
MS m/z 379.2 ([M þ Na]þ); ESI-HRMS calcd for C22H28O4Na
([M þ Na]þ) 379.1880, found 379.1894.
(2S,3S,4E)-2-Methyl-6-(4-methoxybenzyloxy)-hex-4-ene-1,3-
diol (30). A solution of NaBH4 (6.001 g, 158.0 mmol) in H2O
(20 mL) was added dropwise to a solution of (16.8 g, 39.5 mmol)
in THF stirred at 0 °C. After completion of the addition, the
cooling bath was removed and the stirring was continued at
ambient temperature for 2 h. The reaction was quenched with aq
HCl (2 M). The volatiles were removed by rotary evaporation.
The residue was extracted with EtOAc. The organic phase was
washed in turn with water and brine and dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation led to
precipitation of a white solid (the acyloxazolidinone 7), which
was collected by filtrate (5.4 g, 33.1 mmol, 84%). The filtrate was
concentrated on a rotary evaporator. The residue was purified
by column chromatography (1:1 EtOAc/PE) on silica gel to
Data for 33 (the more polar component, yellowish oil): [R]26
D
þ35.1 (c 4.40, CHCl3); 1H NMR (300 MHz, CDCl3) δ
7.32-7.24 (m, 7H), 6.88 (d, J = 9.0 Hz, 2H), 5.88-5.71 (m,
2H), 4.61 (d, J = 12.2 Hz, 1H), 4.46 (s, 2H), 4.33 (d, J = 12.3 Hz,
1H), 4.05 (d, J = 5.1 Hz, 2H), 3.93 (dd, J = 4.5, 7.2 Hz, 1H), 3.78
(s, 3H), 3.65 (dd, J = 7.5, 10.8 Hz, 1H), 3.50 (dd, J = 4.5, 10.9
Hz, 1H), 2.58 (br, 1H), 2.02-1.91 (m, 1H), 0.90 (d, J = 6.9 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 159.1, 138.2, 131.0, 130.3,
130.0, 129.3, 128.3, 127.54, 127.50, 113.7, 82.2, 71.8, 70.3, 69.6,
65.5, 55.1, 39.7, 12.1; FT-IR (film) 3448, 2933, 2861, 1612, 1513,
1454, 1248, 820, 699 cm-1; ESI-MS m/z 379.2 ([M þ Na]þ); ESI-
HRMS calcd for C22H28O4Na ([M þ Na]þ) 379.1880, found
379.1874.
yield the diol 30 (9.8 g, 36.8 mmol, 93%) as a colorless oil: [R]24
-4.3 (c 2.85, CHCl3); H NMR (300 MHz, CDCl3) δ 7.26 (d,
D
1
J = 7.9 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 5.84-5.72 (m, 2H),
4.45 (s, 2H), 4.29 (m, 1H), 4.01 (d, J = 4.4 Hz, 2H), 3.79 (s, 3H),
3.64-3.52 (m, 2H), 3.39 (br, 1H), 3.27 (br, 1H), 1.96-1.82 (m,
1H), 0.84 (d, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
159.1, 133.3, 130.0, 129.4, 127.6, 113.7, 74.6, 71.8, 69.8, 65.8,
55.2, 39.5, 11.2; FT-IR (film) 3423, 2875, 1670, 1612, 1514, 1248,
1032, 821, 758 cm-1; ESI-MS m/z 289.1 ([M þ Na]þ); ESI-
HRMS calcd for C15H22O4Na ([M þ Na]þ) 289.1410, found
289.1417.
(2S,3R,4R,5S,6E)-5-Benzyloxy-1-((4S)-4-benzyl-2-thioxo-oxaz-
olidin-3-yl)-3-hydroxy-2,4-dimethyl-8-(4-methoxybenzyloxy)-
oct-6-en-1-one (36). Dess-Martin periodinane (596 mg, 1.40
mmol) and NaHCO3 (252 mg, 3.0 mmol) were added in turn to a
solution of 33 (356 mg, 1.0 mmol) in dry CH2Cl2 (5 mL) stirred
at ambient temperature. The mixture was stirred until TLC
showed completion of the reaction. Et2O (100 mL) was added.
The solids were filtered off through Celite. The filtrate was con-
centrated on a rotary evaporator. The residue was purified by
column chromatography (1:8 EtOAc/PE) to afford the inter-
mediate aldehyde 34 (334 mg, 0.94 mmol, 94%) as a yellowish
oil.
Freshly distilled TiCl4 (155 μL, 1.42 mmol) was added drop-
wise to a solution of acyloxazolidinethione 35 (337 mg, 1.35
mmol) in dry CH2Cl2 (7 mL) stirred at 0 °C under N2. The
resulting yellow solution was stirred for 10 min before neat
(-)-sparteine (0.78 mL, 3.38 mmol) was added dropwise. The
resulting dark red-brown mixture was stirred at 0 °C for 20 min
before a solution of the above-mentioned aldehyde 34 (319 mg,
0.90 mmol) in dry CH2Cl2 (1.2 mL) was introduced via syringe.
The stirring was continued at the same temperature for 2 h.
(4R,5S)-5-Methyl-4-[(1E)-3-(4-methoxybenzyloxy)-propenyl]-
2-phenyl-1,3-dioxane (31). A solution of diol 30 (9.8 g, 36.8
mmol) and CSA (853 mg, 3.68 mmol) in PhCH(OMe)2 (12
mL) wasstirred at ambient temperature under aspirator vacuum.
When TLC showed completion of the reaction, the mixture was
chromatographed (1:30 to 1:7 EtOAc/PE) on silica gel to yield
acetonide 31 (11.93 g, 33.6 mmol, 91%) as a yellowish oil: [R]24
D
-2.5 (c 0.50, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.53-7.25
(m, 7H), 6.88 (d, J = 8.7 Hz, 2H), 5.90 (dt, J = 5.6, 15.7 Hz, 1H),
5.80 (dd, J = 4.9, 15.8 Hz, 1H), 5.57 (s, 1H), 4.56 (m, 1H), 4.46 (s,
2H), 4.17-4.05 (m, 2H), 4.02 (d, J = 5.6 Hz, 2H), 3.80 (s, 3H),
1.69-1.65 (m, 1H), 1.24 (d, J = 7.1 Hz, 3H); 13C NMR(75 MHz,
CHCl3) δ 159.2, 138.7, 131.2, 130.4, 129.3, 128.8, 128.2, 127.8,
126.2, 113.8, 101.7, 79.4, 73.3, 71.8, 69.9, 55.2, 32.9, 11.5; FT-IR
(film) 3064, 2963, 2851, 1612, 1586, 1513, 1465, 820, 755 cm-1
;
5060 J. Org. Chem. Vol. 75, No. 15, 2010

Ren et al.
JOCArticle
Aqueous NH4Cl was added. The resulting mixture was filtered
through Celite. The filtrate was washed in turn with water and
brine and dried over anhydrous Na2SO4. Rotary evaporation
and column chromatography (1:4 EtOAc/PE) on silica gel
afforded the aldol 36 (509 mg, 0.843 mmol, 94% from 34 or
88% from 33) as a yellow oil: [R]26D þ30.1 (c 4.45, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 7.34-7.19 (m, 12H), 6.86 (d, J = 8.4
Hz, 2H), 5.88-5.72 (m, 2H), 4.92-4.79 (m, 2H), 4.60 (d, J =
11.8 Hz, 1H), 4.45 (s, 2H), 4.36 (d, J = 11.6 Hz, 1H), 4.27-4.16
(m, 3H), 4.10 (m, 1H), 4.05 (d, J = 4.4 Hz, 2H), 3.84 (d, J = 2.8
Hz, 1H), 3.78 (s, 3H), 3.29 (dd, J = 3.2, 13.0 Hz, 1H), 2.74 (dd,
J = 10.4, 13.1 Hz, 1H), 1.90 (m, 1H), 1.28 (d, J = 6.6 Hz, 3H),
0.95 (d, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 184.9,
177.4, 159.1, 138.0, 135.2, 131.0, 130.1, 130.0, 129.30, 129.27,
128.9, 128.3, 127.52, 127.50, 127.3, 113.7, 81.4, 72.9, 71.8, 70.7,
70.0, 69.6, 60.4, 55.1, 40.5, 40.1, 37.4, 11.5, 10.0; FT-IR (film)
127.8, 127.7, 113.8, 80.9, 73.6, 71.9, 70.7, 69.7, 55.3, 51.8, 42.3,
39.9, 11.6, 9.7; FT-IR (film) 3495, 2939, 1736, 1612, 1513, 1455,
1248, 1066, 976, 700 cm-1; ESI-MS m/z 465.2 ([M þ Na]þ); ESI-
HRMS calcd for C26H34O6Na ([M þ Na]þ) 465.2248, found
465.2256.
(3S,4R,5R,6S)-4-Hydroxy-6-(3-hydroxypropyl)-3,5-dimethy-
ltetrahydropyran-2-one (38). A solution of 37 (13 mg, 30.8 μmol)
and 10% Pd-C (33 mg) in MeOH (1 mL) was stirred at ambient
temperature under H2 (1 atm) atmosphere for 24 h. The solid
was filtered off. The filtrate was concentrated on a rotary
evaporator. The residue was dissolved in toluene (1 mL). CSA
(3.6 mg, 15.4 μmol) was added. The mixture was stirred at
ambient temperature for 2 h. Aqueous saturated NaHCO3 was
added. The mixture was extracted with EtOAc (3 ꢀ 5 mL). The
organic phases were combined and washed in turn with water
and brine and dried over anhydrous Na2SO4. Removal of the
solvent by rotary evaporation and column chromatography (4:1
EtOAc/PE) on silica gel yielded the lactone 38 (4.5 mg, 22.3
μmol, 72%) as a colorless oil: [R]26D -92.2 (c 0.40, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 4.31 (d, J = 4.3 Hz, 1H), 4.29 (m,
1H), 3.84 (dt, J = 10.3, 4.1 Hz, 1H), 3.59-3.52 (m, 2H), 3.50 (t,
J = 5.2 Hz, 1H), 2.33 (dq, J = 10.2, 6.8 Hz, 1H), 2.19-2.10 (m,
1H), 1.80-1.70 (m, 1H), 1.70-1.61 (m, 2H), 1.60-1.52 (m, 1H),
1.28 (d, J = 7.0 Hz, 3H), 0.92 (d, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, acetone-d6) δ 173.6, 80.1, 73.8, 62.1, 40.6, 38.3, 29.8,
29.7, 14.6, 4.7; FT-IR (film) 3398, 2942, 1719, 1218, 1039, 983
cm-1; ESI-MS m/z 225.0 ([M þ Na]þ); ESI-HRMS calcd for
C10H18O4Na ([M þ Na]þ) 225.1097, found 225.1107.
3503, 2920, 2851, 1737, 1697, 1513, 1454, 1364, 1191, 957 cm-1
;
ESI-MS m/z 626.4 ([M þ Na]þ); ESI-HRMS calcd for
C35H41NO6SNa ([M þ Na]þ) 626.2547, found 626.2532.
(2S,3R,4R,5S,6E)-5-Benzyloxy-1-((4R)-4-benzyl-2-thioxo-oxa-
zolidin-3-yl)-3-hydroxy-2,4-dimethyl-8-(4-methoxybenzyloxy)-oct-
6-en-1-one (360). Freshly distilled TiCl4 (150 μL, 1.41 mmol) was
added dropwise to a solution of acyloxazolidinethione ent-35
(176 mg, 0.707 mmol) in dry CH2Cl2 (6 mL) stirred at 0 °C under
N2. The resulting yellow solution was stirred for 10 min before
neat (-)-sparteine (180 μL, 0.78 mmol) was added dropwise. The
resulting dark red-brown mixture was stirred at 0 °C for 20 min
before a solution of the above-mentioned aldehyde 34 (167 mg,
0.471 mmol) in dry CH2Cl2 (1 mL) was introduced via syringe.
The stirring was continued at the same temperature for 2 h.
Aqueous NH4Cl was added. The resulting mixture was filtered
through Celite. The filtrate was washed in turn with water and
brine and dried over anhydrous Na2SO4. Rotary evaporation and
column chromatography (1:3 EtOAc/PE) on silica gel afforded 360
as a colorless oil (242 mg, 0.40 mmol, 85%). If the (-)-sparteine
was replaced by i-Pr2NEt (140 μL, 0.78 mmol), 360 was obtained
(4S,5R,6R,7S,8R,2E)-4-Benzyloxy-11-tert-butyldimethylsily-
loxy-1-(4-methoxybenzyloxy)-13-methoxymethoxy-5,7-dimeth-
yl-6-trimethylsilyloxyhexadec-2-en-9-yn-8-ol (41a) and (4S,5R,
6R,7S,8S,4E)-4-Benzyloxy-11-tert-butyldimethylsilyloxy-1-(4-meth-
oxybenzyloxy)-13-methoxymethoxy-5,7-dimethyl-6-trimethylsilyloxy-
hexadec-2-en-9-yn-8-ol (41b). TMSCl (1.20 mL, 9.49 mmol) was
added dropwise to a solution of 36 (2.293 g, 3.80 mmol) and 2,6-
lutidine (1.44 mL, 11.4 mmol) in dry DMF (15 mL) stirred at 0 °C
under N2. After completion of the addition, the cooling bath was
removed. The stirring was continued at ambient temperature for 2 h.
Aqueous saturated NaHCO3 was added. The mixture was extracted
with Et2O (3 ꢀ 50 mL). The organic phases were combined and
washed in turn with water and brine and dried over anhydrous
Na2SO4. Removal of the solvent and column chromatography (1:8
EtOAc/PE) gave the unstable TMS-ether 39 (2.309 g, 3.42 mmol,
90%) as a colorless oil, which was used immediately in the next step:
FT-IR (film) 2957, 2853, 1699, 1612, 1513, 1364, 841, 746 cm-1; ESI-
MS m/z698.4 ([M þ Na]þ);ESI-HRMScalcdforC38H49NO6NaSSi
([M þ Na]þ) 698.2942, found 698.2957.
in 76% yield under the otherwise identical conditions.
1
Data for 360: [R]26 -54.6 (c 1.25, CHCl3); H NMR (300
D
MHz, CDCl3) δ 7.34-7.21 (m, 12H), 6.89 (d, J = 8.6 Hz, 2H),
5.89-5.71 (m, 2H), 4.96 (m, 1H), 4.92 (m, 1H), 4.65 (d, J = 11.7
Hz, 1H), 4.49 (s, 2H), 4.41 (d, J = 11.8 Hz, 1H), 4.31-4.23 (m,
4H), 4.09 (d, J = 4.4 Hz, 2H), 3.81 (s, 3H), 3.80 (br, 1H), 3.30
(dd, J = 3.1, 13.3 Hz, 1H), 2.68 (dd, J = 10.3, 13.3 Hz, 1H), 1.95
(m, 1H), 1.25 (d, J = 6.6 Hz, 3H), 0.99 (d, J = 6.9 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) δ 185.0, 177.3, 159.1, 138.0, 135.2,
131.1, 130.1, 130.0, 129.31, 129.29, 128.9, 128.3, 127.6, 127.3,
113.7, 81.6, 72.6, 71.8, 70.8, 70.1, 69.7, 59.9, 55.2, 40.7, 40.2,
37.7, 11.6, 10.0; FT-IR (film) 3477, 3062, 3028, 2973, 2858, 1702,
1612, 1513, 1454, 1369, 958, 821, 752 cm-1; ESI-MS m/z 626.4
([M þ Na]þ); ESI-HRMS calcd for C35H41NO6SNa ([M þ
Na]þ) 626.2547, found 626.2575.
Methyl (2S,3R,4R,5S,6E)-5-Benzyloxy-3-hydroxy-8-(4-meth-
oxybenzyloxy)-2,4-dimethyloct-6-enate (37). A solution of 36
(80 mg, 0.133 mmol) and DMAP (3.2 mg, 0.027 mmol) in dry
CH2Cl2 (2 mL) and MeOH (0.1 mL) was stirred at ambient
temperature until TLC showed completion of the reaction. The
mixture was diluted with CH2Cl2 (20 mL), washed in turn with
water and brine, and dried over anhydrous Na2SO4. Removal of
the solvent by rotary evaporation and column chromatography
(1:3 EtOAc/PE) on silica gel yielded the methyl ester 37 (42 mg,
0.10 mmol, 70%) as a colorless oil: [R]26D þ32.1 (c 0.75, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.33-7.26 (m, 7H), 6.89 (d, J =
8.4 Hz, 2H), 5.88-5.74 (m, 2H), 4.61 (d, J = 11.6 Hz, 1H), 4.47
(s, 2H), 4.34 (d, J = 11.7 Hz, 1H), 4.22 (m, 1H), 4.06 (d, J = 4.3
Hz, 2H), 3.97 (dt, J = 8.4, 4.0 Hz, 1H), 3.81 (s, 3H), 3.69 (s, 3H),
3.53 (d, J = 3.9 Hz, 1H), 2.51 (m, 1H), 1.81 (m, 1H), 1.15 (d, J =
7.0 Hz, 3H), 0.86 (d, J = 7.0 Hz, 3H); 13C NMR (75 MHz,
CHCl3) δ 176.2, 159.2, 138.0, 131.0, 130.3, 130.2, 129.4, 128.4,
DIBAL-H (1.0 M, in cyclohexane, 8.5 mL, 8.5 mmol) was
added dropwise to a solution of the above-mentioned 39 (2.30 g,
3.41 mmol) in dry CH2Cl2 (10 mL) stirred at -78 °C under
argon. The mixture was stirred at the same temperature for 2 h.
Aqueous saturated potassium sodium tartrate (10 mL) was
added, followed by Et2O (100 mL). The mixture was stirred at
ambient temperature until the phases were clear and separated.
The aqueous layer was back-extracted with Et2O (3 ꢀ 50 mL).
The organic phases were combined and washed in turn with
water and brine and dried over anhydrous Na2SO4. Removal of
the solvent by rotary evaporation followed by column chroma-
tography (1:4 EtOAc/PE) on silica gel gave the intermediate
aldehyde 40 (1.525 g, 3.14 mmol, 92%) as a colorless oil, which
1
was used immediately in the next step: H NMR (300 MHz,
CDCl3) δ 9.71 (s, 1H), 7.24-7.25 (m, 7H), 6.90 (d, J = 8.4 Hz,
2H), 5.90-5.75 (m, 2H), 4.61 (d, J = 12 Hz, 1H), 4.50-4.40 (m,
1H), 4.47 (s, 2H), 4.31 (br d, J = 12 Hz, 1H), 4.22-4.17 (m, 1H),
4.07-4.02 (br s, 2H), 3.81 (s, 3H), 2.50 (m, 1H), 1.70 (m, 1H),
1.07 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H), 0.07 (s, 9H).
n-BuLi (2.5 M in hexanes, 1.44 mL, 3.60 mmol) was added to
a solution of the alkyne (1.081 g, 3.60 mmol) in dry THF (20 mL)
J. Org. Chem. Vol. 75, No. 15, 2010 5061

Ren et al.
JOCArticle
stirred at -20 °C under N2. The stirring was continued at that
temperature for 30 min before a solution of aldehyde 40 (1.579 g,
3.26 mmol) in dry THF (3 mL) was introduced dropwise over
30 min. After completion of the addition, the mixture was stirred
at the same temperature for another 15 min. Aqueous saturated
NH4Cl was added. The mixture was extracted with Et2O (3 ꢀ
100 mL). The organic phases were combined, washed in turn
with water and brine, and dried over NaSO4. Removal of the
solvent and chromatography on silica gel (1:8 EtOAc/PE)
yielded the less polar isomer 41b (1.539 g, 1.96 mmol, 60%)
and the more polar 41a (1.012 g, 1.29 mmol, 40%).
addition, stirring was continued at the same temperature until
TLC showed completion of the reaction. Aqueous saturated
NaHCO3 was added. The mixture was extracted with Et2O (3 ꢀ
100 mL). The organic phases were combined, washed with water
and brine, and dried over anhydrous NaSO4. Removal of the
solvent and chromatography on silica gel (1:4 EtOAc/PE) gave
diol 42b (1.526 g, 2.14 mmol, 95%) as a colorless oil: [R]24D -20.8
1
(c 1.20, CHCl3); H NMR (300 MHz, CDCl3) δ 7.33-7.27 (m,
7H), 6.89 (d, J = 8.5 Hz, 2H), 5.85 (m, 2H), 4.66-4.61 (m, 4H),
4.47 (s, 2H), 4.40 (t. J = 7.1 Hz, 1H), 4.35 (d, J = 11.5 Hz, 1H),
4.24 (m, 1H), 4.05 (m, 3H), 3.85 (br s, 1H), 3.82-3.78 (m, 1H),
3.81 (s, 3H), 3.54 (m, 1H), 3.37 (s, 3H), 2.06-1.84 (m, 2H),
1.82-1.70 (m, 2H), 1.58-1.44 (m, 2H), 1.40-1.31 (m, 2H), 1.02
(d, J = 6.4 Hz, 3H), 0.90 (t, J = 6.9 Hz, 3H), 0.89 (s, 9H), 0.75 (d,
J = 6.9 Hz, 3H), 0.12 (d, J = 7.9 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 159.2, 137.8, 132.2, 130.1, 129.4, 129.3, 128.5, 127.73,
127.67, 113.8, 95.3, 86.3, 85.7, 83.1, 74.4, 72.3, 71.9, 70.5, 69.8,
66.2, 60.8, 55.5, 55.2, 43.6, 40.2, 39.6, 37.0, 25.8, 18.4, 18.1, 14.1,
12.4, 9.4, -4.4, -5.1; FT-IR (film) 3446, 2928, 1614, 1514, 1097,
969, 837 cm-1; ESI-MS m/z 735.4 ([M þ Na]þ); ESI-HRMS calcd
for C41H64O8SiNa ([M þ Na]þ) 735.4263, found 735.4257.
(4S,5R,2E)-4-Benzyloxy-1-(4-methoxy-benzyloxy)-5-[(4R,5S,6R)-
6-(3-tert-butyldimethylsilyl-5-methoxymethoxyoctyn-1-yl)-2,2,5-
trimethyl-1,3-dioxinan-4-yl]-2-hexene (43a). The procedure was
the same as described below for converting 42b into 43b. Datafor
43a (a colorless oil, 63% over two steps from 41a): [R]28D -21.1
(c 0.15, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.32-7.23 (m,
7H), 6.88 (d, J = 8.5 Hz, 2H), 5.82-5.75 (m, 2H), 4.76 (s, 1H),
4.58 (d, J = 6.8 Hz, 2H), 4.56 (d, J = 11.7 Hz, 1H), 4.31 (d, J =
11.7Hz, 1H), 4.55(t, J = 9.0 Hz, 1H), 4.45(s, 2H), 4.39-4.37(m,
1H), 4.28 (d, J = 6.4 Hz, 1H), 4.24 (dd, J = 2.7, 10.3 Hz, 1H),
4.03 (d, J = 5.5 Hz, 2H), 3.80 (s, 3H), 3.71-3.69 (m, 1H), 3.32 (s,
3H), 1.93-1.79 (m, 3H), 1.63-1.60 (m, 1H), 1.51-1.47 (m, 2H),
1.37-1.26 (m, 2H), 1.48 (s, 3H), 1.34 (s, 3H), 1.02 (d, J = 6.9 Hz,
3H), 0.89 (t, J = 7.3 Hz, 3H), 0.87 (s, 9H), 0.86 (t, J = 7.0 Hz,
3H), 0.09 (d, J = 4.6 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ
159.3, 139.2, 132.8, 130.5, 129.3, 128.8, 128.2, 127.2, 127.1, 113.9,
100.6, 95.8, 86.9, 85.1, 77.1 (revealed by HMQC), 74.9, 71.8,
70.9, 70.0, 68.2, 67.5, 60.8, 55.5, 55.3, 43.7, 39.7, 36.9, 36.2, 28.6,
25.8, 23.7, 18.3, 18.1, 14.2, 11.3, 8.1, -4.4, -5.0; FT-IR (film)
2930, 2856, 1613, 1513, 1459, 1010, 837, 778 cm-1; ESI-MS m/z
775.5 ([M þ Na]þ); ESI-HRMS calcd for C44H68O8SiNa ([M þ
Na]þ) 775.4576, found 775.4594.
Data for 41a (a yellowish oil, the more polar component,
(10R)-isomer): [R]24 -21.8 (c 2.50, CHCl3); 1H NMR (300
D
MHz, CDCl3) δ 7.33-7.25 (m, 7H), 6.88 (d, J = 8.6 Hz, 2H),
5.82-5.80 (m, 2H), 4.63 (t, J = 7.0 Hz, 1H), 4.58-4.53 (m, 3H),
4.45 (s, 2H), 4.33 (d, J = 12 Hz, 1H), 4.21 (m, 1H), 4.14 (m, 1H),
4.07-4.02 (m, 3H), 3.84-3.76 (m, 1H), 3.80 (s, 3H), 3.35 (s, 3H),
2.59 (m, 1H), 1.92-1.80 (m, 3H), 1.71 (m, 1H), 1.52-1.43 (m,
2H), 1.41-1.30 (m, 2H), 0.99 (d, J = 6.7 Hz, 3H), 0.93 (d, J =
7.0 Hz, 3H), 0.90 (t, J = 7.0 Hz, 3H), 0.86 (s, 9H), 0.15 (s, 9H),
0.07 (d, J = 1.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 159.1,
139.1, 133.2, 130,.2, 129.5, 129.3, 128.1, 127.0, 126.9, 113.7, 95.1,
87.2, 85.5, 78.9, 74.9, 74.3, 71.8, 69.9, 69.7, 65.9, 60.8, 55.4, 55.2,
43.5, 43.4, 42.7, 37.4, 25.7, 18.4, 18.0, 14.1, 10.4, 8.8, 1.0, -4.4,
-5.2; FT-IR (film) 3438, 2956, 2857, 1676, 1612, 1514, 838
cm-1; ESI-MS m/z 807.5 ([M þ Na]þ); ESI-HRMS calcd for
C44H72Si2O8Na ([M þ Na]þ) 807.4658, found 807.4673.
Data for 41b (a yellowish oil, the less polar component, (10S)-
1
isomer): [R]24 -20.9 (c 2.30, CHCl3); H NMR (300 MHz,
D
CDCl3) δ 7.34-7.27 (m, 7H), 6.89 (d, J = 8.4 Hz, 2H), 5.83-
5.81 (m, 2H), 4.69 (d, J = 6.9 Hz, 1H), 4.65 (d, J = 6.9 Hz, 1H),
4.61-4.58 (m, 2H), 4.47 (s, 2H), 4.34 (d, J = 12.2 Hz, 1H), 4.23
(d, J = 9.1 Hz, 1H), 4.18 (d, J = 4.3 Hz, 1H), 4.12 (dd, J = 5.5,
8.8 Hz, 1H), 3.86-3.81 (m, 1H), 3.81 (s, 3H), 3.40 (s, 3H), 2.41
(m, 1H), 1.98-1.90 (m, 1H), 1.90-1.78 (m, 2H), 1.66 (m, 1H),
1.52 (m, 2H), 1.41 (m, 2H), 0.95-0.91 (m, 18H), 0.16 (s, 9H),
0.14 (d, J = 9.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 159.2,
139.2, 133.4, 130.2, 129.4, 128.1, 127.04, 127.00, 113.8, 95.0,
86.3, 79.0, 74.1, 71.8, 71.7, 69.9, 64.3, 60.9, 55.5, 55.2, 43.5, 43.2,
42.3, 37.3, 25.7, 18.4, 18.1, 14.1, 10.0, 9.7, 0.9, -4.5, -5.1; FT-IR
(film) 3438, 2956, 2857, 1676, 1612, 1514, 838 cm-1; ESI-MS m/z
807.5 ([M þ Na]þ); ESI-HRMS calcd for C44H72Si2O8Na ([M þ
Na]þ) 807.4658, found 807.4658.
(4S,5R,6R,7S,8R,2E)-4-Benzyloxy-11-tert-butyldimethylsilyl-
oxy-1-(4-methoxybenzyloxy)-13-methoxymethoxy-5,7-dimethyl-
hexadec-2-en-9-yne-6,8-diol (42a). The procedure was the same
as described below for converting 41b into 42b. Data for 42a
(a colorless oil, 91% from 41a): [R]24D -18.8 (c 1.80, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 7.35-7.26 (m, 7H), 6.90 (d, J = 8.6
Hz, 2H), 5.91-5.75 (m, 2H), 4.68-4.60 (m, 4H), 4.57 (t, J = 7.8
Hz, 1H), 4.48 (s, 2H), 4.36 (d, J = 11.8 Hz, 1H), 4.09-4.07 (m,
4H), 3.91 (d, J = 9.7 Hz, 1H), 3.83-3.75 (m, 1H), 3.81 (s, 3H),
3.72 (br, 1H), 3.37 (s, 3H), 2.06-1.96 (m, 1H), 1.92-1.84 (m,
1H), 1.83-1.79 (m, 1H), 1.79-1.70 (m, 1H), 1.56-1.43 (m, 2H),
1.42-1.30 (m, 2H), 1.07 (d, J = 6.7 Hz, 3H), 0.91 (t, J = 7.0 Hz,
3H), 0.89 (s, 9H), 0.76 (d, J = 7.4 Hz, 3H), 0.12 (d, J = 9.0 Hz,
6H); 13C NMR (75 MHz, CDCl3) δ 159.2, 137.8, 131.9, 130.1,
129.4, 129.0, 128.5, 127.7, 127.6, 113.8, 95.4, 85.6, 85.0, 82.7,
74.5, 72.0, 70.7, 69.6, 67.7, 60.7, 55.5, 55.2, 43.6, 40.3, 39.8, 37.0,
25.7, 18.3, 18.1, 14.1, 12.2, 5.8, -4.5, -5.1; FT-IR (film) 3445,
2930, 2857, 1613, 1463, 1037, 837, 778 cm-1; ESI-MS m/z 735.4
([M þ Na]þ); ESI-HRMS calcd for C41H64O8SiNa ([M þ Na]þ)
735.4263, found 735.4256.
(4S,5R,2E)-4-Benzyloxy-1-(4-methoxybenzyloxy)-5-[(4R,5S,6S)-
6-(3-tert-butyldimethylsilyl-5-methoxymethoxyoctyn-1-yl)-2,2,5-tri-
methyl-1,3-dioxan-4-yl]-2-hexene (43b). A solution of diol 42b
(1.526 g, 2.14 mmol), PPTS (55 mg, 0.214 mmol), and Me2C-
(OMe)2 (15 mL) in CH2Cl2 (15 mL) was stirred at ambient
temperature until TLC showed completion of the reaction.
Aqueous saturated NaHCO3 was added. The mixture was
extracted with Et2O (3 ꢀ 100 mL). The organic phases were
combined, washed with water and brine, and dried over anhy-
drous NaSO4. Removal of the solvent and chromatography on
silica gel (1:8 EtOAc/PE) gave acetonide 43b (1.571 g, 2.09
mmol, 98%) as a colorless oil: [R]28 -15.8 (c 0.35, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.32-D7.23 (m, 7H), 6.88 (d, J =
8.6 Hz, 2H), 5.82-5.75 (m, 2H), 4.64-4.55 (m, 4H), 4.46 (part of
an AB system, d, J = 11.8 Hz, 1H), 4.44 (part of an AB system,
d, J = 11.8 Hz, 1H), 4.39-4.37 (m, 1H), 4.28 (d, J = 6.4 Hz,
1H), 4.24 (dd, J = 2.7, 10.3 Hz, 1H), 4.03 (d, J = 5.5 Hz, 2H),
3.80 (s, 3H), 3.71-3.69 (m, 1H), 3.32 (s, 3H), 1.93-1.79 (m, 3H),
1.63-1.60 (m, 1H), 1.51-1.47 (m, 2H), 1.37-1.26 (m, 2H), 1.48
(s, 3H), 1.34 (s, 3H), 1.02 (d, J = 6.9 Hz, 3H), 0.89 (t, J = 7.3 Hz,
3H), 0.87 (s, 9H), 0.86 (t, J = 7.0 Hz, 3H), 0.09 (d, J = 4.6 Hz,
6H); 13C NMR (125 MHz, CDCl3) δ 159.3, 139.2, 132.8, 130.5,
129.3, 128.8, 128.2, 127.2, 127.1, 113.9, 100.6, 95.8, 86.9, 85.1,
77.1 (revealed by HMQC), 74.9, 71.8, 70.9, 70.0, 68.2, 67.5, 60.8,
55.5, 55.3, 43.7, 39.7, 36.9, 36.2, 28.6, 25.8, 23.7, 18.3, 18.1, 14.2,
(4S,5R,6R,7S,8S,2E)-4-Benzyloxy-11-tert-butyldimethylsily-
loxy-1-(4-methoxybenzyloxy)-13-methoxymethoxy-5,7-dimethyl-
hexadec-2-en-9-yne-6,8-diol (42b). Aqueous CF3CO2H (50%, 1.0
mL) was added to a solution of alcohol 41b (1.771 g, 2.26 mmol) in
CH2Cl2 (30 mL) stirred at ambient temperature. After complete
5062 J. Org. Chem. Vol. 75, No. 15, 2010

Ren et al.
JOCArticle
74.3, 72.6, 71.9, 70.6, 69.7, 60.5, 55.6, 55.2, 51.1, 42.9, 40.0, 36.7,
11.3, 8.1, -4.4, -5.0; FT-IR (film) 2930, 2856, 1613, 1513, 1459,
1010, 837, 778 cm-1; ESI-MS m/z 775.5 ([M þ Na]þ); ESI-
HRMS calcd for C44H68O8SiNa ([M þ Na]þ) 775.4576, found
775.4594.
25.6, 18.2, 18.0, 14.1, 11.4, 8.9, -4.6, -5.1; FT-IR (film) 3487,
2956, 2857, 2209, 1677, 1612, 1513, 1464, 1250, 838, 780, 699 cm-1
;
ESI-MS m/z 733.4 ([M þ Na]þ); ESI-HRMS calcd for C41H62-
(4S,5R,6R,7S,11S,13S,2E)-4-Benzyloxy-11-(tert-butyldime-
thylsilyloxy)-1-(4-methoxybenzyloxy)-14-methoxymethoxy-5,7-
dimethyl-6-trimethylsilanyloxyheptadec-2-en-9-yn-8-one (44). Dess-
Martin periodinane (465 mg, 1.095 mmol) and NaHCO3 (138 mg,
1.644 mmol) were added to a solution of alcohol 41a (430 mg, 0.548
mmol) in dry CH2Cl2 (5 mL) stirred at ambient temperature. The
mixture was stirred at ambient temperature until TLC showed
completion of the reaction before being diluted with Et2O, filtered
through Celite, and concentrated on a rotary evaporator. The
residue was purified by column chromatography (1:8 EtOAc/PE)
to afford ketone 44 (402 mg, 0.513 mmol, 94%) as a light yellow oil:
[R]24D -8.4 (c 2.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.33 (m,
7H), 6.88 (d, J = 8.6 Hz, 2H), 5.90-5.75 (m, 2H), 4.68 (t, J = 7.1
Hz, 1H), 4.60 (s, 2H), 4.63-4.57 (m, 1H), 4.50 (dd, J = 2.1, 9.1 Hz,
1H), 4.46 (s, 2H), 4.33 (d, J = 11.7 Hz, 1H), 4.19 (br d, J = 4.4 Hz,
1H), 4.03 (d, J = 9.5 Hz, 2H), 3.81 (s, 3H), 3.73-3.65 (m, 1H), 3.33
(s, 3H), 2.72 (m, 1H), 2.01-1.80 (m, 2H), 1.62 (m, 1H), 1.58-1.40
(m, 2H), 1.39-1.21 (m, 2H), 1.11 (d, J = 7.1 Hz, 3H), 0.93 (d, J =
6.5 Hz, 3H), 0.90 (d, J = 6.9 Hz, 3H), 0.88 (s, 9H), 0.12 (s, 3H), 0.10
(s, 3H), 0.07 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 190.0, 159.2,
139.1, 132.9, 134.2, 129.6, 129.4, 128.2, 127.0, 126.9, 113.7, 95.8,
93.6, 83.6, 78.3, 76.6, 74.5, 73.0, 71.9, 69.8, 60.5, 55.5, 55.2, 51.1, 43.5,
43.0, 36.7, 25.6, 18.2, 18.0, 14.2, 10.0, 7.9, 0.8, -4.5, -5.2; FT-IR
(film) 3065, 2956, 2932, 2858, 2207, 1679, 1613, 1514, 1464, 839, 779
cm-1; ESI-MS m/z 805.4 ([M þ Na]þ); ESI-HRMS calcd for
C44H70O8Si2Na ([M þ Na]þ) 805.4502, found 805.4486.
SiO8Na ([M þ Na]þ) 733.4106, found 733.4084.
(4S,5R,2E)-4-Benzyloxy-1-(4-methoxy-benzyloxy)-5-[(4R,5S,6S)-
6-(3-tert-butyldimethylsilyl-5-methoxymethoxyoctyn-1-yl)-2,2,5-tri-
methyl-1,3-dioxan-4-yl]-hex-2-en-1-ol (46). DDQ (51 mg, 0.223
mmol) was added in one portion to a solution of 43b (140 mg,
0.186 mmol) in a two-phase mixture of CH2Cl2 (10 mL) and a pH 7
aq buffer (NaHPO4/Na2HPO4, 1 mL) stirred at ambient tempera-
ture. The mixture was stirred at the same temperature for 1 h before
another portion of DDQ (51 mg, 0.223 mmol) was added. Stirring
was continued until TLC showed completion of the reaction.
Aqueous saturated NaHCO3 was added. The mixture was ex-
tracted with Et2O (3 ꢀ 100 mL). The organic phases were com-
bined, washed with water and brine, and dried over anhydrous
NaSO4. Removal of the solvent and chromatography on silica gel
(1:4 EtOAc/PE) afforded alcohol 46 (110 mg, 0.174 mmol, 93%) as
a colorless oil: [R]28D -26.0 (c 1.05, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.32-7.26 (m, 5H), 5.88 (dt, J = 16.1, 5.3 Hz, 1H), 5.72
(dd,J= 16.3, 6.3 Hz, 1H), 4.61 (d, J= 6.5 Hz, 1H), 4.58 (d, J=6.5
Hz, 1H), 4.55 (m, 1H), 4.54 (d, J = 10.0 Hz, 1H), 4.41-4.39 (m,
1H), 4.33 (d, J = 11.7 Hz, 1H), 4.29-4.22 (m, 2H), 4.17 (d, J = 5.4
Hz, 2H), 3.72 (m, 1H), 3.33 (s, 3H), 1.98-1.74 (m, 3H), 1.64-1.58
(m, 1H), 1.54-1.40 (m, 2H), 1.48 (s, 3H), 1.40-1.26 (m, 2H), 1.34
(s, 3H), 1.03 (d, J = 7.0 Hz, 3H), 0.89 (t, J = 7.2 Hz, 3H), 0.87 (s,
9H), 0.86 (t, J = 7.4 Hz, 3H), 0.09 (d, J = 2.9 Hz, 6H); 13C NMR
(75 MHz, CDCl3) δ 139.2, 131.3, 131.2, 128.2, 127.3, 127.2, 100.6,
95.8, 86.9, 85.0, 74.8, 70.9, 68.2, 67.4, 63.2, 60.8, 55.6, 43.6, 39.7,
36.9, 36.2, 28.6, 25.8, 23.7, 18.3, 18.1, 14.2, 11.3, 8.1, -4.3, -5.0;
L-Selectride Reduction of Ketone 44 Giving 41a and 41b.
L-Selectride (1.0 M, in THF, 2.75 mL, 2.75 mmol) was added to
a solution of ketone 44 (431 mg, 0.55 mmol) in dry THF (4 mL)
stirred at -78 °C under argon. After completion of the addition,
stirring was continued at -78 °C for 3 h. MeOH (2 mL) was
added, followed by aq saturated potassium sodium tartrate
(5 mL) and Et2O (50 mL). The mixturewas then stirred at ambient
temperature for another 2 h, resulting in a two-phase clear
mixture. The phases were separated. The aqueous layer was
extracted with Et2O (3 ꢀ 50 mL). The organic phases were com-
bined, washed with water and brine, and dried over anhydrous
NaSO4. Removal of the solvent and chromatography (1:8 EtOAc/
PE) on silica gel yielded the less polar isomer 41b (340 mg, 0.433
mmol, 79%) and the more polar isomer 41a (56 mg, 0.071 mmol,
13%) as yellowish oils. Data for 41a and 41b are given above
(prepared via coupling of alkyne 9 with aldehyde 40).
(4S,5R,6R,7S,11S,13S,2E)-4-Benzyloxy-11-(tert-butyldime-
thylsilyloxy)-1-(4-methoxybenzyloxy)-14-methoxymethoxy-5,7-di-
methyl-6-hydroxyheptadec-2-en-9-yn-8-one (45). Aqueous CF3-
CO2H (50%, 0.67 mL) was added to a solution of TMS ether 44
(620 mg, 0.792 mmol) in CH2Cl2 (25 mL) stirred at ambient
temperature. After complete of the addition, stirring was contin-
ued at the same temperature until TLC showed completion of the
reaction. Aqueous saturated NaHCO3 was added. The mixture
was extracted with Et2O (3 ꢀ 50 mL). The organic phases were
combined, washed with water and brine, and dried over anhy-
drous NaSO4. Removal of the solvent and chromatography on
FT-IR (film) 3481, 2957, 2858, 1462, 1380, 1257, 837, 778 cm-1
;
ESI-MS m/z 655.6 ([M þ Na]þ); ESI-HRMS calcd for C36H60O7-
SiNa ([M þ Na]þ) 655.4001, found 655.4009.
(4R)-3-{(2R,3S,6S,7R,4E)-6-Benzyloxy-7-[(4R,5S,6S)-6-((3S,5S)-
3-tert-butyldimethylsilyloxy-5-methoxymethoxyoctyn-1-yl)-2,2,5-
trimethyl-1,3-dioxan-4-yl]-3-hydroxy-2-methyl-oct-4-enoyl}-4-
phenyloxazolidin-2-one (48). Dess-Martin periodinane (795 mg,
1.86 mmol) and NaHCO3 (234 mg, 2.79 mmol) wereadded in turn
to a solution of 46 (588 mg, 0.93 mmol) in dry CH2Cl2 (5 mL)
stirred at ambient temperature. The mixture was stirred until TLC
showed completion of the reaction. Et2O (100 mL) was added.
The solids were filtered off through Celite. The filtrate was
concentrated on a rotary evaporator. The residue was chromato-
graphed (1:6 EtOAc/PE) on silica gel to afford the unstable
aldehyde 47 (566 mg, 0.90 mmol, 96%) as a yellowish oil, which
was immediately used in the next step of aldol condensation.
Freshly distilled TiCl4 (0.23 mL, 2.10 mmol) was added
dropwise to a solution of the acyloxazolidinone 7 (438 mg, 2.0
mmol) in dry CH2Cl2 (12 mL) stirred at 0 °C under N2. The
resulting yellow solution was stirred for 10 min before neat
TMEDA (0.80 mL, 5.0 mmol) was added dropwise. The dark
red-brown mixture was stirred at 0 °C for 30 min before a solu-
tion of the above-mentioned aldehyde 47 (566 mg, 0.90 mmol) in
dry CH2Cl2 (2 mL) was introduced via syringe. The stirring was
continued at ambient temperature for 10 h. Aqueous NH4Cl was
added. The resulting mixture was filtered through Celite. The
filtrate was washed in turn with water and brine and dried over
anhydrous Na2SO4. Rotary evaporation and column chroma-
tography (1:3 EtOAc/PE) on silica gel afforded enantiopure
aldol 48 (691 mg, 0.813 mmol, 90% from aldehyde 47 or 86%
from alcohol 46) as a colorless oil: [R]28D -35.2 (c 1.90, CHCl3);
1H NMR (500 MHz, CDCl3) δ 7.39-7.23 (m, 10H), 5.80 (dd,
J = 6.4, 15.6 Hz, 1H), 5.70 (dd, J = 4.9, 15.7 Hz, 1H), 5.40 (dd,
J = 3.8, 8.7 Hz, 1H), 4.65 (t, J = 8.8 Hz, 1H), 4.58-4.53 (m, 5H),
4.39 (m, 1H), 4.32-4.22 (m, 4H), 3.93-3.90 (m, 1H), 3.70 (m,
1H), 3.33 (s, 3H), 2.75 (br, 1H), 1.93-1.77 (m, 3H), 1.64-1.59
(m, 1H), 1.52-1.47 (m, 2H), 1.50 (s, 3H), 1.39-1.26 (m, 2H), 1.35
silica gel (1:4 EtOAc/PE) gave alcohol 45 (547 mg, 0.769 mmol,
97%) as a yellowish oil: [R]24 -3.0 (c 2.50, CHCl3); H NMR
1
D
(300 MHz, CDCl3) δ 7.37-7.26 (m, 7H), 6.90 (d, J = 8.5 Hz, 2H),
5.86-5.79 (m, 2H), 4.70 (t, J = 7.0 Hz, 1H), 4.63 (d, J = 11.7 Hz,
1H), 4.33 (d, J = 11.7 Hz, 1H), 4.63 (s, 2H), 4.47 (s, 2H), 4.21 (m,
1H), 4.16 (m, 1H), 4.05 (d, J = 4.9 Hz, 2H), 3.81 (s, 3H), 3.72 (m,
1H), 3.36 (s, 3H), 3.28 (d, J = 4.2 Hz, 1H), 2.59 (m, 1H),
1.97-1.80 (m, 3H), 1.54-1.47 (m, 2H), 1.40-1.32 (m, 2H), 1.20
(d, J = 6.8 Hz, 3H), 0.93-0.85 (m, 15H), 0.12 (d, J = 9.7 Hz, 6H);
13C NMR (75 MHz, CDCl3) δ 190.4, 159.2, 138.0, 131.0, 130.3,
130.1, 129.4, 128.4, 127.72, 127.68, 113.8, 95.7, 93.7, 82.9, 80.3,
J. Org. Chem. Vol. 75, No. 15, 2010 5063

Ren et al.
JOCArticle
(s, 3H), 1.14 (d, J = 7.1 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.89 (t,
J = 7.3 Hz, 3H), 0.88 (s, 9H), 0.85 (d, J = 7.0 Hz, 3H), 0.08 (d,
J = 4.8 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 176.2, 153.4,
139.2, 138.8, 131.8, 131.1, 129.3, 128.8, 128.2, 127.3, 127.1, 125.6,
100.6, 95.8, 86.9, 85.0, 74.8, 71.7, 71.0, 69.9, 68.2, 67.5, 60.8, 57.7,
55.5, 43.7, 42.8, 39.7, 36.9, 36.2, 28.6, 25.8, 23.7, 18.3, 18.1, 14.2,
11.3, 11.0, 8.1, -4.4, -5.0; FT-IR (film) 3490, 3032, 2957, 2932,
2858, 1783, 1705, 1465, 1382, 1361, 1201, 838, 778 cm-1; ESI-MS
m/z 872.5 ([M þ Na]þ); ESI-HRMS calcd for C48H71NO10SiNa
([M þ Na]þ) 872.4740, found 872.4742.
NMR (75 MHz, CHCl3) δ 176.9, 153.2, 139.4, 138.7, 129.2, 128.7,
128.0, 126.9, 126.7, 125.4, 100.7, 94.9, 77.2, 77.1, 75.3, 71.3, 71.1,
70.4, 69.8, 69.1, 57.4, 55.6, 42.1, 41.4, 38.1, 36.4, 36.3, 34.2, 30.8,
30.3, 27.6, 25.2, 23.8, 18.0, 14.2, 11.7, 10.2, 8.3; FT-IR (film) 3481,
2932, 2874, 1782, 1704, 1456, 1382, 1040, 699 cm-1; ESI-MS m/z
764.4 ([M þ Na]þ); ESI-HRMS calcd for C42H63NO10Na ([M þ
Na]þ) 764.4344, found 764.4350.
(4R)-3-{(2R,3S,6S,7R)-6-Benzyloxy-7-[(4R,5S,6S)-6-((3S,5S)-
3-methanesulfonyloxy-5-methoxymethoxyoctyl)-2,2,5-trimethyl-
1,3-dioxan-4-yl]-3-methanesulfonyloxy-2-methyloctyl}-4-phenyl-
oxazolidin-2-one (51). MsCl (61 μL, 0.742 mmol) was added to a
solution of diol 50 (110 mg, 0.148 mmol) and Et3N (0.10 mL,
0.742 mmol) in CH2Cl2 (5 mL) stirred at ambient temperature
under N2 atmosphere. Stirring was continued at the same
temperature until TLC showed completion of the reaction.
Aqueous saturated NaHCO3 was added. The mixture was
extracted with Et2O (3 ꢀ 20 mL). The organic phases were com-
bined, washed in turn with water and brine, and dried over
anhydrousNaSO4. Removal of the solventand chromatography
(1:32 EtOAc/PE) on silica gel gave dimesylate 51 (126 mg, 0.140
mmol, 95%) as a colorless oil: [R]28D -37.8 (c 0.80, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 7.39-7.26 (m, 10H), 5.32 (dd, J =
3.0, 8.5 Hz, 1H), 5.14 (m, 1H), 4.92 (m, 1H), 4.72-4.60 (m, 4H),
4.46 (AB, J = 11.4 Hz, 1H), 4.26 (dd, J = 3.1, 8.7 Hz, 1H), 4.08
(m, 1H), 3.90-3.78 (m, 2H), 3.64 (m, 1H), 3.38 (s, 3H), 3.24 (m,
1H), 3.02 (s, 3H), 2.99 (s, 3H), 2.07-1.92 (m, 2H), 1.90-1.71 (m,
4H), 1.70-1.44 (m, 6H), 1.43-1.25 (m, 4H), 1.32 (s, 3H), 1.28 (s,
3H), 1.15 (d, J = 7.2 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H), 0.87 (d,
J = 6.3 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 172.1, 153.7, 139.1, 138.9, 128.9, 128.4, 128.0, 126.9,
126.8, 125.6, 100.5, 95.1, 81.2, 80.6, 77.2, 74.5, 73.8, 71.3, 70.2,
69.0, 57.9, 55.5, 41.3, 39.3, 38.4, 38.2, 38.0, 36.42, 36.38, 31.0,
29.5, 29.3, 27.0, 25.1, 23.7, 18.0, 13.9, 11.5, 9.4, 8.3; FT-IR (film)
2935, 1778, 1709, 1456, 1357, 1335, 1173, 910 cm-1; ESI-MS m/z
920.6 ([M þ Na]þ); ESI-HRMS calcd for C44H67NO14S2Na ([Mþ
Na]þ) 920.3895, found 920.3921.
(4R)-3-{(2R,3S,6S,7R,4E)-6-Benzyloxy-7-[(4R,5S,6S)-6-((3S,5S)-
3-hydroxy-5-methoxymethoxyoctyn-1-yl)-2,2,5-trimethyl-1,3-
dioxan-4-yl]-3-hydroxy-2-methyloct-4-enoyl}-4-phenyloxazolidin-
2-one (49). Aqueous HF py (70%, 0.25 mL, 1.74 mmol) was
3
added to a solution of 48 (296 mg, 0.348 mmol) in THF (8 mL)
stirred at ambient temperature. Stirring was continued at the
same temperature until TLC showed completion of the reaction.
Aqueous saturated NaHCO3 was added. The mixture was ex-
tracted with Et2O (3 ꢀ 50 mL). The organic phases were com-
bined, washed in turn with aq saturated CuSO4, water and brine,
and dried over anhydrous NaSO4. Removal of the solvent and
chromatography (2:3 EtOAc/PE) on silica gel gave diol 49 (241
mg, 0.328 mmol, 94%) as a colorless foam: [R]28D -32.2 (c 0.55,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.40-7.25(m, 10H), 5.79
(dd, J = 6.0, 15.3 Hz, 1H), 5.72 (dd, J = 5.3, 15.8 Hz, 1H), 5.41
(dd, J = 3.9, 8.8 Hz, 1H), 4.71-4.54 (m, 6H), 4.33-4.20 (m, 5H),
3.93-3.90 (m, 1H), 3.70 (m, 1H), 3.36 (s, 3H), 2.92 (d, J = 2.7 Hz,
1H), 2.69 (d, J = 4.2 Hz, 1H), 2.02-1.80 (m, 3H), 1.60 (m, 1H),
1.54-1.44 (m, 2H), 1.47 (s, 3H), 1.40-1.22 (m, 2H), 1.36 (s, 3H),
1.16 (d, J = 7.1 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.91 (t, J = 7.1
Hz, 3H), 0.86 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CHCl3) δ
175.7, 153.2, 138.8, 138.6, 131.2, 131.1, 129.0, 128.5, 128.0,
127.04, 126.98, 125.3, 100.6, 95.2, 86.3, 84.7, 76.9, 75.4, 71.5,
70.6, 69.7, 68.0, 66.9, 60.4, 57.4, 55.4, 42.6, 42.2, 39.2, 36.7, 36.4,
27.6, 23.5, 17.9, 14.0, 11.0, 10.9, 8.0; FT-IR (film) 3449, 2959,
2933, 1782, 1702, 1458, 1382, 1201, 1040, 700 cm-1; ESI-MS m/z
758.4 ([M þ Na]þ); ESI-HRMS calcd for C42H57NO10Na ([M þ
Na]þ) 758.3875, found 758.3867.
Acknowledgment. Financial support from the National
Basic Research Program of China (973 Program) (2010CB-
833200), the National Natural Science Foundation of China
(20921091, 20672129, 20621062, 20772143), and the Chinese
Academy of Sciences (“Knowledge Innovation”, KJCX2.
YW.H08) is gratefully acknowledged.
(4R)-3-{(2R,3S,6S,7R)-6-Benzyloxy-7-[(4R,5S,6S)-6-((3S,5S)-
3-hydroxy-5-methoxymethoxyoctyl)-2,2,5-trimethyl-1,3-dioxan-4-
yl]-3-hydroxy-2-methyloctyl}-4-phenyloxazolidin-2-one (50). A so-
lution of enyne 49 (311 mg, 0.423 mmol), 10% Pd-C (311 mg),
and Et3N (0.15 mL, 1.06 mmol) in EtOAc (8 mL) was stirred at
ambient temperature under H2 (1 atm) for 24 h. The solids were
filtered off. The filtrate was concentrated on a rotary evaporator.
The residue was purified by column chromatography (1:1 EtOAc/
PE) on silica gel to afford the saturated diol 50 (295 mg, 0.398
mmol, 94%) as a colorless oil: [R]28D -25.9 (c 0.75, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 7.39-7.24 (m, 10H), 5.40 (dd, J =
3.8, 8.9 Hz, 1H), 4.71 (d, J = 6.9 Hz, 1H), 4.66 (t, J = 8.8 Hz, 1H),
4.65 (d, J = 11.7 Hz, 1H), 4.64 (d, J = 6.7 Hz, 1H), 4.41 (d, J =
11.3 Hz, 1H), 4.22 (dd, J = 3.6, 8.9 Hz, 1H), 3.90-3.77 (m, 6H),
3.49 (br, 1H), 3.39 (s, 3H), 3.30-3.21 (m, 1H), 2.96 (d, J = 2.7 Hz,
1H), 2.08-1.94 (m, 1H), 1.72-1.42 (m, 12H), 1.41-1.31 (m, 3H),
1.32 (s, 3H), 1.27 (s, 3H), 1.17 (d, J = 7.1 Hz, 3H), 0.91 (t, J = 7.4
Note Added after ASAP Publication. The specific rota-
tions for pamamycin 621A were omitted in the version pub-
lished ASAP July 2, 2010; the corrected version with the values
added prior to the Experimental Section was reposted ASAP
July 9, 2010.
Supporting Information Available: General information for
the Experimental Section, physical and spectroscopic data list-
ing, 1H as well as 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Hz, 3H), 0.87 (d, J = 7.1 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H); 13
C
5064 J. Org. Chem. Vol. 75, No. 15, 2010